A Phase 1/2 interventional study of Givinostat in Duchenne Muscular Dystrophy (DMD), sponsored by Italfarmaco. Completed at 4 sites in Italy. Open to male participants aged 7 Years to 11 Years. Per ClinicalTrials.gov, last updated 2023-11-07.
Sponsored by Italfarmaco · Phase 1/2, Interventional, and Treatment
The primary objective of Parts 1 and 2 of the study were to establish the histologic effects of givinostat administered chronically at the selected daily dose.
The secondary objectives of Parts 1 and 2 of the study were as follows:
The primary objective of the Extension of the study was to evaluate the safety and tolerability of long-term administration of givinostat administered chronically at the selected daily dose in children with DMD.
The secondary objectives of the Extensions were:
This is a 2-part, phase II study to assess the effects of Givinostat on muscle histologic parameters and on clinical parameters in ambulant children with DMD.
The safety, tolerability, and pharmacokinetics of Givinostat will also be assessed.
Approximately 20 children were to be enrolled in the study as follows: the first 4 children were to be treated at a low dose level of givinostat (25 mg twice daily [BID] in children who weighed 20 kg to 49 kg and 37.5 mg BID in children who weighed ≥ 50 kg).
If none of the stopping criteria were met after 2 weeks of treatment at the low dose, the review team was to determine the escalated dose level (ie, intermediate dose level) to be used for the treatment of an additional 8 children who were to be treated at the intermediate dose. The 4 children previously treated at the low dose level were also switched to the intermediate dose level.
If none of the stopping criteria were met after 2 weeks of treatment at the intermediate dose, the review team was to determine the subsequent escalated dose level to be used for the treatment of an additional 8 children who were to be treated at the high dose. All children treated at the intermediate dose level were to be switched to the high dose level.
Once all 20 children enrolled during Part 1 of the study had been treated for at least 2 weeks, the review team was to determine the recommended dose (RD) to be used in Part 2 based on the safety and tolerability profile observed and on the pharmacokinetic (PK) analyses. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months of the study (Part 2).
At the end of Part 2 of the study, parents were asked to consent and patients to assent to continuing their participation in the Extension to receive the study treatment at least until the final analysis was performed (Part 3-Extensions; after 52 months of treatment). The patients received givinostat at the same ongoing dose, during the last visit planned at 12 months, and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52).
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Exclusion Criteria:
Givinostat will be administered as 2 oral doses daily while the child is in fed state.
Drug: Givinostat
Givinostat, oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 for two weeks, and 25 mg BID and 37.5 mg BID during Part 2 for 12 months. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient's weight during Extensions 2 and 3 (up to 52 months).
Also known as: ITF2357
Change From Baseline to Part 2 in the Value of Muscle Fiber Area (MFA) % Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat.
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.
Time frame: After12 months of treatment
Change From Baseline to End of Study in Cross Sectional Area (CSA)
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.
Time frame: At 12 months
Change From Baseline to End of Study in Fibrosis, Necrosis, Fatty Replacement
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.
Time frame: After 12 months
Change From Baseline to End of Study in Number of Hypercontracted Fibers
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).
Time frame: At 12 months
Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test
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.
Time frame: At 12 months
Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA)
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.
Time frame: At 12 months
Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the Performance of Upper Limb (PUL)
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.
Time frame: At 12 months
Change From Baseline in Muscular Function After After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test
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.
Time frame: At 24, 36, and 52 months
Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA)
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.
Time frame: At 24, 36, and 52 months
Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the Performance of Upper Limb (PUL)
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.
Time frame: At 24, 36, and 52 months
Number of Children Experiencing Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Type and Severity of TEAEs
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.
