givinostat hydrochloride: has antineoplastic activity [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]
| ID Source | ID |
|---|---|
| PubMed CID | 10095659 |
| SCHEMBL ID | 23529420 |
| MeSH ID | M0585212 |
| Synonym |
|---|
| givinostat hydrochloride |
| histone deacetylase inhibitor |
| unii-z02132r2qq |
| carbamic acid, n-(4-((hydroxyamino)carbonyl)phenyl)-, (6-((diethylamino)methyl)-2-naphthalenyl)methyl ester, hydrochloride (1:1) |
| itf 2357 |
| 199657-29-9 |
| z02132r2qq , |
| CS-4728 |
| givinostat (hydrochloride) |
| HY-14842A |
| AKOS030526700 |
| givinostat hcl |
| mfcd28502062 |
| SCHEMBL23529420 |
| [6-(diethylaminomethyl)naphthalen-2-yl]methyl n-[4-(hydroxycarbamoyl)phenyl]carbamate;hydrochloride |
| givinostat hcl hydrate |
| AS-52365 |
| [6-[(diethylamino)methyl]-2-naphthalenyl]methyl-n-[4-[(hydroxyamino)carbonyl]phenyl]carbamate hydrochloride |
| (6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate hydrochloride |
| SB16937 |
| C76335 |
| Q27294820 |
| P14959 |
| ZHA65729 |
| carbamic acid, n-[4-[(hydroxyamino)carbonyl]phenyl]-, [6-[(diethylamino)methyl]-2-naphthalenyl]methyl ester, hydrochloride (1:1) |
| {6-[(diethylamino)methyl]naphthalen-2-yl}methyl n-[4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride |
| EN300-257964 |
| Z2327390266 |
| EX-A8024 |
| Excerpt | Reference | Relevance |
|---|---|---|
| " There were no serious adverse effects (AEs) and no organ toxicities." | ( Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Dinarello, CA; Fossati, G; Furlan, A; Leoni, F; Mascagni, P; Modena, D; Monzani, V; Reznikov, LL, ) | 0.13 |
| "Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self-limited." | ( Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. D'Urzo, C; Damjanov, N; Dinarello, CA; Furlan, A; Iagaru, N; Pasic, S; Stefan, M; Susic, G; Vojinovic, J, 2011) | 0.37 |
| Excerpt | Relevance | Reference |
|---|---|---|
| " Furthermore, with regard to the relevance in human inflammatory bowel disease, the doses of ITF2357 considered safe in humans and the corresponding serum concentrations are consistent with the efficacious dosing used in our in vivo as well as in vitro experiments." | ( Inhibition of histone deacetylases in inflammatory bowel diseases. Glauben, R; Siegmund, B, ) | 0.13 |
| " Blood removed from the subjects after oral dosing was cultured ex vivo with endotoxin, and the release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1Ra, interferon (IFN)-γ and IL-10 was determined." | ( Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Dinarello, CA; Fossati, G; Furlan, A; Leoni, F; Mascagni, P; Modena, D; Monzani, V; Reznikov, LL, ) | 0.13 |
| Timeframe | Studies, This Drug (%) | All Drugs % |
|---|---|---|
| pre-1990 | 0 (0.00) | 18.7374 |
| 1990's | 0 (0.00) | 18.2507 |
| 2000's | 10 (30.30) | 29.6817 |
| 2010's | 18 (54.55) | 24.3611 |
| 2020's | 5 (15.15) | 2.80 |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be moderate demand-to-supply ratio for research on this compound.
| This Compound (15.93) All Compounds (24.57) |
| Publication Type | This drug (%) | All Drugs (%) |
|---|---|---|
| Trials | 5 (12.20%) | 5.53% |
| Reviews | 4 (9.76%) | 6.00% |
| Case Studies | 0 (0.00%) | 4.05% |
| Observational | 0 (0.00%) | 0.25% |
| Other | 32 (78.05%) | 84.16% |
| [information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023] | ||
| Trial | Phase | Enrollment | Study Type | Start Date | Status | ||
|---|---|---|---|---|---|---|---|
| Phase II High Pulse Dose Clinical Trial of Orally Administered ITF2357 In Patients With Relapsed/Refractory Multiple Myeloma [NCT00792506] | Phase 2 | 1 participants (Actual) | Interventional | 2008-10-31 | Terminated(stopped due to The study was prematurely discontinued for lack of recruitement.) | ||
| Open Label, Uncontrolled, Pilot, Phase II Study of ITF2357 Administered Orally to Subjects With Chronic Lymphocytic Leukemia (CLL) Refractory/Relapsed After Conventional Chemotherapy or Relapsed After Autologous Bone Marrow Transplantation [NCT00792831] | Phase 2 | 3 participants (Actual) | Interventional | 2008-02-29 | Terminated(stopped due to Protocol needs complete restructuring in order to make it feasible and to complete the enrollment of 23 patients.) | ||
| Phase II Study of the Histone-deacetylase Inhibitor ITF2357 in Very High-risk Relapsed/Refractory Hodgkin's Lymphoma Patients [NCT00496431] | Phase 1/Phase 2 | 19 participants (Actual) | Interventional | 2007-05-31 | Terminated(stopped due to Study accrual was stopped earlier than planned by the Sponsor for 2 main reasons: very slow recruitment rate; lower than estimated efficacy of the drug when delivered as single agent.) | ||
| Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate the Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy [NCT05933057] | Phase 3 | 138 participants (Anticipated) | Interventional | 2023-12-31 | Not yet recruiting | ||
| Randomized, Open-label, Multicenter Phase 3 Study to Assess the Efficacy and Safety of GIVinostat Versus Hydroxyurea IN JAK2V617F-positive High-risk Polycythemia Vera Patients: the GIV-IN PV TRIAL [NCT06093672] | Phase 3 | 220 participants (Anticipated) | Interventional | 2023-12-31 | Not yet recruiting | ||
| Phase II, Open Label, International, Multicentre Clinical Trial to Investigate Safety and Efficacy of Oral ITF2357 in Patients With Active Systemic Onset Juvenile Idiopathic Arthritis (SOJIA) [NCT00570661] | Phase 2 | 17 participants (Actual) | Interventional | 2006-09-12 | Completed | ||
| An Open-label, Single-center, Three-part Study in Healthy Subjects to Investigate the Effect of Givinostat on the Pharmacokinetics of Midazolam and Dabigatran, the Effect of Clarithromycin on the Pharmacokinetics of Givinostat and the Pharmacokinetics of [NCT05492318] | Phase 1 | 54 participants (Actual) | Interventional | 2022-03-21 | Completed | ||
| A Phase IIA Study of the Histone-deacetylase Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases [NCT00606307] | Phase 2 | 29 participants (Actual) | Interventional | 2007-12-31 | Completed | ||
| Phase II Trial of the Histone-Deacetylase Inhibitor ITF2357 Followed by Mechlorethamine in Relapsed/Refractory Hodgkin's Lymphoma Patients [NCT00792467] | Phase 1/Phase 2 | 24 participants (Actual) | Interventional | 2008-02-29 | Completed | ||
| Phase II Study of the Histone-deacetylase Inhibitor GIVINOSTAT (ITF2357) in Combination With Hydroxyurea in Patients With JAK2V617F Positive Polycythemia Vera Non-responder to Hydroxyurea Monotherapy. [NCT00928707] | Phase 2 | 45 participants (Actual) | Interventional | 2009-06-30 | Completed | ||
| A Two-part Study Top Assess the Safety and Preliminary Efficacy of Givinostat in Patients With JAK2V617F Positive Polycythemia Vera [NCT01901432] | Phase 1/Phase 2 | 48 participants (Actual) | Interventional | 2013-10-31 | Completed | ||
| An Open-label, Single-center, Study in Healthy Subjects to Evaluate the Plasma and Urine Pharmacokinetics of Givinostat and Its Metabolites Following Single and Multiple Oral Doses of Givinostat (Part 3). [NCT05860114] | Phase 1 | 8 participants (Actual) | Interventional | 2022-03-21 | Completed | ||
| Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of ITF2357 on Mucosal Healing in Patients With Moderate-to-severe Active Crohn's Disease [NCT00792740] | Phase 1/Phase 2 | 51 participants (Actual) | Interventional | 2007-10-22 | Terminated(stopped due to As no safety warnings were detected, Interim analysis from the first 40 patients recommends to stop the trial for futility) | ||
| The Effects and Side Effects of ITS2357 in Autoinflammatory Syndromes [NCT00442182] | Phase 2 | 20 participants | Interventional | 2006-09-30 | Recruiting | ||
| Long-term Study Evaluating the Effect of Givinostat in Patients With JAK2V617F Positive Chronic Myeloproliferative Neoplasms [NCT01761968] | Phase 2 | 90 participants (Anticipated) | Interventional | 2013-03-31 | Active, not recruiting | ||
| An Open-Label Extension of the Dose Finding Study (DSC/08/2357/36) in Patients With Polyarticular Course Juvenile Idiopathic Arthritis (Poly JIA) [NCT01557452] | 1 participants (Actual) | Interventional | 2011-12-28 | Terminated(stopped due to Previous study DSC/08/2357/36 did not show efficacy for Givinostat in JIA. Sponsor decision to stop development of Givinostat in polyarticular course Juvenile Idiopathic Arthritis wasn't related to any tolerability concerns.) | |||
| Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy [NCT02851797] | Phase 3 | 179 participants (Actual) | Interventional | 2017-06-06 | Completed | ||
| A Randomized, Partially Double-Blind, Four-Period, Four-Treatment, Crossover Study Investigating the Placebo-Corrected Effects of a Therapeutic Dose (100 mg) and a Supratherapeutic Dose (300 mg) of ITF2357 (Givinostat) and Moxifloxacin on QT/QTC Interval [NCT04821063] | Phase 1 | 31 participants (Actual) | Interventional | 2021-04-13 | Completed | ||
| A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, and Effects on Histology and Different Clinical Parameters of Givinostat in Ambulant Children With Duchenne Muscular Dystrophy [NCT01761292] | Phase 1/Phase 2 | 20 participants (Actual) | Interventional | 2013-04-30 | Completed | ||
| [information is prepared from clinicaltrials.gov, extracted Sep-2024] | |||||||
The Childhood Health Assessment Questionnaire (CHAQ) is from 0 to 3. For each of 8 section (Dressing and care, Getting up, Eating, Walking, Hygiene, Grasping, Catching, Activities) answers patient is getting 0,1,2 or 3 points (no difficulties, some difficulties, much difficulties, unable to do, respectively). The sum of points is then divided by 8 to get score 0 - 3. The lower the score, the better the outcome. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | units on a scale (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 1.75 | 1.39 | 1.23 | 1.02 | 0.85 | 0.85 | 0.95 | 1.02 | 0.85 |
| ITF2357 - PP Population | 1.55 | 1.13 | 0.93 | 0.75 | 0.58 | 0.55 | 0.58 | 0.56 | 0.58 |
Measurements of erythrocyte sedimentation rate (ESR) were performed at the local laboratory cooperating with each study site. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | mm/hr (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 62.71 | 59.12 | 59.50 | 53.90 | 49.92 | 59.25 | 54.14 | 46.31 | 41.00 |
| ITF2357 - PP Population | 65.22 | 53.44 | 52.67 | 57.67 | 49.33 | 58.33 | 56.44 | 39.89 | 44.57 |
Number of active joints is from 0 to 75. The lower the score, the better the outcome. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | units on a scale (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 9.82 | 8.41 | 6.38 | 3.57 | 3.42 | 2.75 | 4.86 | 3.88 | 5.00 |
| ITF2357 - PP Population | 9.33 | 7.11 | 3.78 | 3.44 | 3.67 | 2.89 | 3.44 | 3.00 | 3.33 |
Number of joints with limited range of motion is from 0 to 75. The lower the score, the better the outcome. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | units on a scale (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 11.59 | 10.41 | 7.44 | 7.86 | 4.67 | 4.42 | 8.79 | 7.94 | 7.20 |
| ITF2357 - PP Population | 10.00 | 8.56 | 6.44 | 5.78 | 5.78 | 5.22 | 4.78 | 5.00 | 5.22 |
Patient/parent global Visual Analogue Scale (VAS) is from 0 to 100. The lower the score, the better the outcome. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | units on a scale (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pre-treatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 47.71 | 42.47 | 28.88 | 22.36 | 18.00 | 22.33 | 24.21 | 26.56 | 22.71 |
| ITF2357 - PP Population | 48.00 | 43.33 | 21.22 | 19.11 | 17.22 | 17.44 | 19.11 | 18.11 | 15.38 |
Physician global Visual Analogue Scale (VAS) is from 0 to 100. The lower the score, the better the outcome. (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month and 3 months follow up (FU1, FU3) in the PP and ITT populations respectively.
