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CompletedNCT03238235Updated Nov 18, 2024Results posted

Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Becker Muscular Dystrophy

A Phase 2 interventional study of Givinostat and Placebo in Becker Muscular Dystrophy, sponsored by Italfarmaco. Completed at 2 sites in 2 countries. Open to male participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-11-18.

Sponsored by Italfarmaco · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
51
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
Male
01

Study summary

Objectives:

Primary objective: to establish the histological effects of Givinostat versus placebo administered over 12 months.

Secondary Objectives:

  • To establish the macroscopic muscle effects of Givinostat versus placebo administered over 12 months assessed by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS).
  • To determine the other histological effects of Givinostat versus placebo administered over 12 months.
  • To establish the efficacy of Givinostat versus placebo administered chronically over 12 months in slowing disease progression.
  • To assess the safety and tolerability of Givinostat versus placebo administered chronically.
  • To evaluate the pharmacokinetic (PK) profile of Givinostat administered chronically in the target population.
  • To evaluate the impact of Givinostat versus placebo administered chronically on quality of life and activities of daily living.
Read the detailed description

This was a phase 2, randomised, double-blind, placebo-controlled study. Eligible patients were randomized in a 2:1 ratio to receive Givinostat or placebo for 12 months. Randomization was stratified by concomitant steroid use at baseline (yes or no). The study comprised twelve (12) visits: screening (V1, V2), randomization (V3), treatment (V4-V10), end of study (V11) and follow-up (V12). Visits during treatment took place every 12 weeks, except for the first 2 months, when they occurred every 2 weeks to allow closer monitoring of safety.

Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients and corresponded to the reduced dose of the original protocol (i.e., 26.7-46.7 mg b.i.d according to body weight, i.e., low dose).

51 patients were to be enrolled to provide a sample size of 48 patients with evaluable baseline biopsies. Seventy patients provided written informed consent, 51 (72.86%) completed screening successfully and were randomized; 34 patients (66.67%) to the Givinostat group and 17 (33.33%) to the placebo group.

02

Conditions studied

  • Becker Muscular Dystrophy

Keywords

  • Givinostat
  • Becker Dystrophy
03

In context

Muscular Dystrophies

548 studies on the registry are indexed under Muscular Dystrophies; 89 are open to participants now.

This study's enrollment of 51 is above the median of 24 across 344 interventional studies indexed under Muscular Dystrophies.

Browse Muscular Dystrophies studies →

Lead sponsor

Italfarmaco is the lead sponsor of 35 studies on the registry; 5 are open to participants now.

Of its 6 completed or terminated interventional studies of FDA-regulated products, 6 (100%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
Male
Accepts healthy volunteers
No

Inclusion criteria

  1. Ambulant patients with BMD diagnosis confirmed by genetic testing.
  2. Able and willing to give informed consent in writing.
  3. Able to perform 6MWT at screening with a minimum distance of 200 m and maximum distance of 450 m.
  4. If in treatment with systemic corticosteroids and/or angiotensin-converting-enzyme (ACE) inhibitor , and/or β or α adrenergic receptor blocker, no significant change in dosage or dosing regimen (excluding changes related to body weight) was to be presented for a minimum of 6 months prior to start of study treatment.

  5. Patients had to be willing to use adequate contraception from randomization until 3 months after the last dose of study treatment, and included the following:

    • True abstinence when in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods) and withdrawal were not acceptable methods of contraception.
    • Condom with spermicide, with the female partner using an acceptable method of contraception, such as an oral, transdermal, injectable or implanted steroid-based contraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as a cervical cap with spermicide jelly.

Exclusion criteria

Exclusion Criteria:

  1. Exposure to another investigational drug within 3 months prior to the start of study treatment.
  2. Use of any pharmacological treatment, other than corticosteroids, that could have affected muscle strength or function within 3 months prior to the start of study treatment (e.g., growth hormone). vitamin D, calcium, and other supplements were allowed.
  3. Surgery that could have affected muscle strength or function within 3 months before study entry or planned surgery at any time during the study.
  4. Presence of other clinically significant disease that in the Investigator's opinion could have adversely affected the safety of the patient or could have impaired the assessment of study results.
  5. A diagnosis of other uncontrolled neurological diseases or presence of relevant somatic disorders not related to BMD that could have interfered with the ability to perform the muscle function tests and/or to comply with the study protocol procedures.
  6. Platelet count, white blood cell (WBC) count and hemoglobin at screening less than the lower limit of normal (LLN). If laboratory screening results were \< LLN, platelet count, WBC count and hemoglobin were to be repeated once, and if again \< LLN became exclusionary.
  7. Symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction \< 50% at screening or with heart transplant.
  8. Current liver disease or impairment, including but not limited to elevated total bilirubin (>. 1.5 x upper limit of normal [ULN]), unless secondary to Gilbert's disease or pattern consistent with Gilbert's disease.
  9. Inadequate renal function defined by serum cystatin C > 2 x ULN. If the value was > 2 x ULN, serum Cystatin C was to be repeated once, and if again > 2 x ULN became exclusionary.
  10. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening.
  11. Baseline corrected QT interval using Fridericia's correction (QTcF) > 450 msec (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome).
  12. Current psychiatric illness/social situations rendering the patient unable to understand or comply with the muscle function tests and/or with the study protocol procedures.
  13. Hypersensitivity to the components of the study medication.
  14. Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance.
  15. Contraindications for muscle biopsy.
  16. Contraindications forMRI/MRS (e.g., claustrophobia, metal implants or seizure disorders).
  17. Hypertriglyceridemia (˃ 1.5 x ULN). At screening, patients with hypertriglyceridemia could be enrolled if on stable treatment and with controlled levels of triglycerides (i.e., within normal range) for at least six months.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
51 participants (actual)

Study arms

  • Experimental
    Givinostat

    Givinostat oral suspension (10 mg/mL) twice daily in a fed state

    Drug: Givinostat

  • Placebo comparator
    Placebo

    Placebo oral suspension (10 mg/mL) twice daily in a fed state

    Drug: Placebo

Interventions

  • DrugGivinostat

    suspension of Givinostat (10 mg/mL)

    Also known as: ITF2357

  • DrugPlacebo

    suspension manufactured to mimic Givinostat

    Also known as: Placebo Comparator: placebo

06

What researchers measure

Primary outcomes

  1. Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies

    The primary efficacy assessment was the mean total fibrosis (%) on log scale assessed through histological examination of bicep muscle biopsies at two timepoints (At baseline and at Visit 11). More particularly, patients underwent two biopsies of muscle from the brachial biceps: the first before starting the study treatment (Visit 2, baseline), and the second at the end of treatment (Visit 11). For each patient, the percentage of total fibrosis was calculated as log of the least square mean of the available fields at each evaluation.