Time frame: Part 1, Part 2, and Extensions 1, 2, and 3
| Milestone | Givinostat |
|---|---|
| Started | 20 |
| Patients receiving drug in part 1 | 19 |
| Completed | 18 |
| Not completed | 2 |
| Withdrew: Adverse event | 1 |
| Withdrew: Not receiving treatment in part 1 | 1 |
| Milestone | Givinostat |
|---|---|
| Started | 19 |
| Completed | 19 |
| Not completed | 0 |
| Milestone | Givinostat |
|---|---|
| Started | 19 |
| Completed | 18 |
| Not completed | 1 |
| Withdrew: Withdrawal by subject | 1 |
| Milestone | Givinostat |
|---|---|
| Started | 18 |
| Completed | 18 |
| Not completed | 0 |
| Milestone | Givinostat |
|---|---|
| Started | 18 |
| Completed | 18 |
| Not completed | 0 |
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.
| percentage change | Overall |
|---|---|
| Change From Baseline to Part 2 in the Value of Muscle Fiber Area (MFA) % Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat. | 12.76 (6.17 to 21.23) |
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.
| μm2 | Overall |
|---|---|
| Change From Baseline to End of Study in Cross Sectional Area (CSA) | 865.269 ± 555.3543 |
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.
| percentage of total area | Baseline |
|---|---|
| Total fibrosis | -12.640 ± 4.6493 |
| Perimysial fibrosis | -7.585 ± 6.4779 |
| Endomysial fibrosis | -5.056 ± 6.2531 |
| Fatty replacement | -0.302 ± 0.2756 |
| Necrosis | -0.964 ± 0.6260 |
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).
| number of fibers | Overall |
|---|---|
| Change From Baseline to End of Study in Number of Hypercontracted Fibers | -1.204 ± 0.6621 |
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.
| meters | Overall |
|---|---|
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test | -24.6 ± 36.11 |
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.
| score on a scale | Overall |
|---|---|
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA) | -2.8 ± 3.15 |
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.
| score on a scale | Overall |
|---|---|
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the Performance of Upper Limb (PUL) | -0.2 ± 2.69 |
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.
| meters | Overall |
|---|---|
| Extension 1 | -80.0 ± 110.69 |
| Extension 2 | -127.0 ± 110.40 |
| Extension 3 | -287.8 ± 159.47 |
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.
| score on a scale | Overall |
|---|---|
| Extension 1 | -5.2 ± 5.06 |
| Extension 2 | -7.4 ± 5.90 |
| Extension 3 | -15.2 ± 7.83 |
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.
| score on a scale | Overall |
|---|---|
| Extension 1 | -0.2 ± 2.71 |
| Extension 2 | -0.2 ± 2.75 |
| Extension 3 | -4.4 ± 6.09 |
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.
| participants | Overall |
|---|---|
| TEAEs | 20 |
| Any treatment-related TEAE | 20 |
| Any mild TEAE | 20 |
| Any moderate TEAE | 16 |
| Any severe TEAE | 9 |
| Any life-threatening or disabling TEAE | 1 |
| Ant TEAE resulting in death | 0 |
| Any SAE | 8 |
| Any TEAE resulting in study discontinuation | 1 |
Collected over Adverse events (AE) were assessed throughout the study: in Part 1 (screen, weeks 0, 1, 2, 3, 4, 5); Part 2 (months 0, 1, 2, 3, 4.5, 6, 7.5, 9, 10.5,12); Extension 1 (months 14,16,18, 20, 22, 24, FU); Extension 2 (months 26,28, 30,32, 34, 36, FU); Extension 3 (months 40, 44, 48, 52, FU). Extensions 1, 2 and 3 together represent Part 3 of the study.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1 - 25 mg | 0/4 (0%) | 0/4 (0%) | 3/4 (75%) |