| Intervention | units on a scale (Mean) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Pretreatment | Week 2 | Week 4 | Week 6 | Week 8 | Week 10 | Week 12 | FU1 | FU3 | |
| ITF2357 - ITT Population | 47.71 | 42.47 | 28.88 | 22.36 | 18.00 | 22.33 | 24.21 | 26.56 | 22.71 |
| ITF2357 - PP Population | 48.00 | 43.33 | 21.22 | 19.11 | 17.22 | 17.44 | 19.11 | 18.11 | 15.38 |
"The primary endpoint describes the number of patients who has completed week 12 of treatment with ITF2357, both in the Per protocol (PP) population and in the Intention to treat (ITT) population.~ITF2357 hard gelatine capsules were administered orally, in fed conditions, at the cumulative daily dose of 1.5 mg/kg achieved by administration of 0.75 mg/kg at 12-hour interval for 4 weeks initially. The doses of 1.5 mg/kg/day were achieved by administration of an appropriate number of capsules of definite strength. Treatment was further prolonged up to 12 weeks in total if so suggested by the observed benefits and the lack of treatment-limiting toxicity." (NCT00570661)
Timeframe: At week 12
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| Completers | Non completers | |
| ITF2357 - ITT Population | 10 | 7 |
| ITF2357 - PP Population | 9 | 0 |
"Clinical improvement at week 2, 4, 6, 8, 10 and 12 was evaluated on the basis of JIA30, JIA50 and JIA70 plus SFS (two points decrease in SFS) as per protocol.~Patients were considered as improved and with positive therapeutic response if 3 or more JIA Core Set Variables improved by 30% and no more than one worsened by 30%. JIA50 and JIA70 were defined as an improvement of 3 or more JIA Core Set Variables by 50% and 70%, respectively, and no more than 1 worsened by 30%. Additionally two points decrease in Systemic Feature Score were considered as disease improvement." (NCT00570661)
Timeframe: At weeks 2, 4, 6, 8, 10 and 12.
| Intervention | participants (Number) | |||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| JIA30 plus SFS - W2 - Clinical improvement | JIA30 plus SFS - W2 - Absence of clinical improvement | JIA30 plus SFS - W4 - Clinical improvement | JIA30 plus SFS - W4 - Absence of clinical improvement | JIA30 plus SFS - W6 - Clinical improvement | JIA30 plus SFS - W6 - Absence of clinical improvement | JIA30 plus SFS - W8 - Clinical improvement | JIA30 plus SFS - W8 - Absence of clinical improvement | JIA30 plus SFS - W10 - Clinical improvement | JIA30 plus SFS - W10 - Absence of clinical improvement | JIA30 plus SFS - W12 - Clinical improvement | JIA30 plus SFS - W12 - Absence of clinical improvement | JIA50 plus SFS - W2 - Clinical improvement | JIA50 plus SFS - W2 - Absence of clinical improvement | JIA50 plus SFS - W4 - Clinical improvement | JIA50 plus SFS - W4 - Absence of clinical improvement | JIA50 plus SFS - W6 - Clinical improvement | JIA50 plus SFS - W6 - Absence of clinical improvement | JIA50 plus SFS - W8 - Clinical improvement | JIA50 plus SFS - W8 - Absence of clinical improvement | JIA50 plus SFS - W10 - Clinical improvement | JIA50 plus SFS - W10 - Absence of clinical improvement | JIA50 plus SFS - W12 - Clinical improvement | JIA50 plus SFS - W12 - Absence of clinical improvement | JIA70 plus SFS - W2 - Clinical improvement | JIA70 plus SFS - W2 - Absence of clinical improvement | JIA70 plus SFS - W4 - Clinical improvement | JIA70 plus SFS - W4 - Absence of clinical improvement | JIA70 plus SFS - W6 - Clinical improvement | JIA70 plus SFS - W6 - Absence of clinical improvement | JIA70 plus SFS - W8 - Clinical improvement | JIA70 plus SFS - W8 - Absence of clinical improvement | JIA70 plus SFS - W10 - Clinical improvement | JIA70 plus SFS - W10 - Absence of clinical improvement | JIA70 plus SFS - W12 - Clinical improvement | JIA70 plus SFS - W12 - Absence of clinical improvement | |
| ITF2357 - ITT Population | 11 | 6 | 12 | 5 | 12 | 5 | 11 | 6 | 11 | 6 | 10 | 7 | 11 | 6 | 10 | 7 | 11 | 6 | 10 | 7 | 9 | 8 | 9 | 8 | 10 | 7 | 10 | 7 | 10 | 7 | 9 | 8 | 9 | 8 | 9 | 8 |
| ITF2357 - PP Population | 7 | 2 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 | 7 | 2 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 | 6 | 3 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 | 8 | 1 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~At the pre-treatment visit CRP was scored as present or not present according to the following criterion: CRP considered as elevated if ≥ 10 mg/L.~At the subsequent visits CRP was scored 0 (Not present) if decreased by at least 30% compared to pre-treatment value or normalized (< 10 mg/L); score 1 (Present) if increased or decreased less than 30%." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| CRP - Pretreatment - absence | CRP - Pretreatment - presence | CRP - Week 4 - absence | CRP - Week 4 - presence | CRP - Week 8 - absence | CRP - Week 8 - presence | CRP - Week 12 - absence | CRP - Week 12 - presence | CRP - FU1 - absence | CRP - FU1 - presence | |
| ITF2357 - ITT Population | 0 | 17 | 8 | 8 | 6 | 6 | 6 | 8 | 10 | 6 |
| ITF2357 - PP Population | 0 | 9 | 5 | 4 | 4 | 5 | 5 | 4 | 6 | 3 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~At the pre-treatment visit ESR was scored as present or not present according to the following criterion: ESR considered as elevated if ≥ 20 mm/h (first hour)~At the subsequent visits ESR was scored 0 (Not present) if decreased by at least 30% as compared to pre-treatment value or normalized (< 20 mm/h); score 1 (Present) if increased or decreased less than 30%." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ESR - Pretreatment - absence | ESR - Pretreatment - presence | ESR - Week 4 - absence | ESR - Week 4 - presence | ESR - Week 8 - absence | ESR - Week 8 - presence | ESR - Week 12 - absence | ESR - Week 12 - presence | ESR - FU1 - absence | ESR - FU1 - presence | |
| ITF2357 - ITT Population | 1 | 16 | 5 | 11 | 4 | 8 | 5 | 9 | 6 | 10 |
| ITF2357 - PP Population | 0 | 9 | 2 | 7 | 4 | 5 | 3 | 6 | 4 | 5 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~At the pre-treatment visit Hb was scored as present or not present according to the following criterion: Haemoglobin considered as lowered if below 11g/dL.~At the subsequent visits Hb was scored 0 (Not present) if increased by 20% compared to pre-treatment value or normalized (> 11 g/dL); score 1 (Present) if decreased or increased less than 20%." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Hb - Pretreatment - absence | Hb - Pretreatment - presence | Hb - Week 4 - absence | Hb - Week 4 - presence | Hb - Week 8 - absence | Hb - Week 8 - presence | Hb - Week 12 - absence | WBC - Week 12 - presence | Hb - FU1 - absence | Hb - FU1 - presence | |
| ITF2357 - ITT Population | 6 | 11 | 6 | 10 | 6 | 6 | 6 | 8 | 8 | 8 |
| ITF2357 - PP Population | 3 | 6 | 4 | 5 | 4 | 5 | 4 | 5 | 4 | 5 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~Hepatomegaly and/or splenomegaly was scored as present if confirmed by ultrasound evaluation and established after comparison to age standards for organ size." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Hepatomegaly - Pretreatment - absence | Hepatomegaly - Pretreatment - presence | Hepatomegaly - Week 4 - absence | Hepatomegaly - Week 4 - presence | Hepatomegaly - Week 8 - absence | Hepatomegaly - Week 8 - presence | Hepatomegaly - Week 12 - absence | Hepatomegaly - Week 12 - presence | Hepatomegaly - FU1 - absence | Hepatomegaly - FU1 - presence | |
| ITF2357 - ITT Population | 16 | 1 | 16 | 0 | 12 | 0 | 14 | 0 | 16 | 0 |
| ITF2357 - PP Population | 8 | 1 | 9 | 0 | 9 | 0 | 9 | 0 | 9 | 0 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~Lymphadenopathy was scored as present or not present according to the following criterion: lymph node (nodes) enlargement to 1.5 cm or more, localized anywhere within the body." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lymphadenopathy - Pretreatment - absence | Lymphadenopathy - Pretreatment - presence | Lymphadenopathy - Week 4 - absence | Lymphadenopathy - Week 4 - presence | Lymphadenopathy - Week 8 - absence | Lymphadenopathy - Week 8 - presence | Lymphadenopathy - Week 12 - absence | Lymphadenopathy - Week 12 - presence | Lymphadenopathy - FU1 - absence | Lymphadenopathy - FU1 - presence | |
| ITF2357 - ITT Population | 13 | 4 | 16 | 0 | 12 | 0 | 14 | 0 | 16 | 0 |