    Time frame: after 12 months of treatment (at Visit 11)

Secondary outcomes

  1. Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus

    Evaluation was performed comparing Magnetic Resonance Spectroscopy (MRS) before and after 12 months of treatment with Givinostat versus placebo. Please note that Statistics data are expressed as log least square mean (IC 95%) for the vastus lateralis and as least square mean (IC 95%) back-transformed on the original scale for the soleus.

    Time frame: after 12 months of treatment (at Visit 11)

  2. Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles

    Evaluation was performed comparing Dixon Magnetic Resonance Imaging (MRI) before and after 12 months of treatment with Givinostat versus placebo. The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle. Please note that statistics data are expressed as: Least Square Means (95% CI) for whole thigh, quadriceps, hamstrings, triceps surae and pelvis girdle; while as Log Least Square Means (95% CI) for medial thigh.

    Time frame: after 12 months of treatment (at Visit 11)

  3. Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles

    Evaluation was performed comparing Dixon MRI findings before and after 12 months of treatment with Givinostat versus placebo. Dixon technique has advantages in multiple applications for evaluation of musculoskeletal system diseases. It allows more robust fat suppression than do other sequences and can be used in combination with multiple different sequences (GRE and SE) and using different weightings (T1, T2, or proton density). The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle (data showed as least square mean)

    Time frame: after 12 months of treatment (Visit 11)

  4. Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI)

    A summary of mean change in the contractile area of lower limb muscles comparing MRI findings before and after 12 months of treatment in the ITT set is reported. The lower limb muscles considered are the same as the outcome 3. Please note that statistic data are expressed as Least Square Means (95% CI) except for Hamstrings which is expressed as Log Least Square Means.

    Time frame: after 12 months of treatment

  5. Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA

    A summary of the mean change in cross-sectional area (CSA) by type after 12 months of treatment in the ITT set is reported. Please note that descriptive statistic data are expressed as Log Least Square Means (95% CI) for CSA type I fibers, and as Least Square Means (95% CI) for CSA type II fibers and Total CSA.

    Time frame: After 12 months of treatment (Visit 11)

  6. Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%).

    Evaluation of histologic parameters such as Fiber with nuclear centralizations (%), Total number of fibers (%), and Regenerative fibers (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean for Regenerative fibers (%), and total number of fibers (Slides I), while are expressed as least square mean for Fibers with nuclear centralizations (%) and total number of fibers (Slides II and III).

    Time frame: after 12 months of treatment (Visit 11)

  7. Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%)

    Evaluation of histology parameters such as Muscle Fibers Area \[MFA\](%), were performed comparing muscle biopsies after 12 months of treatment with Givinostat. MFA fraction was determined from biopsies using the mean of available fields. Please note that descriptive statistic data are expressed as least square mean.

    Time frame: after 12 months of treatment (Visit 11)

  8. Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%)

    Evaluation of histology parameters such as Adipose tissue (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean.

    Time frame: after 12 months of treatment (Visit 11)

  9. Mean Change From Baseline to Visit 11 in Other Histological Structures

    Evaluation of other histological structures like necrotic cells, vessels and any other nonconnective tissue present in the microscopic field were performed comparing muscle biopsies after 12 months of treatment with Givinostat. The value is shown as % compared to the arithmetic mean of the two positive control (i.e., healthy subjects) bands present in the same western blot. Please note that descriptive statistic data are expressed as log least square mean.

    Time frame: after 12 months of treatment (Visit 11)

  10. Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean)

    Evaluation were performed using the MFM32 scale, that is a tool designed for neuromuscular diseases and is applicable to all degrees of disease severity. It was validated in terms of reproducibility, construct validity, and concurrent validity. It consists of 32 items (tasks) classified into three dimensions: D1, standing and transfers; D2, axial and proximal motor capacity; and D3, distal motor capacity. Each item is scored on a four-point Likert scale. The generic grading is measured as follows: 0, cannot initiate the task or cannot maintain the starting position; 1, partially performs the task; 2, performs the task with compensatory movements (position maintained for an insufficient period of time, slowness, uncontrolled movements, etc.); and 3, performs the task fully and 'normally', the movement being controlled, mastered, directed, and performed at a constant speed. The overall total score ranging from 0 (severe functional impairment) to 100 (no functional impairment).

    Time frame: after 12 months of treatment (Visit 11)

  11. Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters

    TFT is assessed through 3 different parameters one of which is time to walk/run 10 m. The test was performed with or without orthoses as the patient preferred. He/she was not asked to run, but rather to arrive at the finish line as soon as possible leaving him the choice on how to do so. The assessor walked alongside the patient for safety but couldn't help her/him in any way. The walk/run speed was calculated as 10/time in seconds taken to run/walk 10 m. The test was graded as follows: 1. Unable to walk independently. 2. Unable to walk independently but can walk with full leg calipers (KAFOs) or with support of a person. 3. Highly adapted wide-based lordotic gait. Can't increase walking speed. 4. Moderately adapted gait. Can pick up speed but can't run. 5. Able to pick up speed but runs with a double stance phase, i.e., cannot achieve both feet off the ground. 6. Runs and gets both feet off the ground (with no double stance phase). The higher the grade, the better the outcome.