| Part 1 - 50 mg | 0/12 (0%) | 1/12 (8.3%) | 12/12 (100%) |
| Part 1 - 37.5 mg | 0/7 (0%) | 0/7 (0%) | 6/7 (85.7%) |
| Part 2 - 37.5 mg | 0/19 (0%) | 1/19 (5.3%) | 19/19 (100%) |
| Part 2 - 25 mg | 0/12 (0%) | 1/12 (8.3%) | 12/12 (100%) |
| Overall (Part 1 + Part 2 + Extensions 1, 2, 3 ) | 0/20 (0%) | 8/20 (40%) | 20/20 (100%) |
| Event | Part 1 - 25 mg | Part 1 - 50 mg | Part 1 - 37.5 mg | Part 2 - 37.5 mg | Part 2 - 25 mg | Overall (Part 1 + Part 2 + Extensions 1, 2, 3 ) |
|---|---|---|---|---|---|---|
| Femural fractureInjury, poisoning and procedural complications | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 2/20 |
| Platelet count decreasedInvestigations | 0/4 | 1/12 | 0/7 | 0/19 | 0/12 | 2/20 |
| Lower limb fractureGeneral disorders | 0/4 | 0/12 | 0/7 | 0/19 | 1/12 | 1/20 |
| RhabdomyolysisMusculoskeletal and connective tissue disorders | 0/4 | 0/12 | 0/7 | 1/19 | 0/12 | 1/20 |
| Cushing's syndromeEndocrine disorders | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 1/20 |
| CataractsEye disorders | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 1/20 |
| Chest painGeneral disorders | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 1/20 |
| HaematuriaRenal and urinary disorders | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 1/20 |
| HypertensionVascular disorders | 0/4 | 0/12 | 0/7 | 0/19 | 0/12 | 1/20 |
| Event | Part 1 - 25 mg | Part 1 - 50 mg | Part 1 - 37.5 mg | Part 2 - 37.5 mg | Part 2 - 25 mg | Overall (Part 1 + Part 2 + Extensions 1, 2, 3 ) |
|---|---|---|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 2/4 | 5/12 | 3/7 | 9/19 | 6/12 | 15/20 |
| Platelet count decreasedInvestigations | 0/4 | 1/12 | 0/7 | 13/19 | 5/12 | 13/20 |
| Abdominal painGastrointestinal disorders | 0/4 | 1/12 | 2/7 | 5/19 | 0/12 | 11/20 |
| CoughRespiratory, thoracic and mediastinal disorders | 0/4 | 0/12 | 0/7 | 2/19 | 0/12 | 10/20 |
| PyrexiaGeneral disorders | 0/4 | 1/12 | 1/7 | 3/19 | 3/12 | 9/20 |
| InfluenzaInfections and infestations | 0/4 | 0/12 | 1/7 | 2/19 | 1/12 | 9/20 |
| VomitingGastrointestinal disorders | 0/4 | 0/12 | 1/7 | 2/19 | 3/12 | 8/20 |
| FallInjury, poisoning and procedural complications | 0/4 | 0/12 | 1/7 | 1/19 | 2/12 | 8/20 |
| Decreased appetiteMetabolism and nutrition disorders | 0/4 | 0/12 | 1/7 | 4/19 | 2/12 | 7/20 |
| White blood cell count decreasedInvestigations | 0/4 | 4/12 | 0/7 | 1/19 | 0/12 | 4/20 |
The ITT population included all children who were enrolled in the Part 1 portion or entered the Part 2 portion of the study. Patients were analyzed according to the dose level to which they were allocated. Twenty patients were included in the ITT population.
| Age, Categorical(Participants) | ITF2357 25 mg BID | ITF2357 50 mg BID | ITF2357 37.5 mg BID | Total |
|---|---|---|---|---|
| <=18 years | 4 | 8 | 8 | 20 |
| Between 18 and 65 years | 0 | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 | 0 |
| Age, Continuous(years) | ITF2357 25 mg BID | ITF2357 50 mg BID | ITF2357 37.5 mg BID | Total |
|---|---|---|---|---|
| Mean | 7.8 ± 0.96 | 8.8 ± 1.16 | 7.9 ± 1.13 | 8.2 ± 1.15 |
| Sex: Female, Male(Participants) | ITF2357 25 mg BID | ITF2357 50 mg BID | ITF2357 37.5 mg BID | Total |
|---|---|---|---|---|
| Female | 0 | 0 | 0 | 0 |
| Male | 4 | 8 | 8 | 20 |
| Region of Enrollment(participants) | ITF2357 25 mg BID | ITF2357 50 mg BID | ITF2357 37.5 mg BID | Total |
|---|---|---|---|---|
| Italy | 4 | 8 | 8 | 20 |
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