| ITF2357 - PP Population | 6 | 3 | 9 | 0 | 9 | 0 | 9 | 0 | 9 | 0 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~Serositis (pericarditis, pleuritis or peritonitis) was scored as present if confirmed by ultrasound and/or X-ray exploration or by the presence of typical ECG findings in the case of pericarditis." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Serositis - Pretreatment - absence | Serositis - Pretreatment - presence | Serositis - Week 4 - absence | Serositis - Week 4 - presence | Serositis - Week 8 - absence | Serositis - Week 8 - presence | Serositis - Week 12 - absence | Serositis - Week 12 - presence | Serositis - FU1 - absence | Serositis - FU1 - presence | |
| ITF2357 - ITT Population | 16 | 1 | 15 | 1 | 12 | 0 | 13 | 1 | 16 | 0 |
| ITF2357 - PP Population | 9 | 0 | 9 | 0 | 9 | 0 | 9 | 0 | 9 | 0 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~Temperature was scored as present or not present according to the following criterion: body temperature ≥ 37.5 °C at least once a day during at least five consecutive days or presence of typical SOJIA intermittent temperature chart (patients' temperature chart analysis)." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Temp - Pretreatment - absence | Temp - Pretreatment - presence | Temp - Week 4 - absence | Temp - Week 4 - presence | Temp - Week 8 - absence | Temp - Week 8 - presence | Temp - Week 12 - absence | Temp - Week 12 - presence | Temp - FU1 - absence | Temp - FU1 - presence | |
| ITF2357 - ITT Population | 10 | 7 | 12 | 4 | 10 | 2 | 11 | 3 | 12 | 3 |
| ITF2357 - PP Population | 4 | 5 | 8 | 1 | 8 | 1 | 7 | 2 | 7 | 2 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~At the pre-treatment visit thrombocyte count was scored as present or not present according to the following criterion: Thrombocyte count considered as increased if ≥ 400x103/μL.~At the subsequent visits thrombocyte count was scored 0 (Not present) if decreased by 20% compared to pretreatment value or normalized (< 400x103/μL); score 1 (Present) if increased or decreased less than 20%." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Thrombocytes - Pretreatment - absence | Thrombocytes - Pretreatment - presence | Thrombocytes - Week 4 - absence | Thrombocytes - Week 4 - presence | Thrombocytes - Week 8 - absence | Thrombocytes - Week 8 - presence | Thrombocytes - Week 12 - absence | Thrombocytes - Week 12 - presence | Thrombocytes - FU1 - absence | Thrombocytes - FU1 - presence | |
| ITF2357 - ITT Population | 2 | 15 | 15 | 1 | 11 | 1 | 14 | 0 | 9 | 7 |
| ITF2357 - PP Population | 1 | 8 | 9 | 0 | 8 | 1 | 9 | 0 | 6 | 3 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~Typical SOJIA is a salmon pink rash on the trunk during the febrile episodes." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Rash - Pretreatment - absence | Rash - Pretreatment - presence | Rash - Week 4 - absence | Rash - Week 4 - presence | Rash - Week 8 - absence | Rash - Week 8 - presence | Rash - Week 12 - absence | Rash - Week 12 - presence | Rash - FU1 - absence | Rash - FU1 - presence | |
| ITF2357 - ITT Population | 14 | 3 | 16 | 0 | 12 | 0 | 14 | 0 | 16 | 0 |
| ITF2357 - PP Population | 6 | 3 | 9 | 0 | 9 | 0 | 9 | 0 | 9 | 0 |
"SFS variables included:~temperature~rash~lymph nodes~liver and spleen size~clinical evidence of serositis (pericarditis, pleuritis or peritonitis)~ESR~CRP~leukocyte count~haemoglobin~thrombocyte count~At the pre-treatment visit WBC was scored as present or not present according to the following criterion: Leukocyte count considered as elevated if ≥ 12 x 103/μL.~At the subsequent visits WBC was scored 0 (Not present) if decreased by 20% compared to pre-treatment value or normalized (< 12x103/μL); score 1 (Present) if increased or decreased less than 20%." (NCT00570661)
Timeframe: Pre-treatment, Weeks 4, 8, 12, and 1-month follow up
| Intervention | participants (Number) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| WBC - Pretreatment - absence | WBC - Pretreatment - presence | WBC - Week 4 - absence | WBC - Week 4 - presence | WBC - Week 8 - absence | WBC - Week 8 - presence | WBC - Week 12 - absence | WBC - Week 12 - presence | WBC - FU1 - absence | WBC - FU1 - presence | |
| ITF2357 - ITT Population | 4 | 13 | 10 | 6 | 10 | 2 | 10 | 4 | 6 | 10 |
| ITF2357 - PP Population | 2 | 7 | 6 | 3 | 7 | 2 | 7 | 2 | 5 | 4 |
Therapeutic response at week 4 was considered sufficient by the Investigator if a decrease in Systemic Feature Score of 2 (at least one of the first five variables) and/or JIA30 response (or above: 50 or 70) was obtained. (NCT00570661)
Timeframe: At week 4
| Intervention | participants (Number) | |
|---|---|---|
| Therapeutic response | Absence of therapeutic response | |
| ITF2357 - ITT Population | 11 | 6 |
| ITF2357 - PP Population | 8 | 1 |
"Modified Systemic Feature Score (SFS) variables included:~temperature, rash, lymph nodes, liver and spleen size, and clinical evidence of serositis (clinical variables)~ESR, CRP, leukocyte count, haemoglobin, thrombocyte count (laboratory variables).~Items in both sets of variables were scored as present (1) or not present (0) based on predefined criteria.~SFS data were presented as the sum of the first 5 items and the sum of the last 5 items. Each sum could range from a minimum of 0 to a maximum of 5." (NCT00570661)
Timeframe: At pretreatment visit, at weeks 2, 4, 6, 8, 10 and 12 (End of treatment), 1 month follow-up (FU1) in the PP and ITT populations respectively.
| Intervention | score on a scale (Mean) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Sum of first 5 (clinical) variables - pre-treatment | Sum of first 5 (clinical) variables - Week 2 | Sum of first 5 (clinical) variables - Week 4 | Sum of first 5 (clinical) variables - Week 6 | Sum of first 5 (clinical) variables - Week 8 | Sum of first 5 (clinical) variables - Week 10 | Sum of first 5 (clinical) variables - Week 12 | Sum of first 5 (clinical) variables - FU1 | Sum of last 5 (lab) variables - pretreatment | Sum of last 5 (lab) variables - week 2 | Sum of last 5 (lab) variables - week 4 | Sum of last 5 (lab) variables - week 6 | Sum of last 5 (lab) variables - week 8 | Sum of last 5 (lab) variables - week 10 | Sum of last 5 (lab) variables - week 12 | Sum of last 5 (lab) variables - FU1 | |
| ITF2357 - ITT Population | 0.94 | 0.35 | 0.31 | 0.14 | 0.17 | 0.33 | 0.29 | 0.20 | 4.24 | 2.65 | 2.25 | 1.93 | 1.92 | 2.08 | 2.07 | 2.56 |
| ITF2357 - PP Population | 1.33 | 0.44 | 0.11 | 0.11 | 0.11 | 0.11 | 0.22 | 0.22 | 4.33 | 2.44 | 2.11 | 1.56 | 2.00 | 2.00 | 1.89 | 2.22 |
"This outcome was assessed by quantitative real time Polymerase Chain Reaction (RT PCR).~At each time point, the number of patients is the following:~Screening: N=29 Week 12: N=20 Week 24: N=18 EOT: N=24. End of treatment corresponds to the last visit performed before treatment discontinuation." (NCT00606307)
Timeframe: At screening, at week 12, at week 24, at the end of treatment (EOT) visit
| Intervention | percentage of change in allele burden (Mean) | |||
|---|---|---|---|---|
| screening | week 12 | week 24 | EOT | |
| ITF2357 | 54.0 | 49.4 | 47.1 | 49.0 |
"An adverse event (AE) is any untoward occurrence in a patient or clinical investigation subject administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.~The adverse events must to be followed to the end of study (28 days after the last study drug intake).~A serious AE (SAE) is defined as an untoward (unfavourable) medical occurrence that at any dose results in death, or is life-threatening or requires inpatient hospitalisation or prolongation of existing hospitalisation, or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect." (NCT00606307)
Timeframe: At weekly visits (Days 8, 15, 22, 36, 43, 50, 64, 71, 78, 99, 127, 155); At monthly visits (Days 29, 57, 85 113, 141,169); at end of treatment visit
| Intervention | Participants (Count of Participants) | |
|---|---|---|
| number of patients with AE | number of patients with serious AE | |
| ITF2357 | 29 | 3 |
PFS is defined as the time from the 1st day of the 1st cycle of treatment until objective tumor progression or death. It included deaths, thus could be correlated to overall survival. If a patient did not have disease progression, PFS was censored at the date of last available tumor assessment (including those at end of study or follow-up visit). (NCT00792467)
Timeframe: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, assessed up to 450 days from the start of the first cycle of treatment
| Intervention | Days (Mean) |
|---|---|
| ITT Population | 164.53 |
| PP Population | 183.94 |
Duration of objective response (CR or PR) was applied only to patients whose best overall response was CR or PR. (NCT00792467)
Timeframe: From the first day of the first cycle of treatment until objective tumor progression or death, whichever came first, or last available tumor assessment (assessed up to 350 days from the start of the first cycle of treatment).