    Time frame: after 12 months of treatment (Visit 11)

  12. Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps

    TFT is assessed through 3 parameters, one of which is "time to climb 4 standard steps". The patient was asked to stand at the bottom of the stairs with his arms by his sides. At the "go" signal, he/she had to walk up the stairs as quickly and safely as possible (using handrails if needed) until reaching an erect position on the top stair. The stair climb speed was calculated as 4/time in seconds taken to climb the 4 standard stairs. Grading of the 4-step ascent was:1. Unable to climb 4 stairs.2. Climbs 4 stairs "marking time" (climbs one foot at a time with both feet on a step before moving to next step), using both arms on one or both handrails.3. Climbs 4 stairs "marking time" (idem as up), using one arm on one handrail.4. Climbs 4 stairs "marking time" (idem as up), not needing handrail.5. Climbs 4 stairs alternating feet, needs handrail for support.6. Climbs 4 stairs alternating feet, not needing handrail support.The higher the grade, the better the outcome.

    Time frame: after 12 months of treatment (Visit 11)

  13. Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor

    Time function test (TFT) is assessed through 3 different parameters, one of which was "time to rise from the floor". The patient started the test lying on his back with arms at his sides and was asked to get up as quickly as possible. The rise from floor velocity was calculated as 1/time in seconds taken to stand up. Grading was as follows: 1. Unable to stand, even with use of a chair. 2. Assisted Gowers' sign - requires furniture to assist in rising to full upright posture. 3. Full Gowers' sign - rolls over, stands up with both hands "climbing up" the legs to achieve full upright posture. 4. Half Gowers' sign - rolls over, stands up with one hand support on leg. 5. Rolls to the side and/or stands up with one hand or both hands on the floor to start to rise up but does not touch legs. 6. Stands up without rolling over or using hands. The higher the grade, the better the outcome.

    Time frame: after 12 months of treatment (Visit 11)

  14. Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean)

    The 6-minute walk/run test (6MWT) assessed the distance walked in 6 minutes. The 6MWT was performed indoors on a flat, smooth path, at least 30 m long and 3 m wide, with a cone at each end around which the patient had to walk. Six progressively numbered markers were used to mark the distance travelled at each minute. Five progressively lettered markers were used to indicate any falls. Two staff members were present during the test; the physiotherapist, to give the patient instructions, and a staff member who followed the patient giving encouragements. The patient was instructed to go from cone to cone as fast as he could but without running, and that he could stop to rest whenever he/she wanted. The time walked, distance walked after each minute, time of each fall and distance walked before each fall were registered. A summary of the 6-minute maximum distance walked/run after 12 months of treatment is reported in minutes.

    Time frame: after 12 months of treatment (Visit 11)

  15. Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment.

    Percentage of patients with \< 10% worsening in 6-Minute Walking Test after 12 months of treatment with Givinostat comparing to placebo patients.

    Time frame: after 12 months of treatment (Visit 11)

  16. Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12)

    Percentage of patients losing the ability to ambulate from baseline to the end of study (Visit 11 or Month 12)

    Time frame: from baseline to the end of month 12

  17. Percentage of Patients Who Fell During the 6MWT

    A summary of the number of patients who fell and the number of falls occurring during the 6MWT is shown.

    Time frame: after 12 months of treatment (Visit 11)

  18. Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion

    Evaluation was performed by mean left and right knee extension, mean left and right elbow flexion using the Hand Held Myometry (HHM). Using it, the muscle strength of the knee extensor and elbow flexor were measured via standardized procedures; 3 measurements were recorded from each muscle group on each side. The mean of the 3 measurements was calculated. Knee Extension: the pt was sitting, pelvis and knee at a 90° angle. His/her feet were above the ground with the femur in neutral rotation. He/she could hold on to the edge of the bed/chair and, in case, additional stabilization was provided at the distal third of the thigh, just above the knee. The HHM was placed on the anterior surface of the lower third of the tibia, proximal to the ankle joint. Elbow flexion: pt lying on his back, arm by his side, elbow flexed at a 90° angle, forearm in supine position. The MMH was placed between the middle and distal third of the forearm, proximal to the radial styloid process.

    Time frame: after 12 months of treatment (Visit 11)

  19. Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36])

    A summary of QoL (SF-36, Single items Short Form survey) in the ITT set is shown. QoL (SF-36) is assessed considering: * Physical Functioning (PF) * Role-Physical (RP) * Bodily Pain (BP) * General Health (GH) * Vitality (VT) * Social Functioning (SF) * Role-Emotional (RE) * Mental Health (MH) * Physical Component Summary (PCS) * Mental Component Summary (MCS) The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score, the greater the disability. The SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and are widely utilized by managed care organizations for routine monitoring and assessment of care outcomes in adult patients.

    Time frame: after 12 months of treatment (Visit 11)

  20. Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS).

    Treatment-emergent adverse events (TEAEs) are defined as those events with an onset date after study treatment initiation. An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. A serious AE is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.

    Time frame: Throughout the study, till week 52 +/-7 days

  21. Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log)

    Evaluation was performed comparing Dixon Magnetic Resonance Imaging (MRI) before and after 12 months of treatment with Givinostat versus placebo. The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle. Please note that statistics data are expressed as: Least Square Means (95% CI) for whole thigh, quadriceps, hamstrings, triceps surae and pelvis girdle; while as Log Least Square Means (95% CI) for medial thigh.

    Time frame: after 12 months of treatment (at Visit 11)

  22. Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log)

    A summary of mean change in the contractile area of lower limb muscles comparing MRI findings before and after 12 months of treatment in the ITT set is reported. The lower limb muscles considered are the same as the outcome 3. Please note that statistic data are expressed as Least Square Means (95% CI) except for Hamstrings which is expressed as Log Least Square Means.

    Time frame: after 12 months of treatment

  23. Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log)

    A summary of the mean change in cross-sectional area (CSA) by type after 12 months of treatment in the ITT set is reported. Please note that descriptive statistic data are expressed as Log Least Square Means (95% CI) for CSA type I fibers, and as Least Square Means (95% CI) for CSA type II fibers and Total CSA.

    Time frame: After 12 months of treatment (Visit 11)

  24. Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). (Log)

    Evaluation of histologic parameters such as Fiber with nuclear centralizations (%), Total number of fibers (%), and Regenerative fibers (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean for Regenerative fibers (%), and total number of fibers (Slides I), while are expressed as least square mean for Fibers with nuclear centralizations (%) and total number of fibers (Slides II and III).