| Intervention | Days (Mean) |
|---|---|
| ITT Population | 199.96 |
| PP Population | 199.96 |
"TTR is defined as the time from the 1st day of the 1st cycle until the date of achieving a response (CR or PR).~In case of no objective response, TTR was censored at the date of last available tumor assessment (including those at end of study or follow-up visit)." (NCT00792467)
Timeframe: From the first day of the first cycle until the date of achieving a response assessed up to 250 days from the start of the first cycle of treatment
| Intervention | Days (Mean) |
|---|---|
| ITT Population | 123.52 |
| PP Population | 114.34 |
"OR rate among patients treated is defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group.~In medicine, a response rate is the percentage of patients whose cancer shrinks or disappears after treatment.~The FDA definition of ORR is the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.~The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology.~The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials." (NCT00792467)
Timeframe: At each 21-day cycle for a maximum of 12 cycles
| Intervention | percentage of patients (Number) | |
|---|---|---|
| Objective Response achieved | Objective Response not achieved | |
| ITT Population | 25.00 | 75.00 |
| PP Population | 37.50 | 62.50 |
"Complete responder (CR) and partial responder (PR) among patients treated are defined according to the Revised Response Criteria for Malignant Lymphoma of the International Working Group.~CR is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.~PR is defined as regression of measurable disease and no new sites. The frequencies of patients achieving objective response (i.e. subjects whose best overall response was CR or PR) and the frequencies of patients who did not achieve an objective response (i.e.subjects whose best overall response was equal to stable disease - SD, progressive disease - PD - or not evaluable) in ITT and PP populations are reported.~NED= no evidence of disease" (NCT00792467)
Timeframe: At each 21-day cycle for a maximum of 12 cycles
| Intervention | percentage of participants (Number) | ||||
|---|---|---|---|---|---|
| CR/NED | PR | SD | PD | Not evaluable | |
| ITT Population | 4.17 | 20.83 | 29.17 | 37.50 | 8.33 |
| PP Population | 6.25 | 31.25 | 25.00 | 37.50 | 0 |
"CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon; A patient was defined 'endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than six points.~CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon ).~The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated.~The higher the score, the worse is patient's situation.~Score Scale:~< 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity.~A patient was defined 'endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than six points." (NCT00792740)
Timeframe: At week 8
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 3 |
| ITF2357 | 5 |
"The outcome is assessed by endoscopy, in patients with endoscopic and clinical evidence of active moderate-to-severe Crohn's disease not controlled by conventional therapies.~The outcome measure defines the rate of patients achieving complete healing in ITT population, i.e disappearance of mucosal ulceration, obtained with ITF2357 treatment." (NCT00792740)
Timeframe: At week 8
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 0 |
| ITF2357 | 1 |
"CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit.~The higher the score, the worse is patient's situation A patient is defined 'remissed' whether the CDAI score is lower than 150 points.~A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points" (NCT00792740)
Timeframe: Weeks 4 and 8, and follow-up at 1 month
| Intervention | score on a scale (Mean) | ||
|---|---|---|---|
| At week 4 | At week 8 | At follow-up 1 month | |
| ITF2357 | -32.7 | -54.7 | -83.8 |
| Placebo | -85.3 | -119 | -106 |
Individual plasma levels of Metabolite ITF2375 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed. (NCT00792740)
Timeframe: Pre dose, week 2, week 4, week 6.
| Intervention | ng/mL (Mean) | |||
|---|---|---|---|---|
| pre-dose | week 2 | week 4 | week 6 | |
| ITF2357 | 0.00 | 121.23 | 112.80 | 101.36 |
Individual plasma levels of metabolite ITF2374 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed. (NCT00792740)
Timeframe: Pre-dose, week 2, week 4, week 6
| Intervention | ng/mL (Mean) | |||
|---|---|---|---|---|
| Pre-dose | Week 2 | Week 4 | Week 6 | |
| ITF2357 | 0.00 | 15.09 | 12.93 | 13.24 |
Individual plasma levels of ITF2357 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed. (NCT00792740)
Timeframe: Pre-dose, week 2, week 4, week 6
| Intervention | ng/mL (Mean) | |||
|---|---|---|---|---|
| Pre-dose | Week 2 | Week 4 | Week 6 | |
| ITF2357 | 0.00 | 16.87 | 16.97 | 14.50 |
"Response is defined as the reaction to a stimulus or to a treatment, especially in a favorable way.~CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit.~The higher the score, the worse is patient's situation. A patient is defined 'remissed' whether the CDAI score is lower than 150 points.~A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points" (NCT00792740)
Timeframe: Weeks 4 and 8, and follow-up at 1 month
| Intervention | Participants (Count of Participants) | ||
|---|---|---|---|
| At week 4 | At week 8 | At follow up, after one month | |
| ITF2357 | 6 | 8 | 11 |
| Placebo | 11 | 14 | 14 |
"Remission is defined as the disappearance of signs and symptoms of the disease.~CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit.~The higher the score, the worse is patient's situation A patient is defined 'remissed' whether the CDAI score is lower than 150 points.~A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points" (NCT00792740)
Timeframe: Weeks 4 and 8, and follow-up at 1 month
| Intervention | Participants (Count of Participants) | ||
|---|---|---|---|
| At week 4 | At week 8 | At follow-up after one month | |
| ITF2357 | 4 | 7 | 9 |
| Placebo | 10 | 14 | 11 |
"SES-CD is another index to determ the endoscopic severity of Crohn's disease. Its score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). These 4 parameters are:~ulcers? 0: no; 1: aphthous (0.1-0.5 cm); 2: large (0.5-2 cm); 3: very large (>2 cm); Surface involved by inflammation 0: 0%~1: <50% 2: 50-75% 3: >75% Surface involved by ulcerations 0: 0%~<10%~10-30%~>30% Stenosis?~0: No~Single, can be passed~Multiple, can be passed~Cannot be passed The scores for each individual segment are added together as a sum score (min=0; max=60) The higher the score, the worse the outcome.~Decoding score 0 - 2 remission 3 - 6 mild endoscopic activity 7 - 15 moderate endoscopic activity > 15 severe endoscopic activity" (NCT00792740)
Timeframe: From Baseline to week 8
| Intervention | score on a scale (Mean) |
|---|---|
| Placebo | -2.6 |
| ITF2357 | -2.0 |
"CDEIS is an index to determ the endoscopic severity of Crohn's disease. Its score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). These 4 parameters are: Deep ulcerations (12 if present, 0 if absent = total 1); Superficial ulcerations (6 if present, 0 if absent = total 2); Surface involved by disease (mm/10 on VAS = = total 3); Surface involved by ulcerations (mm/10 on VAS = total 4).~Sum of Totals 1+2+3+4 =Total A Number of segments visualized in part or entirely (from 1 to 5)= n Total A/n =Total B if ulcerated stenosis in any segment, add 3 =Total C If non-ulcerated stenosis in any segment, add 3= Total D Total B+C+D=CDEIS grand score (min=0; max=NA)~Decoding score < 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity.~The higher the score, the worse is patient's status." (NCT00792740)
Timeframe: From Baseline to week 8
| Intervention | score on a scale (Mean) |
|---|---|
| Placebo | -2.5 |
| ITF2357 | -2.4 |
Treatment-related adverse events are adverse events (AE) which occurs during an interventional study and which are surely related to study treatment dosing. (NCT00792740)
Timeframe: At Pre-Treatment period (Week 0); At treatment period (Week 1, Week 2, Week 4, week 6, Week 8); At Follow-up period (1month)
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 13 |
| ITF2357 | 12 |
"CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon; A patient was defined 'fully endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than three points~CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon.~The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated.~Score Scale:~< 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity.~The higher the score, the worse is patient's situation." (NCT00792740)
Timeframe: At Week 8
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 2 |
| ITF2357 | 1 |
"CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon;~A patient was considered in 'endoscopic response' whether the change in CDEIS score at week 8 versus baseline was equal or greater than 4.5 points.~CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon ).~The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated.~The higher the score, the worse is patient's situation~Score Scale:~< 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity.~A patient was considered in 'endoscopic response' whether the change in CDEIS score at week 8 versus baseline was equal or greater than 4.5 points." (NCT00792740)
Timeframe: At week 8
| Intervention | Participants (Count of Participants) |
|---|---|
| Placebo | 6 |
| ITF2357 | 7 |
To determine JAK2V617F mutational status, a quantitative RT-PCR (Real Time-Polymerase Chain Reaction) is executed on peripheral blood granulocyte and haematopoietic colonies (with and without hepatocyte growth factors - HGFs). (NCT00928707)
Timeframe: "At weeks 12, 24, at drop out visit and at End of Study (EOS). EOS stays for 7 days after last drug intake if patient is withdrawn from the study before week 24."
| Intervention | percent change (Mean) | |||
|---|---|---|---|---|
| Week 12 | Week 24 | Drop-out | EOS | |
| GIVINOSTAT + MTD Hydroxyurea_1 | -2.6 | -3.8 | -4.0 | -3.8 |
| GIVINOSTAT + MTD Hydroxyurea_2 | 0.00 | 4.6 | -9.5 | 3.0 |
"JAK2V617F genotyping and quantification were performed on gradient-separated mononuclear cells during the pre-treatment evaluations (baseline), halfway through the study (12th weeks) and at the end of the study period (24th weeks).~Baseline: n=22 (50 mg od); 22 (50 mg bid) Week 12: n=20 (50 mg od); 19 (50 mg bid) Week 24: n=18 (50 mg od); 18 (50 mg bid)" (NCT00928707)
Timeframe: Baseline, at weeks 12 and 24
| Intervention | percentage of participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Baseline - heterozygous | Baseline - homozygous | Baseline - not done | week 12 - heterozygous | week 12 - homozygous | week 12 - not done | week 24 - heterozygous | week 24 - homozygous | week 24 - not done | |
| GIVINOSTAT + MTD Hydroxyurea_1 | 27.3 | 72.7 | 0 | 25.0 | 70.0 | 5.0 | 22.2 | 72.2 | 5.6 |
| GIVINOSTAT + MTD Hydroxyurea_2 | 22.7 | 72.7 | 4.5 | 31.6 | 63.2 | 5.3 | 11.1 | 77.8 | 11.1 |
The percentage of patients with overall (complete or partial) response at week 12 were assessed. · Complete response: 1. HCT (Hematocrit) < 45% without phlebotomy, and 2. platelets ≤ 400 x109/L, and 3. WBC (white blood cell) ≤ 10 x 109/L, and 4. no splenomegaly, and 5. no disease related systemic symptoms (microvascular disturbances, pruritus, headache); · Partial response: 1. HCT < 45% without phlebotomy, or 2. fulfilment of at least 3 of the other above mentioned criteria; · No response: any response that did not satisfy the criteria set for partial response. (NCT00928707)
Timeframe: At week 12 of treatment
| Intervention | percentage of particpants (Number) | |
|---|---|---|
| Responder | Non responder | |
| GIVINOSTAT + MTD Hydroxyurea_1 | 54.5 | 45.5 |
| GIVINOSTAT + MTD Hydroxyurea_2 | 50.0 | 50.0 |
"Haematological response after a 50 mg increase of the initial Givinostat dose in non-responder patients at the time when the primary endpoint was assessed (week 12).~Complete response:~HCT< 45% without phlebotomy, and~platelets ≤ 400 x109/L, and~WBC ≤ 10 x 109/L, and~no splenomegaly, and~no disease related systemic symptoms (microvascular disturbances, pruritus, headache);~Partial response:~HCT < 45% without phlebotomy, or~fulfilment of at least 3 of the other above mentioned criteria;~No response:~any response that did not satisfy the criteria set for partial response." (NCT00928707)
Timeframe: At week 24 of treatment
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Responder | Non responder | |
| GIVINOSTAT + MTD Hydroxyurea_1 | 63.6 | 36.4 |
| GIVINOSTAT + MTD Hydroxyurea_2 | 40.9 | 59.1 |
"This is an open-label treatment extension of the 2010-019094-15 study, an antecedent dose-ranging trial of Givinostat ready-to-use oral suspension formulation. Eligible patients were those who had completed the previous study achieving a clinical benefit, i.e. patients achieving at least an ACR Paediatric 30 (PedACR30).~PedACR70 is defined as at least a 70% improvement from baseline in any three of the following six variables in juvenile idiopathic arthritis (JIA) patients, with no more than one variable worsening by more than 30%:~physician's global assessment of disease activity;~parent/guardian's or patient's global assessment of overall wellbeing;~functional ability;~number of joints with active arthritis;~number of joints with limited range of motion;~ESR.~(ACR stands for American College of Rheumatology)" (NCT01557452)
Timeframe: At weeks 48, 60 and 108
| Intervention | participants (Number) | ||
|---|---|---|---|
| week 48 | week 60 | week 108 | |
| Givinostat | 0 | 1 | 0 |
"This is an open-label treatment extension of the 2010-019094-15 study, an antecedent dose-ranging trial of Givinostat ready-to-use oral suspension formulation. Eligible patients were those who had completed the previous study achieving a clinical benefit, i.e. patients achieving at least an ACR Paediatric 30 (PedACR30).~PedACR30 is defined as at least a 30% improvement from baseline in any three of the following six variables in juvenile idiopathic arthritis (JIA) patients, with no more than one variable worsening by more than 30%:~physician's global assessment of disease activity;~parent/guardian's or patient's global assessment of overall wellbeing;~functional ability;~number of joints with active arthritis;~number of joints with limited range of motion;~ESR.~(ACR stands for American College of Rheumatology)" (NCT01557452)
Timeframe: At weeks 48, 60 and 108
| Intervention | participants (Number) | ||
|---|---|---|---|
| week 48 | week 60 | week 108 | |
| Givinostat | 1 | 0 | 1 |
"During the entire study period it was reported only one adverse event considered not drug related by the investigator (Mild flu at week 107 of study treatment).~No action was taken and the patient recovered spontaneously" (NCT01557452)
Timeframe: Through end of treatment, up to 108 weeks.
| Intervention | participants (Number) | |
|---|---|---|
| non serious AE | serious AE | |
| Givinostat | 1 | 0 |
"This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes.~The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment.~The longer the walked distance the better the outcome." (NCT01761292)
Timeframe: At 24, 36, and 52 months
| Intervention | meters (Mean) | ||
|---|---|---|---|
| Extension 1 | Extension 2 | Extension 3 | |
| Overall | -80.0 | -127.0 | -287.8 |
These histological parameters were evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. (NCT01761292)
Timeframe: After 12 months
| Intervention | percentage of total area (Mean) | ||||
|---|---|---|---|---|---|
| Total fibrosis | Perimysial fibrosis | Endomysial fibrosis | Fatty replacement | Necrosis | |
| Baseline | -12.640 | -7.585 | -5.056 | -0.302 | -0.964 |
Summary of Treatment-emergent Adverse Events (TEAE) Reporting from Baseline to the End of Extension 3 (Month 52). In the analysis were included: Any TEAE, Any treatment-related TEAE, Any mild or moderate or severe TEAE, Any life-threatening or disabling TEAE, Any TEAE resulting in death, any serious adverse event, and Any TEAE resulting in study discontinuation. (NCT01761292)
Timeframe: Part 1, Part 2, and Extensions 1, 2, and 3
| Intervention | participants (Number) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| TEAEs | Any treatment-related TEAE | Any mild TEAE | Any moderate TEAE | Any severe TEAE | Any life-threatening or disabling TEAE | Ant TEAE resulting in death | Any SAE | Any TEAE resulting in study discontinuation | |
| Overall | 20 | 20 | 20 | 16 | 9 | 1 | 0 | 8 | 1 |
"This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes.~The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment.~The longer the walked distance the better the outcome." (NCT01761292)
Timeframe: At 12 months
| Intervention | meters (Mean) |
|---|---|
| Overall | -24.6 |
"The NSAA, which is composed by 17 items, was graded, for each item, using the standard scorecard with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity.~The subscales scores are summed up to compute a total score, ranging from 0 to 34. The higher the total score, the better the outcome.~The mean Change From Baseline to EoS in NSAA total score is reported hereunder." (NCT01761292)
Timeframe: At 12 months
| Intervention | score on a scale (Mean) |
|---|---|
| Overall | -2.8 |
"The PUL (version 1.2) was used to assess the change in motor performance of the upper limb over time in patients with Becker and Duchenne muscular dystrophy, from when they are still ambulant, until they loose all arm function when non-ambulant.~The revised version of the PUL included 22 items. These include one entry item to define the starting functional level, and 21 items subdivided into:~shoulder level (Question B to E; minimum score 0 and maximum score 16)~elbow level (Question F to N; minimum score 0 and maximum score 34)~distal level dimension (Question O to V; minimum score 0 and maximum score 24) The total score is calculated by the sum of all the scores of the three subscales (total score range: 0-74) (scores from Question A entry item did not contribute). For all items, the higher the score, the better the outcome." (NCT01761292)
Timeframe: At 12 months
| Intervention | score on a scale (Mean) |
|---|---|
| Overall | -0.2 |
This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. (NCT01761292)
Timeframe: At 12 months
| Intervention | μm2 (Mean) |
|---|---|
| Overall | 865.269 |
This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. The number of fibers is calculated per microscopic field (20x). (NCT01761292)
Timeframe: At 12 months
| Intervention | number of fibers (Mean) |
|---|---|
| Overall | -1.204 |
"The primary endpoint was the change in histology comparing the brachial biceps biopsies before and after ≥12 months of treatment with Givinostat.~Muscle biopsies: A first brachial biceps biopsy (baseline) was taken prior to the first dose of study drug. A second brachial biceps biopsy was taken at Visit 10 (12 months) from the opposite arm.~The muscle biopsy samples from the biceps muscle were collected by open biopsy. The minimum amount of muscle tissue required was a piece of muscle of at least 0.5 × 0.5 × 0.5 cm." (NCT01761292)
Timeframe: After12 months of treatment
| Intervention | percentage change (Median) |
|---|---|
| Overall | 12.76 |
"The NSAA, which is composed by 17 items, was graded, for each item, using the standard scorecard with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity.~The subscales scores are summed up to compute a total score, ranging from 0 to 34. The higher the total score, the better the outcome.~The mean Change From Baseline to EoS in NSAA total score is reported hereunder." (NCT01761292)
Timeframe: At 24, 36, and 52 months
| Intervention | score on a scale (Mean) | ||
|---|---|---|---|
| Extension 1 | Extension 2 | Extension 3 | |
| Overall | -5.2 | -7.4 | -15.2 |
"The PUL (version 1.2) was used to assess the change in motor performance of the upper limb over time in patients with Becker and Duchenne muscular dystrophy, from when they are still ambulant, until they loose all arm function when non-ambulant.~The revised version of the PUL included 22 items taking. These include one entry item to define the starting functional level, and 21 items subdivided into:~shoulder level (Question B to E; minimum score 0 and maximum score 16)~elbow level (Question F to N; minimum score 0 and maximum score 34)~distal level dimension (Question O to V; minimum score 0 and maximum score 24) The total score is calculated by the sum of all the scores of the three subscales (total score range: 0-74) (scores from Question A entry item did not contribute). For all items, the higher the score, the better the outcome." (NCT01761292)
Timeframe: At 24, 36, and 52 months
| Intervention | score on a scale (Mean) | ||
|---|---|---|---|
| Extension 1 | Extension 2 | Extension 3 | |
| Overall | -0.2 | -0.2 | -4.4 |
"The MTD of givinostat was based only on Cycle 1 DLTs. A DLT was defined as the following drug-related toxicity:~Grade 4 hematological toxicity, or~Grade 3 febrile neutropenia, or~Grade ≥3 non-hematological toxicity (with the exception Grade 3 diarrhea without adequate supportive care lasting less than 3 days, and Grade 3 nausea or vomiting without adequate supportive care lasting less than 3 days), or~Any drug-related serious AE, or~Any toxicity clearly not related to disease progression or intercurrent illness requiring interruption of dosing for more than 3 days during first cycle.~At end of Cycle 1, for the third patient in each DL, the safety of the 3 patients treated for 1 cycle was reviewed and it was decided if the dose should be escalated or not. Results are reported as the number of patients with DLT events for Cycle 1 in Part A." (NCT01901432)
Timeframe: 28 days (up to Cycle 1 Day 28 in Part A).
| Intervention | participants (Number) |
|---|---|
| Givinostat DL0 (50 mg b.i.d.) (Part A) | 0 |
| Givinostat DL1 (100 mg b.i.d.) (Part A) | 1 |
| Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) | 0 |
| Givinostat DL6 (100 mg + 50 mg) (Part A) | 0 |
ORR following administration of givinostat at the MTD for 6 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. (NCT01901432)
Timeframe: 168 days (up to Cycle 6 Day 28 in Part B).