    Time frame: after 12 months of treatment (Visit 11)

07

Results

Posted Nov 18, 2024

Participant flow

Seventy patients provided written informed consent to participate in this study. Fifty-one patients (72.86%) completed screening successfully and were randomized; 34 patients (66.67%) were assigned to the Givinostat group and 17 (33.33%) to the placebo group.

Participant flow — Overall Study
MilestoneGivinostatPlacebo
Started3417
Per protocol2514
Itt3417
Safety3417
Pk3417
Completed3017
Not completed40
Withdrew: Adverse event20
Withdrew: Patients unable to travel to the site due to the covid-19 pandemic20

Outcome measures

PrimaryMean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies

The primary efficacy assessment was the mean total fibrosis (%) on log scale assessed through histological examination of bicep muscle biopsies at two timepoints (At baseline and at Visit 11). More particularly, patients underwent two biopsies of muscle from the brachial biceps: the first before starting the study treatment (Visit 2, baseline), and the second at the end of treatment (Visit 11). For each patient, the percentage of total fibrosis was calculated as log of the least square mean of the available fields at each evaluation.

Time frame:
after 12 months of treatment (at Visit 11)
Reported as:
Least squares mean · log[percentage of total fibrosis]
Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies
log[percentage of total fibrosis]GivinostatPlacebo
Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies-0.017 (-0.367 to 0.333)-0.054 (-0.507 to 0.399)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.8282 (ANCOVA model was performed considering the difference between log of total fibrosis and log baseline values as dependent variable; log baseline value was included as covariate, treatment and concomitant steroid use as independent class variables.) · Log difference of the least square means: 0.04 · 95% CI -0.30 to 0.38
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.6465 · Log difference of least square means: -0.11 · 95% CI -0.59 to 0.37
SecondaryMean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus

Evaluation was performed comparing Magnetic Resonance Spectroscopy (MRS) before and after 12 months of treatment with Givinostat versus placebo. Please note that Statistics data are expressed as log least square mean (IC 95%) for the vastus lateralis and as least square mean (IC 95%) back-transformed on the original scale for the soleus.

Time frame:
after 12 months of treatment (at Visit 11)
Reported as:
Least squares mean · log[percentage of fat in muscle]
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus
log[percentage of fat in muscle]GivinostatPlacebo
Vastus Lateralis0.017 (-0.053 to 0.086)0.064 (-0.019 to 0.147)
Soleus-4.287 (-6.126 to -2.447)-4.021 (-6.404 to -1.637)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.1991 (ANCOVA model was performed considering baseline fat fraction of vastus lateralis or fat fraction in the soleus value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Log difference of least square means: -0.05 · 95% CI -0.12 to 0.03
  • Givinostat vs Placebo · ANCOVA · p = 0.7849 (ANCOVA model was performed considering baseline fat fraction of vastus lateralis or fat fraction in the soleus value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Difference of the least square means: -0.27 · 95% CI -2.22 to 1.69
SecondaryMean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles

Evaluation was performed comparing Dixon Magnetic Resonance Imaging (MRI) before and after 12 months of treatment with Givinostat versus placebo. The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle. Please note that statistics data are expressed as: Least Square Means (95% CI) for whole thigh, quadriceps, hamstrings, triceps surae and pelvis girdle; while as Log Least Square Means (95% CI) for medial thigh.

Time frame:
after 12 months of treatment (at Visit 11)
Reported as:
Least squares mean · percentage of fat in muscle
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles
percentage of fat in muscleGivinostatPlacebo
Whole Thigh0.642 (-0.328 to 1.611)1.996 (0.813 to 3.180)
Quadriceps0.610 (-0.506 to 1.726)2.572 (1.227 to 3.918)
Hamstrings0.877 (-0.627 to 2.381)1.455 (-0.400 to 3.309)
Triceps Surae-0.276 (-2.862 to 2.310)1.317 (-1.686 to 4.319)
Pelvis Girdle0.584 (-0.509 to 1.676)1.471 (0.112 to 2.830)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.0149 (ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: -1.35 · 95% CI -2.43 to -0.28
  • Givinostat vs Placebo · ANCOVA · p = 0.0022 (ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: -1.96 · 95% CI -3.18 to -0.75
  • Givinostat vs Placebo · ANCOVA · p = 0.4869 (ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: -0.58 · 95% CI -2.24 to 1.08
  • Givinostat vs Placebo · ANCOVA · p = 0.0939 (ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: -1.59 · 95% CI -3.47 to 0.29
  • Givinostat vs Placebo · ANCOVA · p = 0.1579 (ANCOVA model was performed considering baseline Fat Fraction of lower limb muscles value as covariate and treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: -0.89 · 95% CI -2.13 to 0.36
SecondaryMean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles

Evaluation was performed comparing Dixon MRI findings before and after 12 months of treatment with Givinostat versus placebo. Dixon technique has advantages in multiple applications for evaluation of musculoskeletal system diseases. It allows more robust fat suppression than do other sequences and can be used in combination with multiple different sequences (GRE and SE) and using different weightings (T1, T2, or proton density). The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle (data showed as least square mean)

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · centimeters^2
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles
centimeters^2GivinostatPlacebo
whole thigh2.782 (0.151 to 5.413)2.377 (-0.820 to 5.575)
quadriceps0.997 (-0.169 to 2.163)1.082 (-0.329 to 2.494)
medial thigh0.669 (-0.468 to 1.807)0.321 (-1.060 to 1.702)
hamstrings1.103 (0.108 to 2.098)0.994 (-0.207 to 2.195)
triceps surae-0.033 (-3.699 to 3.634)0.183 (-3.756 to 4.122)
pelvic girdle1.284 (-0.494 to 3.062)0.965 (-1.187 to 3.116)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.7770 (ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.40 · 95% CI -2.45 to 3.26
  • Givinostat vs Placebo · ANCOVA · p = 0.8926 (ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: -0.09 · 95% CI -1.35 to 1.18
  • Givinostat vs Placebo · ANCOVA · p = 0.5720 (ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.35 · 95% CI -0.88 to 1.58
  • Givinostat vs Placebo · ANCOVA · p = 0.8386 (ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.11 · 95% CI -0.97 to 1.18
  • Givinostat vs Placebo · ANCOVA · p = 0.8591 (ANCOVA model was performed considering baseline CSA as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: -0.22 · 95% CI -2.68 to 2.25
  • Givinostat vs Placebo · ANCOVA · p = 0.7392 · Difference of least square means: 0.32 · 95% CI -1.60 to 2.24
SecondaryMean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI)

A summary of mean change in the contractile area of lower limb muscles comparing MRI findings before and after 12 months of treatment in the ITT set is reported. The lower limb muscles considered are the same as the outcome 3. Please note that statistic data are expressed as Least Square Means (95% CI) except for Hamstrings which is expressed as Log Least Square Means.