| Intervention | percentage of participants (Number) |
|---|---|
| Givinostat at MTD (100 mg b.i.d.) (Part B) | 80.6 |
Evaluations were performed on the type, incidence and severity of TEAEs, graded according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03, following administration of givinostat for up to 6 cycles of treatment in Part A. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / treatment-emergent serious adverse event (TESAE) corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. (NCT01901432)
Timeframe: 168 days (up to Cycle 6 Day 28 in Part A).
| Intervention | Participants (Count of Participants) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TEAE | Drug-related TEAE | TESAE | Drug-related TESAE | Death due to any cause | Grade 3 TEAE | Grade 3 drug-related TEAE | Grade 4 TEAE | Grade 4 drug-related TEAE | Grade 5 TEAE | Discontinuation due to TEAE | Discontinuation due to drug-related TEAE | Discontinuation due to TESAE | Discontinuation due to drug-related TESAE | |
| Givinostat DL0 (50 mg b.i.d.) (Part A) | 3 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Givinostat DL1 (100 mg b.i.d.) (Part A) | 3 | 3 | 1 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Givinostat DL1 Expanded (100 mg b.i.d.) (Part A) | 3 | 3 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 0 |
| Givinostat DL6 (100 mg + 50 mg) (Part A) | 3 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
ORR following administration of givinostat after 3 cycles and after 6 cycles in Part A, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological ELN response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis. Analysis performed using the dataset for all Part A patients combined. (NCT01901432)
Timeframe: 84 and 168 days (up to Cycle 3 Day 28 and Cycle 6 Day 28 in Part A).
| Intervention | percentage of participants (Number) | |
|---|---|---|
| Cycle 3 Day 28 | Cycle 6 Day 28 | |
| Givinostat Total (Part A) | 72.7 | 72.7 |
"ORR, CR and PR following administration of givinostat at MTD for 3 cycles in Part B, reported as percentage of patients with a response. Response was evaluated according to the clinico-hematological European LeukemiaNet (ELN) response criteria. If Investigator's clinical response assessment (taking into account the overall medical judgment of the specific patient's case) was not in agreement with exact application of the ELN response criteria, the Investigator's assessment superseded the mathematical application of these criteria and was used for analysis.~CR defined as:~Hematocrit (HCT) <45% without phlebotomy, and~Platelets ≤400 x10^9/litre (L), and~White Blood Cell count ≤10 x10^9/L, and~Normal spleen size, and~No disease-related systemic symptoms (i.e. pruritus, headache, microvascular disturbances).~PR defined as: Patients not fulfilling CR and~HCT <45% without phlebotomy, or~Response in ≥3 other criteria." (NCT01901432)
Timeframe: 84 days (up to cycle 3 Day 28 in Part B).
| Intervention | percentage of participants (Number) | ||
|---|---|---|---|
| ORR (CR + PR) | CR | PR | |
| Givinostat at MTD (100 mg b.i.d.) (Part B) | 80.6 | 9.7 | 71.0 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL0 (50 mg b.i.d.) (Part A PK Analysis Set) | 7.97 | 8.05 | 3.00 |
"Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | nanograms per millilitre (ng/mL) (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2374 Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL1 (100 mg b.i.d.) (Part A PK Analysis Set) | 54.3 | 3.74 | 68.6 | 73.3 | 19.7 | 259 |
| Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set) | 82.5 | 5.69 | 101 | 290 | 31.3 | 376 |
"Pharmacokinetic (PK) evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | nanograms per millilitre (ng/mL) (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL0 (50 mg b.i.d.) (Part A PK Analysis Set) | 60.2 | 22.4 | 110 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng/mL (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 100 mg b.i.d. (Part B PK Analysis Set) | 71.5 | 7.85 | 161 | 90.8 | 32.3 | 320 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng/mL (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 75 mg b.i.d. (Part B PK Analysis Set) | 64.0 | 22.6 | 203 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Cmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng/mL (Mean) | |
|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | |
| Givinostat 50 mg b.i.d. (Part B PK Analysis Set) | 62.6 | 21.4 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 100 mg b.i.d. (Part B PK Analysis Set) | 289 | 28.5 | 888 | 459 | 216 | 1830 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 75 mg b.i.d. (Part B PK Analysis Set) | 323 | 161 | 1210 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |
|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | |
| Givinostat 50 mg b.i.d. (Part B PK Analysis Set) | 269 | 145 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |||
|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 100 mg b.i.d. (Part B PK Analysis Set) | 372 | 1080 | 561 | 2460 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |
|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 75 mg b.i.d. (Part B PK Analysis Set) | 410 | 1460 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2374 (Cycle 1 Day 28) across all dose groups and for ITF2375 in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) |
|---|---|
| Givinostat Cycle 2 Day 28 | |
| Givinostat 50 mg b.i.d. (Part B PK Analysis Set) | 326 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2374 Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL1 (100 mg b.i.d.) (Part A PK Analysis Set) | 238 | 14.4 | 416 | 359 | 102 | 1390 |
| Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set) | 429 | 29.6 | 611 | 1100 | 158 | 1780 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUClast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUClast was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL0 (50 mg b.i.d.) (Part A PK Analysis Set) | 208 | 132 | 263 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | |||
|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL1 (100 mg b.i.d.) (Part A PK Analysis Set) | 289 | 598 | 533 | 2020 |
| Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set) | 508 | 870 | 1180 | 2340 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of AUC0-12 following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis and AUC0-12 was calculated using the linear trapezoidal rule. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note:concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) across all dose groups and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | ng*h/mL (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL0 (50 mg b.i.d.) (Part A PK Analysis Set) | 235 | 161 | 863 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2374 Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL1 (100 mg b.i.d.) (Part A PK Analysis Set) | 8.00 | 8.00 | 8.00 | 7.00 | 7.00 | 7.00 |
| Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set) | 8.00 | 8.00 | 8.00 | 8.02 | 8.02 | 6.70 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Median) | ||
|---|---|---|---|
| Givinostat Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL0 (50 mg b.i.d.) (Part A PK Analysis Set) | 2.00 | 3.90 | 2.00 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 1 cycle in Part A. PK calculations were performed by standard non-compartmental analysis. Results are reported for Cycle 1 Day 1 and Cycle 1 Day 28.~Note: concentration data for ITF2374 (Cycle 1 Day 1 and Cycle 1 Day 28) and for ITF2375 (Cycle 1 Day 1) in the DL0 dose group of Part A were not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part A on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 1 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Median) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 1 Day 28 | ITF2374 Cycle 1 Day 28 | ITF2375 Cycle 1 Day 28 | |
| Givinostat DL1 (100 mg b.i.d.) (Part A PK Analysis Set) | 2.00 | 8.00 | 3.00 | 1.50 | 8.00 | 1.99 |
| Givinostat DL6 (100 mg + 50 mg) (Part A PK Analysis Set) | 3.00 | 8.00 | 2.50 | 2.05 | 2.00 | 4.00 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Mean) | |
|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | |
| Givinostat 50 mg b.i.d. (Part B PK Analysis Set) | 7.99 | 7.99 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Mean) | ||
|---|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 75 mg b.i.d. (Part B PK Analysis Set) | 7.98 | 7.98 | 8.00 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tlast following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Mean) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 100 mg b.i.d. (Part B PK Analysis Set) | 7.42 | 7.42 | 8.00 | 8.00 | 8.00 | 7.75 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Median) | |
|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | |
| Givinostat 50 mg b.i.d. (Part B PK Analysis Set) | 0.985 | 5.99 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Median) | ||
|---|---|---|---|
| Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 75 mg b.i.d. (Part B PK Analysis Set) | 2.00 | 3.04 | 2.00 |
"PK evaluation of givinostat and metabolites (ITF2374 and ITF2375) by assessment of Tmax following administration of givinostat for 2 cycles in Part B. PK calculations were performed by standard non-compartmental analysis. Following definition of the MTD in Part A, during Part B Cycle 1, givinostat was administered at 100 mg b.i.d. and during Part B Cycle 2 was administered at 100 mg, 75 mg and 50 mg b.i.d. (since dose reductions due to TEAEs were allowed from Cycle 2 onwards, as per protocol). Results are reported for Cycle 1 Day 1 and Cycle 2 Day 28 for the doses administered during Part B.~Note: PK evaluation for the givinostat 75 mg and 50 mg b.i.d. dose groups for Cycle 1 Day 1 was not applicable (since all received givinostat 100 mg b.i.d.). Additionally, concentration data for ITF2375 (Cycle 1 Day 28) in the 50 mg b.i.d. dose group was not available for PK analysis." (NCT01901432)
Timeframe: Blood samples were collected in Part B on Cycle 1 Day 1: pre-dose and 2, 3 and 8 hours post-dose; and on Cycle 2 Day 28: pre-dose and 1, 2, 4 and 8 hours post-dose.
| Intervention | hours (Median) | |||||
|---|---|---|---|---|---|---|
| Givinostat Cycle 1 Day 1 | ITF2374 Cycle 1 Day 1 | ITF2375 Cycle 1 Day 1 | Givinostat Cycle 2 Day 28 | ITF2374 Cycle 2 Day 28 | ITF2375 Cycle 2 Day 28 | |
| Givinostat 100 mg b.i.d. (Part B PK Analysis Set) | 2.00 | 8.00 | 3.00 | 2.00 | 4.00 | 2.00 |
Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 3 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. (NCT01901432)
Timeframe: 84 days (up to Cycle 3 Day 28 in Part B).
| Intervention | Participants (Count of Participants) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TEAE | Drug-related TEAE | TESAE | Drug-related TESAE | Death due to any cause | Grade 3 TEAE | Grade 3 drug-related TEAE | Grade 4 TEAE | Grade 4 drug-related TEAE | Grade 5 TEAE | Discontinuation due to TEAE | Discontinuation due to drug-related TEAE | Discontinuation due to TESAE | Discontinuation due to drug-related TESAE | |
| Givinostat at MTD (100 mg b.i.d.) (Part B) | 35 | 33 | 2 | 1 | 0 | 10 | 7 | 0 | 0 | 0 | 2 | 2 | 0 | 0 |
Evaluations were performed on the type, incidence and severity of TEAEs, graded according to CTCAE v. 4.03, following administration of givinostat at the MTD for up to 6 cycles of treatment in Part B. Grades 1 through 5 were as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening or requiring hospitalisation; Grade 4: Life threatening consequences; Grade 5: Death related to AE. Results are reported as number of patients with TEAEs for each of the indicated categories. Definitions: drug-related TEAE / TESAE corresponded to reasonable suspicion that the TEAE / TESAE was associated with the use of the study drug, according to investigator assessment; discontinuation refers to discontinuation from treatment. Results are reported as number of patients with TEAEs for each of the indicated categories. (NCT01901432)
Timeframe: 168 days (up to Cycle 6 Day 28 in Part B).
| Intervention | participants (Number) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TEAE | Drug-related TEAE | TESAE | Drug-related TESAE | Death due to any cause | Grade 3 TEAE | Grade 3 drug-related TEAE | Grade 4 TEAE | Grade 4 drug-related TEAE | Grade 5 TEAE | Discontinuation due to TEAE | Discontinuation due to drug-related TEAE | Discontinuation due to TESAE | Discontinuation due to drug-related TESAE | |
| Givinostat at MTD (100 mg b.i.d.) (Part B) | 35 | 33 | 2 | 1 | 0 | 12 | 10 | 0 | 0 | 0 | 2 | 2 | 0 | 0 |
An analysis of time (in seconds) to rise from the floor by change from baseline at 18 months is presented for the Target Population in the ITT analysis set. The shorter the time, the better the outcome. (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Givinostat | 9.33 |
| Placebo | 12.61 |
The total North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure functional motor abilities in ambulant children with Duchenne Muscular Dystrophy (DMD). It is usually used to monitor the progression of the disease and treatment effects. The 17 items of the NSAA, ranging from standing to running 10 meters, were graded using the standard score card with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. This scale is ordinal with 0 as the minimum score (indicating full disfunctionality, i.e. the worst outcome) and with 34 as the maximum score indicating fully-independent function (the best outcome). (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | score on a scale (Least Squares Mean) |
|---|---|
| Givinostat | -2.66 |
| Placebo | -4.58 |
Vastus lateralis muscle fat fraction (VL MFF) was expressed as fat infiltration in this muscle. Fat infiltration was assessed by Magnetic Resonance (MRS). (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | percentage of fat (Least Squares Mean) |
|---|---|
| Givinostat | 7.63 |
| Placebo | 10.56 |
Acceptability and palatability of the oral suspension over time are presented. More in details, child perception of the medicine at the three timepoints hereunder specified; parent perception of the medicine based on the child's reaction at the same three timepoints; and parent problems administering the medication at the same timepoints are reported. (NCT02851797)
Timeframe: Week 4, EOS, early withdrawal
| Intervention | Participants (Count of Participants) | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Child perception - week 4 - dislike very much | Child perception - week 4 - dislike a little | Child perception - week 4 - not sure | Child perception - week 4 - like a little | Child perception - week 4 - like very much | Child perception - EOS - dislike very much | Child perception - EOS - dislike a little | Child perception - EOS - not sure | Child perception - EOS - like a little | Child perception - EOS - like very much | Child perception - early withdrawal - dislike very much | Child perception - early withdrawal - dislike a little | Child perception - early withdrawal - not sure | Child perception - early withdrawal - like a little | Child perception - early withdrawal - like very much | Parent perception - week 4 - unpleasant | Parent perception - week 4 - not sure | Parent perception - week 4 - pleasant | Parent perception - EOS - unpleasant | Parent perception - EOS - not sure | Parent perception - EOS - pleasant | Parent perception - early withdrawal - unpleasant | Parent perception - early withdrawal - not sure | Parent perception - early withdrawal - pleasant | Parent admin problems - week 4 - yes | Parent admin problems - week 4 - no | Parent admin problems - EOS - yes | Parent admin problems - EOS - no | Parent admin - early withdrawal - yes | Parent admin - early withdrawal - no | |
| Givinostat | 31 | 21 | 30 | 19 | 11 | 21 | 24 | 34 | 19 | 7 | 1 | 1 | 2 | 1 | 0 | 50 | 28 | 35 | 42 | 40 | 26 | 1 | 3 | 1 | 6 | 107 | 5 | 102 | 0 | 5 |
| Placebo | 11 | 17 | 16 | 12 | 3 | 7 | 13 | 16 | 10 | 9 | 0 | 0 | 0 | 0 | 0 | 31 | 10 | 18 | 14 | 22 | 19 | 0 | 0 | 0 | 1 | 58 | 0 | 55 | 0 | 0 |
"Subject cumulative number of failures across all postbaseline visits was the endpoint of interest for analysis.~For each subject at each postbaseline visit, failure to perform each of the 17 items of the NSAA was assessed, where failure was defined as a score transition from 2 or 1 at baseline to 0 at the respective visit. The total number of failed items for the visit was calculated (maximum of 17 failed items per visit per subject). The subject's cumulative number of failures across all visits was the sum of the total failures at each postbaseline visit." (NCT02851797)
Timeframe: over 18 months
| Intervention | cumulative number of failures (Number) |
|---|---|
| Givinostat | 3.42 |
| Placebo | 5.56 |
"Adverse Events are unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.~Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned." (NCT02851797)
Timeframe: Baseline through end of study, that is the end of 18° month
| Intervention | Participants (Count of Participants) | ||||
|---|---|---|---|---|---|
| Subjects with TEAE | Subjects with serious AE | Subjects with mild AE | Subjects with moderate AE | Subjects with severe AE | |
| Givinostat | 112 | 8 | 69 | 38 | 5 |
| Placebo | 57 | 2 | 39 | 17 | 1 |
The time (in seconds) to climb 4 standard-sized stairs is a TFT that represents stair-climbing ability. The test was evaluated by qualified functional evaluators (ie, physiotherapists) who were different from the site personnel who reviewed subjects' safety results. The test was performed in a standardised manner described in a specific site manual. Baseline 4SC was the measurement taken at the randomization assessment, unless this was missing, in which case baseline was taken as the last non missing value recorded prior to or on the date of first study treatment. The shorter the time, the better the outcome. (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | seconds (Least Squares Mean) |
|---|---|
| Givinostat | 1.27 |
| Placebo | 1.48 |
"This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes.~The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. A modified version of the 6MWT recommended by American Thoracic Society (2002) for use in adults was performed.~The longer the walked distance the better the outcome." (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | meters (Least Squares Mean) |
|---|---|
| Givinostat | -38.43 |
| Placebo | -48.38 |
The mean change of muscle strength normalized was evaluated by knee extension and elbow flexion normalized by subject weight, both measured by hand-held myometry (HHM). (NCT02851797)
Timeframe: Baseline and 18 months
| Intervention | Newtons/kg (Least Squares Mean) | |
|---|---|---|
| Overall knee extension | Overall elbow flexion | |
| Givinostat | -0.32 | -0.10 |
| Placebo | -0.50 | -0.19 |
| Substance | Relationship Strength | Studies | Trials | Classes | Roles |
|---|---|---|---|---|---|
| carbamates [no description available] | 2.41 | 1 | 0 | amino-acid anion | |
| toluene methylbenzene : Any alkylbenzene that is benzene substituted with one or more methyl groups. | 2.04 | 1 | 0 | methylbenzene; toluenes; volatile organic compound | cholinergic antagonist; fuel additive; neurotoxin; non-polar solvent |
| valproic acid Valproic Acid: A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of EPILEPSY and BIPOLAR DISORDER. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GAMMA-AMINOBUTYRIC ACID levels in the brain or by altering the properties of VOLTAGE-GATED SODIUM CHANNELS.. valproic acid : A branched-chain saturated fatty acid that comprises of a propyl substituent on a pentanoic acid stem. | 2.73 | 3 | 0 | branched-chain fatty acid; branched-chain saturated fatty acid | anticonvulsant; antimanic drug; EC 3.5.1.98 (histone deacetylase) inhibitor; GABA agent; neuroprotective agent; psychotropic drug; teratogenic agent |
| pifithrin pifithrin: a tetrahydrobenzothiazol; inhibitor of P53 that protects mice from the side effects of cancer therapy; structure in first source | 2.04 | 1 | 0 | aromatic ketone | |
| vorinostat Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME.. vorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL). | 2.73 | 3 | 0 | dicarboxylic acid diamide; hydroxamic acid | antineoplastic agent; apoptosis inducer; EC 3.5.1.98 (histone deacetylase) inhibitor |
| azacitidine Azacitidine: A pyrimidine analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent.. 5-azacytidine : An N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via an N-glycosidic linkage. An antineoplastic agent, it is used in the treatment of myeloid leukaemia. | 2.15 | 1 | 0 | N-glycosyl-1,3,5-triazine; nucleoside analogue | antineoplastic agent |
| trichostatin a trichostatin A: chelates zinc ion in the active site of histone deacetylases, resulting in preventing histone unpacking so DNA is less available for transcription; do not confuse with TRICHOSANTHIN which is a protein; found in STREPTOMYCES | 4.15 | 3 | 1 | antibiotic antifungal agent; hydroxamic acid; trichostatin | bacterial metabolite; EC 3.5.1.98 (histone deacetylase) inhibitor; geroprotector |
| panobinostat Panobinostat: An indole and hydroxamic acid derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used as an antineoplastic agent in combination with BORTEZOMIB and DEXAMETHASONE for the treatment of MULTIPLE MYELOMA.. panobinostat : A hydroxamic acid obtained by formal condensation of the carboxy group of (2E)-3-[4-({[2-(2-methylindol-3-yl)ethyl]amino}methyl)phenyl]prop-2-enoic acid with the amino group of hydroxylamine. A histone deacetylase inhibitor used (as its lactate salt) in combination with bortezomib and dexamethasone for the treatment of multiple myeloma. | 2.96 | 1 | 0 | cinnamamides; hydroxamic acid; methylindole; secondary amino compound | angiogenesis modulating agent; antineoplastic agent; EC 3.5.1.98 (histone deacetylase) inhibitor |