Time frame:
after 12 months of treatment
Reported as:
Least squares mean · centimeters^2
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI)
centimeters^2GivinostatPlacebo
Contractile Area in the Whole Thigh0.309 (-0.853 to 1.470)-1.057 (-2.466 to 0.352)
Contractile Area in the Quadriceps0.139 (-0.458 to 0.735)-0.493 (-1.195 to 0.210)
Contractile Area in the Medial Thigh0.162 (-0.342 to 0.665)-0.197 (-0.813 to 0.420)
Contractile Area in the Triceps Surae-0.542 (-3.598 to 2.514)-1.291 (-4.632 to 2.050)
Contractile Area in the Pelvis Girdle0.257 (-0.420 to 0.933)-0.287 (-1.133 to 0.559)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.0375 (ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 1.37 · 95% CI 0.08 to 2.65
  • Givinostat vs Placebo · ANCOVA · p = 0.0528 (ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.63 · 95% CI -0.01 to 1.27
  • Givinostat vs Placebo · ANCOVA · p = 0.2012 (ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: 0.36 · 95% CI -0.20 to 0.91
  • Givinostat vs Placebo · ANCOVA · p = 0.4676 (ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.75 · 95% CI -1.33 to 2.83
  • Givinostat vs Placebo · ANCOVA · p = 0.1549 (ANCOVA model was performed considering baseline Contractile Area value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: 0.54 · 95% CI -0.21 to 1.30
SecondaryMean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA

A summary of the mean change in cross-sectional area (CSA) by type after 12 months of treatment in the ITT set is reported. Please note that descriptive statistic data are expressed as Log Least Square Means (95% CI) for CSA type I fibers, and as Least Square Means (95% CI) for CSA type II fibers and Total CSA.

Time frame:
After 12 months of treatment (Visit 11)
Reported as:
Least squares mean · micrometers^2
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA
micrometers^2GivinostatPlacebo
CSA type II fibers-25.320 (-1438.395 to 1387.755)593.875 (-1177.854 to 2365.604)
Total CSA642.505 (-603.081 to 1888.092)1215.047 (-359.764 to 2789.857)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.3240 (ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: -619.20 · 95% CI -1872.37 to 633.98
  • Givinostat vs Placebo · ANCOVA · p = 0.3070 (ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: -572.54 · 95% CI -1690.73 to 545.64
SecondaryMean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%).

Evaluation of histologic parameters such as Fiber with nuclear centralizations (%), Total number of fibers (%), and Regenerative fibers (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean for Regenerative fibers (%), and total number of fibers (Slides I), while are expressed as least square mean for Fibers with nuclear centralizations (%) and total number of fibers (Slides II and III).

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · percentage of fibers
Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%).
percentage of fibersGivinostatPlacebo
Fibers with nuclear centralizations0.196 (-0.183 to 0.576)0.463 (0.006 to 0.921)
Total number of fibers (Slide II)-24.573 (-59.132 to 9.986)-22.346 (-64.799 to 20.106)
Total number of fibers (Slide III)-9.804 (-22.511 to 2.904)-14.521 (-30.335 to 1.293)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.1055 (ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Log difference of least square means: -0.27 · 95% CI -0.59 to 0.06
  • Givinostat vs Placebo · ANCOVA · p = 0.8846 (ANCOVA model was performed considering baseline biopsy histological parameters (Slide II) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Difference of least square means: -2.23 · 95% CI -33.05 to 28.59
  • Givinostat vs Placebo · ANCOVA · p = 0.4054 (ANCOVA model was performed considering baseline biopsy histological parameters (Slide III) value as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: 4.72 · 95% CI -6.62 to 16.06
SecondaryMean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%)

Evaluation of histology parameters such as Muscle Fibers Area \[MFA\](%), were performed comparing muscle biopsies after 12 months of treatment with Givinostat. MFA fraction was determined from biopsies using the mean of available fields. Please note that descriptive statistic data are expressed as least square mean.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · percentage of muscle fiber area
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%)
percentage of muscle fiber areaGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%)0.422 (-10.200 to 11.043)-2.028 (-16.254 to 12.199)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.6340 (ANCOVA model was performed considering baseline Biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables) · Difference of least square means: 2.45 · 95% CI -7.87 to 12.77
SecondaryMean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%)

Evaluation of histology parameters such as Adipose tissue (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · percentage of total tissue
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%)
percentage of total tissueGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%)0.088 (-0.364 to 0.540)0.226 (-0.346 to 0.798)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.4893 · Log difference of least square means: -0.14 · 95% CI -0.54 to 0.26
SecondaryMean Change From Baseline to Visit 11 in Other Histological Structures

Evaluation of other histological structures like necrotic cells, vessels and any other nonconnective tissue present in the microscopic field were performed comparing muscle biopsies after 12 months of treatment with Givinostat. The value is shown as % compared to the arithmetic mean of the two positive control (i.e., healthy subjects) bands present in the same western blot. Please note that descriptive statistic data are expressed as log least square mean.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · percentage of total tissue
Mean Change From Baseline to Visit 11 in Other Histological Structures
percentage of total tissueGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Other Histological Structures-0.297 (-0.832 to 0.238)0.045 (-0.611 to 0.701)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.1498 (This model was performed considering baseline biopsy histological parameters (Slide I) value as covariate, treatment and concomitant steroid use at baseline as independent class variables.) · Log difference of least square means: -0.34 · 95% CI -0.81 to 0.13
SecondaryMean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean)

Evaluation were performed using the MFM32 scale, that is a tool designed for neuromuscular diseases and is applicable to all degrees of disease severity. It was validated in terms of reproducibility, construct validity, and concurrent validity. It consists of 32 items (tasks) classified into three dimensions: D1, standing and transfers; D2, axial and proximal motor capacity; and D3, distal motor capacity. Each item is scored on a four-point Likert scale. The generic grading is measured as follows: 0, cannot initiate the task or cannot maintain the starting position; 1, partially performs the task; 2, performs the task with compensatory movements (position maintained for an insufficient period of time, slowness, uncontrolled movements, etc.); and 3, performs the task fully and 'normally', the movement being controlled, mastered, directed, and performed at a constant speed. The overall total score ranging from 0 (severe functional impairment) to 100 (no functional impairment).

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · score on a scale
Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean)
score on a scaleGivinostatPlacebo
Standing and transfers (D1)-0.038 (-0.087 to 0.011)-0.100 (-0.165 to -0.035)
Axial and proximal motor function (D2)-0.004 (-0.012 to 0.004)-0.007 (-0.018 to 0.003)
Distal motor function (D3)-0.003 (-0.013 to 0.006)-0.001 (-0.014 to 0.011)
Total Score-0.011 (-0.025 to 0.002)-0.026 (-0.044 to -0.008)
Statistical analysis
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.0602 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Log difference of least square means: 0.06 · 95% CI -0.00 to 0.13
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.5906 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Log difference of least square means: 0.00 · 95% CI -0.01 to 0.01
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.7799 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Log difference of least square means: -0.00 · 95% CI -0.01 to 0.01
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.1116 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Log difference of least square means: 0.01 · 95% CI -0.00 to 0.03
SecondaryMean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters

TFT is assessed through 3 different parameters one of which is time to walk/run 10 m. The test was performed with or without orthoses as the patient preferred. He/she was not asked to run, but rather to arrive at the finish line as soon as possible leaving him the choice on how to do so. The assessor walked alongside the patient for safety but couldn't help her/him in any way. The walk/run speed was calculated as 10/time in seconds taken to run/walk 10 m. The test was graded as follows: 1. Unable to walk independently. 2. Unable to walk independently but can walk with full leg calipers (KAFOs) or with support of a person. 3. Highly adapted wide-based lordotic gait. Can't increase walking speed. 4. Moderately adapted gait. Can pick up speed but can't run. 5. Able to pick up speed but runs with a double stance phase, i.e., cannot achieve both feet off the ground. 6. Runs and gets both feet off the ground (with no double stance phase). The higher the grade, the better the outcome.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · sec
Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters
secGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters0.013 (-0.100 to 0.125)0.078 (-0.072 to 0.228)
Statistical analysis
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.4346 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate) · Log difference of least square means: -0.07 · 95% CI -0.23 to 0.10
SecondaryMean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps

TFT is assessed through 3 parameters, one of which is "time to climb 4 standard steps". The patient was asked to stand at the bottom of the stairs with his arms by his sides. At the "go" signal, he/she had to walk up the stairs as quickly and safely as possible (using handrails if needed) until reaching an erect position on the top stair. The stair climb speed was calculated as 4/time in seconds taken to climb the 4 standard stairs. Grading of the 4-step ascent was:1. Unable to climb 4 stairs.2. Climbs 4 stairs "marking time" (climbs one foot at a time with both feet on a step before moving to next step), using both arms on one or both handrails.3. Climbs 4 stairs "marking time" (idem as up), using one arm on one handrail.4. Climbs 4 stairs "marking time" (idem as up), not needing handrail.5. Climbs 4 stairs alternating feet, needs handrail for support.6. Climbs 4 stairs alternating feet, not needing handrail support.The higher the grade, the better the outcome.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · sec
Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps
secGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps-0.144 (-0.339 to 0.051)-0.123 (-0.396 to 0.149)
Statistical analysis
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.8914 · Log difference of least square means: -0.02 · 95% CI -0.32 to 0.28
SecondaryMean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor

Time function test (TFT) is assessed through 3 different parameters, one of which was "time to rise from the floor". The patient started the test lying on his back with arms at his sides and was asked to get up as quickly as possible. The rise from floor velocity was calculated as 1/time in seconds taken to stand up. Grading was as follows: 1. Unable to stand, even with use of a chair. 2. Assisted Gowers' sign - requires furniture to assist in rising to full upright posture. 3. Full Gowers' sign - rolls over, stands up with both hands "climbing up" the legs to achieve full upright posture. 4. Half Gowers' sign - rolls over, stands up with one hand support on leg. 5. Rolls to the side and/or stands up with one hand or both hands on the floor to start to rise up but does not touch legs. 6. Stands up without rolling over or using hands. The higher the grade, the better the outcome.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · sec
Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor
secGivinostatPlacebo
Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor1.392 (-0.968 to 3.753)0.774 (-3.014 to 4.562)
Statistical analysis
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.7629 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Difference of least square means: 0.62 · 95% CI -3.51 to 4.75
SecondaryChange From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean)

The 6-minute walk/run test (6MWT) assessed the distance walked in 6 minutes. The 6MWT was performed indoors on a flat, smooth path, at least 30 m long and 3 m wide, with a cone at each end around which the patient had to walk. Six progressively numbered markers were used to mark the distance travelled at each minute. Five progressively lettered markers were used to indicate any falls. Two staff members were present during the test; the physiotherapist, to give the patient instructions, and a staff member who followed the patient giving encouragements. The patient was instructed to go from cone to cone as fast as he could but without running, and that he could stop to rest whenever he/she wanted. The time walked, distance walked after each minute, time of each fall and distance walked before each fall were registered. A summary of the 6-minute maximum distance walked/run after 12 months of treatment is reported in minutes.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · log [meters]
Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean)
log [meters]GivinostatPlacebo
Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean)-0.058 (-0.118 to 0.002)-0.046 (-0.128 to 0.036)
Statistical analysis
  • Givinostat vs Placebo · Mixed Models Analysis · p = 0.8106 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate) · Log difference of least square means: -0.01 · 95% CI -0.11 to 0.08
SecondaryPercentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment.