| givinostat [no description available] | 2.9 | 2 | 0 | carbamate ester | |
| transforming growth factor beta Transforming Growth Factor beta: A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. | 2.13 | 1 | 0 | ||
| pemetrexed pemetrexed disodium : An organic sodium salt that is the disodium salt of N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid. Inhibits thymidylate synthase (TS), 421 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). | 2.6 | 1 | 0 | N-acyl-L-glutamic acid; pyrrolopyrimidine | antimetabolite; antineoplastic agent; EC 1.5.1.3 (dihydrofolate reductase) inhibitor; EC 2.1.1.45 (thymidylate synthase) inhibitor; EC 2.1.2.2 (phosphoribosylglycinamide formyltransferase) inhibitor |
| Condition | Indicated | Relationship Strength | Studies | Trials |
|---|---|---|---|---|
| Anoxia-Ischemia, Brain [description not available] | 0 | 2.41 | 1 | 0 |
| Anoxemia [description not available] | 0 | 2.41 | 1 | 0 |
| Asphyxia Neonatorum Respiratory failure in the newborn. (Dorland, 27th ed) | 0 | 2.41 | 1 | 0 |
| Innate Inflammatory Response [description not available] | 0 | 2.81 | 3 | 0 |
| Hypoxia Sub-optimal OXYGEN levels in the ambient air of living organisms. | 0 | 2.41 | 1 | 0 |
| Inflammation A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. | 0 | 2.81 | 3 | 0 |
| Ischemia A hypoperfusion of the BLOOD through an organ or tissue caused by a PATHOLOGIC CONSTRICTION or obstruction of its BLOOD VESSELS, or an absence of BLOOD CIRCULATION. | 0 | 3.81 | 2 | 0 |
| Hypoxia-Ischemia, Brain A disorder characterized by a reduction of oxygen in the blood combined with reduced blood flow (ISCHEMIA) to the brain from a localized obstruction of a cerebral artery or from systemic hypoperfusion. Prolonged hypoxia-ischemia is associated with ISCHEMIC ATTACK, TRANSIENT; BRAIN INFARCTION; BRAIN EDEMA; COMA; and other conditions. | 0 | 2.41 | 1 | 0 |
| Acute Kidney Failure [description not available] | 0 | 3.52 | 1 | 0 |
| Blood Pressure, High [description not available] | 0 | 3.52 | 1 | 0 |
| Injury, Ischemia-Reperfusion [description not available] | 0 | 3.52 | 1 | 0 |
| Hypertension Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more. | 0 | 3.52 | 1 | 0 |
| Reperfusion Injury Adverse functional, metabolic, or structural changes in tissues that result from the restoration of blood flow to the tissue (REPERFUSION) following ISCHEMIA. | 0 | 3.52 | 1 | 0 |
| Acute Kidney Injury Abrupt reduction in kidney function. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions. | 0 | 3.52 | 1 | 0 |
| Benign Meningeal Neoplasms [description not available] | 0 | 3.33 | 4 | 0 |
| Angioblastic Meningioma [description not available] | 0 | 3.33 | 4 | 0 |
| Meningeal Neoplasms Benign and malignant neoplastic processes that arise from or secondarily involve the meningeal coverings of the brain and spinal cord. | 0 | 3.33 | 4 | 0 |
| Meningioma A relatively common neoplasm of the CENTRAL NERVOUS SYSTEM that arises from arachnoidal cells. The majority are well differentiated vascular tumors which grow slowly and have a low potential to be invasive, although malignant subtypes occur. Meningiomas have a predilection to arise from the parasagittal region, cerebral convexity, sphenoidal ridge, olfactory groove, and SPINAL CANAL. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2056-7) | 0 | 3.33 | 4 | 0 |
| Carcinoma, Non-Small Cell Lung [description not available] | 0 | 2.66 | 2 | 0 |
| Cancer of Lung [description not available] | 0 | 2.66 | 2 | 0 |
| Carcinoma, Non-Small-Cell Lung A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy. | 0 | 2.66 | 2 | 0 |
| Lung Neoplasms Tumors or cancer of the LUNG. | 0 | 2.66 | 2 | 0 |
| Malignant Melanoma [description not available] | 0 | 2.6 | 1 | 0 |
| Melanoma A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445) | 0 | 2.6 | 1 | 0 |
| Left Ventricular Dysfunction [description not available] | 0 | 2.17 | 1 | 0 |
| Cardiac Failure [description not available] | 0 | 2.17 | 1 | 0 |
| Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION. | 0 | 2.17 | 1 | 0 |
| Ventricular Dysfunction, Left A condition in which the LEFT VENTRICLE of the heart was functionally impaired. This condition usually leads to HEART FAILURE; MYOCARDIAL INFARCTION; and other cardiovascular complications. Diagnosis is made by measuring the diminished ejection fraction and a depressed level of motility of the left ventricular wall. | 0 | 2.17 | 1 | 0 |
| Rheumatoid Arthritis [description not available] | 0 | 2.52 | 2 | 0 |
| Arthritis, Rheumatoid A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated. | 0 | 2.52 | 2 | 0 |
| Autoimmune Diabetes [description not available] | 0 | 2.52 | 2 | 0 |
| Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. | 0 | 2.52 | 2 | 0 |
| Diabetes Mellitus, Type 1 A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence. | 0 | 2.52 | 2 | 0 |
| Colitis Inflammation of the COLON section of the large intestine (INTESTINE, LARGE), usually with symptoms such as DIARRHEA (often with blood and mucus), ABDOMINAL PAIN, and FEVER. | 0 | 2.47 | 2 | 0 |
| Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms. | 0 | 2.1 | 1 | 0 |
| Libman-Sacks Disease [description not available] | 0 | 2.1 | 1 | 0 |
| Lupus Erythematosus, Systemic A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys, and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. | 0 | 2.1 | 1 | 0 |
| Proteinuria The presence of proteins in the urine, an indicator of KIDNEY DISEASES. | 0 | 2.1 | 1 | 0 |
| B-Cell Lymphoma [description not available] | 0 | 2.1 | 1 | 0 |
| Lymphoma, B-Cell A group of heterogeneous lymphoid tumors generally expressing one or more B-cell antigens or representing malignant transformations of B-lymphocytes. | 0 | 2.1 | 1 | 0 |
| Candidiasis, Chronic Mucocutaneous A clinical syndrome characterized by development, usually in infancy or childhood, of a chronic, often widespread candidiasis of skin, nails, and mucous membranes. It may be secondary to one of the immunodeficiency syndromes, inherited as an autosomal recessive trait, or associated with defects in cell-mediated immunity, endocrine disorders, dental stomatitis, or malignancy. | 0 | 3.5 | 1 | 1 |
| Cirrhosis [description not available] | 0 | 2.13 | 1 | 0 |
| Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. | 0 | 2.13 | 1 | 0 |
| Graft-Versus-Host Disease [description not available] | 0 | 2.04 | 1 | 0 |
| Graft vs Host Disease The clinical entity characterized by anorexia, diarrhea, loss of hair, leukopenia, thrombocytopenia, growth retardation, and eventual death brought about by the GRAFT VS HOST REACTION. | 0 | 2.04 | 1 | 0 |
| Kahler Disease [description not available] | 0 | 5.26 | 4 | 1 |
| Multiple Myeloma A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY. | 0 | 5.26 | 4 | 1 |
| Acute Brain Injuries [description not available] | 0 | 2.05 | 1 | 0 |
| Brain Injuries Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits. | 0 | 2.05 | 1 | 0 |
| Agnogenic Myeloid Metaplasia [description not available] | 0 | 3.44 | 1 | 1 |
| Erythremia [description not available] | 0 | 3.84 | 2 | 1 |
| Hemorrhagic Thrombocythemia [description not available] | 0 | 3.84 | 2 | 1 |
| Myeloproliferative Disorders Conditions which cause proliferation of hemopoietically active tissue or of tissue which has embryonic hemopoietic potential. They all involve dysregulation of multipotent MYELOID PROGENITOR CELLS, most often caused by a mutation in the JAK2 PROTEIN TYROSINE KINASE. | 0 | 3.44 | 1 | 1 |
| Polycythemia Vera A myeloproliferative disorder of unknown etiology, characterized by abnormal proliferation of all hematopoietic bone marrow elements and an absolute increase in red cell mass and total blood volume, associated frequently with splenomegaly, leukocytosis, and thrombocythemia. Hematopoiesis is also reactive in extramedullary sites (liver and spleen). In time myelofibrosis occurs. | 0 | 3.84 | 2 | 1 |
| Thrombocythemia, Essential A clinical syndrome characterized by repeated spontaneous hemorrhages and a remarkable increase in the number of circulating platelets. | 0 | 3.84 | 2 | 1 |
| Primary Myelofibrosis A de novo myeloproliferation arising from an abnormal stem cell. It is characterized by the replacement of bone marrow by fibrous tissue, a process that is mediated by CYTOKINES arising from the abnormal clone. | 0 | 3.44 | 1 | 1 |
| Arthritis, Juvenile Chronic [description not available] | 0 | 4.37 | 1 | 1 |
| Arthritis, Juvenile Arthritis in children, with onset before 16 years of age. The terms juvenile rheumatoid arthritis (JRA) and juvenile idiopathic arthritis (JIA) refer to classification systems for chronic arthritis in children. Only one subtype of juvenile arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent. | 0 | 4.37 | 1 | 1 |
| Hepatocellular Carcinoma [description not available] | 0 | 2.72 | 3 | 0 |
| Cancer of Liver [description not available] | 0 | 2.72 | 3 | 0 |
| Carcinoma, Hepatocellular A primary malignant neoplasm of epithelial liver cells. It ranges from a well-differentiated tumor with EPITHELIAL CELLS indistinguishable from normal HEPATOCYTES to a poorly differentiated neoplasm. The cells may be uniform or markedly pleomorphic, or form GIANT CELLS. Several classification schemes have been suggested. | 0 | 2.72 | 3 | 0 |
| Liver Neoplasms Tumors or cancer of the LIVER. | 0 | 2.72 | 3 | 0 |
| Acute Myelogenous Leukemia [description not available] | 0 | 2.44 | 2 | 0 |
| Leukemia, Myeloid, Acute Clonal expansion of myeloid blasts in bone marrow, blood, and other tissue. Myeloid leukemias develop from changes in cells that normally produce NEUTROPHILS; BASOPHILS; EOSINOPHILS; and MONOCYTES. | 0 | 2.44 | 2 | 0 |
| Leucocythaemia [description not available] | 0 | 2.04 | 1 | 0 |
| Leukemia A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006) | 0 | 2.04 | 1 | 0 |
| Cancer of Colon [description not available] | 0 | 2.04 | 1 | 0 |
| Colonic Neoplasms Tumors or cancer of the COLON. | 0 | 2.04 | 1 | 0 |