Percentage of patients with \< 10% worsening in 6-Minute Walking Test after 12 months of treatment with Givinostat comparing to placebo patients.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Count of participants · Participants
Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment.
ParticipantsGivinostatPlacebo
Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment.71
Statistical analysis
  • Givinostat vs Placebo · Cochran-Mantel-Haenszel · p = 0.1626 (P-value is obtained from the two-sided Cochran-Mantel-Haenszel chi-squared test, stratified for concomitant steroid use at baseline)
SecondaryCount of Participant Who Lose Ambulation During the Study (From Baseline to Month 12)

Percentage of patients losing the ability to ambulate from baseline to the end of study (Visit 11 or Month 12)

Time frame:
from baseline to the end of month 12
Reported as:
Count of participants · Participants
Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12)
ParticipantsGivinostatPlacebo
Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12)00
SecondaryPercentage of Patients Who Fell During the 6MWT

A summary of the number of patients who fell and the number of falls occurring during the 6MWT is shown.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Count of participants · Participants
Percentage of Patients Who Fell During the 6MWT
ParticipantsGivinostatPlacebo
Percentage of Patients Who Fell During the 6MWT11
SecondaryMean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion

Evaluation was performed by mean left and right knee extension, mean left and right elbow flexion using the Hand Held Myometry (HHM). Using it, the muscle strength of the knee extensor and elbow flexor were measured via standardized procedures; 3 measurements were recorded from each muscle group on each side. The mean of the 3 measurements was calculated. Knee Extension: the pt was sitting, pelvis and knee at a 90° angle. His/her feet were above the ground with the femur in neutral rotation. He/she could hold on to the edge of the bed/chair and, in case, additional stabilization was provided at the distal third of the thigh, just above the knee. The HHM was placed on the anterior surface of the lower third of the tibia, proximal to the ankle joint. Elbow flexion: pt lying on his back, arm by his side, elbow flexed at a 90° angle, forearm in supine position. The MMH was placed between the middle and distal third of the forearm, proximal to the radial styloid process.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · Newton
Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion
NewtonGivinostatPlacebo
Left Knee Extension (N)-1.479 (-10.208 to 7.251)-5.051 (-15.952 to 5.851)
Right Knee Extension (N)0.703 (-5.212 to 6.618)-0.460 (-7.705 to 6.784)
Left Elbow Flexion (N)1.551 (-10.046 to 13.148)-2.373 (-17.487 to 12.742)
Right Elbow Flexion (N)-1.277 (-13.384 to 10.830)-5.381 (-21.270 to 10.508)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.5099 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Difference of least square means: 3.57 · 95% CI -7.27 to 14.41
  • Givinostat vs Placebo · ANCOVA · p = 0.7355 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Difference of least square means: 1.16 · 95% CI -5.73 to 8.06
  • Givinostat vs Placebo · ANCOVA · p = 0.6037 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Difference of least square means: 3.92 · 95% CI -11.22 to 19.06
  • Givinostat vs Placebo · ANCOVA · p = 0.6178 (Least squares mean is obtained from the mixed effects model for repeated measures with treatment, visit, visit by treatment interaction and concomitant steroid use at baseline as fixed effect; baseline value is included as a covariate.) · Difference of least square means: 4.10 · 95% CI -12.35 to 20.55
SecondaryMean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36])

A summary of QoL (SF-36, Single items Short Form survey) in the ITT set is shown. QoL (SF-36) is assessed considering: * Physical Functioning (PF) * Role-Physical (RP) * Bodily Pain (BP) * General Health (GH) * Vitality (VT) * Social Functioning (SF) * Role-Emotional (RE) * Mental Health (MH) * Physical Component Summary (PCS) * Mental Component Summary (MCS) The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score, the greater the disability. The SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and are widely utilized by managed care organizations for routine monitoring and assessment of care outcomes in adult patients.

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Mean · units on a scale
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36])
units on a scaleGivinostatPlacebo
Physical Functioning-1.03 ± 16.274-5.00 ± 11.989
Role-Physical-2.21 ± 19.6970.37 ± 16.006
Bodily Pain5.12 ± 19.3842.12 ± 15.227
General Health0.82 ± 14.5321.47 ± 13.267
Vitality0.55 ± 11.6543.68 ± 12.705
Social Functioning2.94 ± 22.4158.82 ± 20.139
Role-Emotional0.00 ± 20.2054.90 ± 15.607
Mental Health4.12 ± 15.9974.41 ± 13.793
Physical Component Summary-0.17 ± 5.633-1.20 ± 5.535
Mental Component Summary1.41 ± 7.3453.70 ± 7.177
SecondaryNumber of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS).

Treatment-emergent adverse events (TEAEs) are defined as those events with an onset date after study treatment initiation. An AE is an untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. A serious AE is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.

Time frame:
Throughout the study, till week 52 +/-7 days
Reported as:
Count of participants · Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS).
ParticipantsGivinostatPlacebo
Number of patients with any TEAEs309
Number of patients with serious TEAEs00
Number of patients with TEAEs leading to interruption of study treatment111
Number of patients with fatal TEAEs00
Number of patients with mild TEAEs309
Number of patients with moderate TEAEs121
Number of patients with severe TEAEs50
Number of patients with TEAEs related to study treatment294
Number of patients with TEAEs not related to study treatment258
SecondaryMean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log)

Evaluation was performed comparing Dixon Magnetic Resonance Imaging (MRI) before and after 12 months of treatment with Givinostat versus placebo. The lower limb muscles assessed were: whole thigh, quadriceps, medial thigh, hamstrings, triceps surae and pelvic girdle. Please note that statistics data are expressed as: Least Square Means (95% CI) for whole thigh, quadriceps, hamstrings, triceps surae and pelvis girdle; while as Log Least Square Means (95% CI) for medial thigh.

Time frame:
after 12 months of treatment (at Visit 11)
Reported as:
Least squares mean · log[percentage of fat in muscle]
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log)
log[percentage of fat in muscle]GivinostatPlacebo
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log)0.012 (-0.017 to 0.041)0.038 (0.003 to 0.073)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.1165 (ANCOVA model was performed considering baseline fat fraction of lower limb muscles value as covariate and treatment and concomitant steroids use at baseline as independent class variables) · Log difference of least square means: -0.03 · 95% CI -0.06 to 0.01
SecondaryMean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log)

A summary of mean change in the contractile area of lower limb muscles comparing MRI findings before and after 12 months of treatment in the ITT set is reported. The lower limb muscles considered are the same as the outcome 3. Please note that statistic data are expressed as Least Square Means (95% CI) except for Hamstrings which is expressed as Log Least Square Means.

Time frame:
after 12 months of treatment
Reported as:
Least squares mean · centimeters^2
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log)
centimeters^2GivinostatPlacebo
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log)0.025 (-0.042 to 0.092)-0.022 (-0.104 to 0.059)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.1939 (ANCOVA model was performed considering baseline CSA as covariate and treatment and concomitant steroids use at baseline as independent class variables) · Log difference of least square means: 0.05 · 95% CI -0.02 to 0.12
SecondaryMean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log)

A summary of the mean change in cross-sectional area (CSA) by type after 12 months of treatment in the ITT set is reported. Please note that descriptive statistic data are expressed as Log Least Square Means (95% CI) for CSA type I fibers, and as Least Square Means (95% CI) for CSA type II fibers and Total CSA.

Time frame:
After 12 months of treatment (Visit 11)
Reported as:
Least squares mean · log [micrometers^2]
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log)
log [micrometers^2]GivinostatPlacebo
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log)0.255 (-0.069 to 0.579)0.246 (-0.166 to 0.658)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.9493 (ANCOVA model was performed considering baseline biopsy histological parameters (slide III) value as covariate, treatment and concomitant steroids use at baseline as independent class variables) · Log difference of least square means: 0.01 · 95% CI -0.29 to 0.30
SecondaryMean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). (Log)

Evaluation of histologic parameters such as Fiber with nuclear centralizations (%), Total number of fibers (%), and Regenerative fibers (%) were performed comparing muscle biopsies after 12 months of treatment with Givinostat. Please note that descriptive statistic data are expressed as log least square mean for Regenerative fibers (%), and total number of fibers (Slides I), while are expressed as least square mean for Fibers with nuclear centralizations (%) and total number of fibers (Slides II and III).

Time frame:
after 12 months of treatment (Visit 11)
Reported as:
Least squares mean · log[percentage of fibers]
Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). (Log)
log[percentage of fibers]GivinostatPlacebo
Total number of fibers (Slide I)-0.207 (-0.446 to 0.032)-0.257 (-0.552 to 0.037)
Regenerative fibers0.667 (-0.031 to 1.365)1.104 (0.248 to 1.961)
Statistical analysis
  • Givinostat vs Placebo · ANCOVA · p = 0.6265 (ANCOVA model was performed considering baseline biopsy histological parameters (slide I) value as covariate, treatment and concomitant steroids use at baseline as independent class variables) · Log difference of least square means: 0.05 · 95% CI -0.16 to 0.26
  • Givinostat vs Placebo · ANCOVA · p = 0.1562 (ANCOVA model was performed considering baseline biopsy histological parameters (slide II) value as covariate, treatment and concomitant steroids use at baseline as independent class variables) · Log difference of least square means: -0.44 · 95% CI -1.05 to 0.17

Adverse events

Collected over Throughout the study, from screening (visits 1 and 2) to EOS/early withdrawal (V11, at week 48 ± 7 days) till follow-up visit (visit 12, at week 52 ± 7 days). This means the AEs were monitored from screening to day 364 ± 7.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Givinostat0/34 (0%)0/34 (0%)30/34 (88.2%)
Placebo0/17 (0%)0/17 (0%)9/17 (52.9%)
Most frequent other events
Showing 10 of 74
Most frequent other events
EventGivinostatPlacebo
Platelet count decreasedInvestigations17/340/17
DiarrhoeaGastrointestinal disorders16/340/17
HypertriglyceridaemiaMetabolism and nutrition disorders10/341/17
FallInjury, poisoning and procedural complications2/342/17
Ligament sprainInjury, poisoning and procedural complications4/341/17
Blood triglycerides increasedInvestigations4/341/17
Abdominal pain upperGastrointestinal disorders3/341/17
DyspepsiaGastrointestinal disorders3/341/17
CoughRespiratory, thoracic and mediastinal disorders3/340/17
Sinus tachycardiaCardiac disorders0/341/17

Baseline characteristics

Intent-To-Treat Analysis (ITT) Set: all patients assigned treatment by randomization who received at least one dose of study medication. According to the intent to treat principle, patients were analyzed according to the treatment assigned. Efficacy analyses were performed on the ITT set.

Age, Categorical
Age, Categorical(Participants)GivinostatPlaceboTotal
<=18 years000
Between 18 and 65 years341751
>=65 years000
Age, Continuous
Age, Continuous(years)GivinostatPlaceboTotal
Mean36.5 ± 11.5639.2 ± 9.8437.4 ± 10.99
Sex: Female, Male
Sex: Female, Male(Participants)GivinostatPlaceboTotal
Female000
Male341751
Race (NIH/OMB)
Race (NIH/OMB)(Participants)GivinostatPlaceboTotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American11718
White33033
More than one race000
Unknown or Not Reported000
Region of Enrollment
Region of Enrollment(participants)GivinostatPlaceboTotal
Netherlands336
Italy311445
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Study locations

2 sites
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS
    Milan, 20122, Italy
  • Leiden University Medical Center LUMC
    Leiden, ZH 2300 RC, Netherlands
09

References and documents

Study documents

  • Study protocol · Jun 20, 2017
  • Statistical analysis plan · Apr 27, 2021

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Nov 18, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT03238235
Lead sponsor
Italfarmaco
Responsible party
Sponsor
First posted
Aug 3, 2017
Start date
Jan 9, 2018
Primary completion
Mar 19, 2021
Completion
Mar 19, 2021
Results posted
Nov 18, 2024
Last update
Nov 18, 2024

Study contacts

Giacomo Comi, MD
principal investigator · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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