Trial Outcomes & Findings for Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Becker Muscular Dystrophy (NCT NCT03238235)

Last Updated: 2024-11-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

51 participants

Primary outcome timeframe

after 12 months of treatment (at Visit 11)

Results posted on

2024-11-18

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 milestones

Participant milestones
Measure	Givinostat Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo Placebo oral suspension (10 mg/mL) twice daily in a fed state Placebo: suspension manufactured to mimic givinostat
Overall Study STARTED	34	17
Overall Study Per Protocol	25	14
Overall Study ITT	34	17
Overall Study Safety	34	17
Overall Study PK	34	17
Overall Study COMPLETED	30	17
Overall Study NOT COMPLETED	4	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Givinostat Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo Placebo oral suspension (10 mg/mL) twice daily in a fed state Placebo: suspension manufactured to mimic givinostat
Overall Study Adverse Event	2	0
Overall Study patients unable to travel to the site due to the COVID-19 pandemic	2	0

Baseline Characteristics

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

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: after 12 months of treatment (at Visit 11)

Population: 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.

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies	-0.017 log[percentage of total fibrosis] Interval -0.367 to 0.333	-0.054 log[percentage of total fibrosis] Interval -0.507 to 0.399

SECONDARY outcome

Timeframe: after 12 months of treatment (at Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=1 muscle images for timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=1 muscle images for timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus Vastus Lateralis	0.017 log[percentage of fat in muscle] Interval -0.053 to 0.086	0.064 log[percentage of fat in muscle] Interval -0.019 to 0.147
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus Soleus	-4.287 log[percentage of fat in muscle] Interval -6.126 to -2.447	-4.021 log[percentage of fat in muscle] Interval -6.404 to -1.637

SECONDARY outcome

Timeframe: after 12 months of treatment (at Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=5 MRI images for each timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=5 MRI images for each timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles Quadriceps	0.610 percentage of fat in muscle Interval -0.506 to 1.726	2.572 percentage of fat in muscle Interval 1.227 to 3.918
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles Whole Thigh	0.642 percentage of fat in muscle Interval -0.328 to 1.611	1.996 percentage of fat in muscle Interval 0.813 to 3.18
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles Hamstrings	0.877 percentage of fat in muscle Interval -0.627 to 2.381	1.455 percentage of fat in muscle Interval -0.4 to 3.309
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles Triceps Surae	-0.276 percentage of fat in muscle Interval -2.862 to 2.31	1.317 percentage of fat in muscle Interval -1.686 to 4.319
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles Pelvis Girdle	0.584 percentage of fat in muscle Interval -0.509 to 1.676	1.471 percentage of fat in muscle Interval 0.112 to 2.83

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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)

Outcome measures

Outcome measures
Measure	Givinostat n=5 MRI images for each timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=5 MRI images for each timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles whole thigh	2.782 centimeters^2 Interval 0.151 to 5.413	2.377 centimeters^2 Interval -0.82 to 5.575
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles quadriceps	0.997 centimeters^2 Interval -0.169 to 2.163	1.082 centimeters^2 Interval -0.329 to 2.494
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles medial thigh	0.669 centimeters^2 Interval -0.468 to 1.807	0.321 centimeters^2 Interval -1.06 to 1.702
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles hamstrings	1.103 centimeters^2 Interval 0.108 to 2.098	0.994 centimeters^2 Interval -0.207 to 2.195
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles triceps surae	-0.033 centimeters^2 Interval -3.699 to 3.634	0.183 centimeters^2 Interval -3.756 to 4.122
Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles pelvic girdle	1.284 centimeters^2 Interval -0.494 to 3.062	0.965 centimeters^2 Interval -1.187 to 3.116

SECONDARY outcome

Timeframe: after 12 months of treatment

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.

Outcome measures

Outcome measures
Measure	Givinostat n=5 MRI muscle images for each timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=5 MRI muscle images for each timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) Contractile Area in the Whole Thigh	0.309 centimeters^2 Interval -0.853 to 1.47	-1.057 centimeters^2 Interval -2.466 to 0.352
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) Contractile Area in the Quadriceps	0.139 centimeters^2 Interval -0.458 to 0.735	-0.493 centimeters^2 Interval -1.195 to 0.21
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) Contractile Area in the Medial Thigh	0.162 centimeters^2 Interval -0.342 to 0.665	-0.197 centimeters^2 Interval -0.813 to 0.42
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) Contractile Area in the Triceps Surae	-0.542 centimeters^2 Interval -3.598 to 2.514	-1.291 centimeters^2 Interval -4.632 to 2.05
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) Contractile Area in the Pelvis Girdle	0.257 centimeters^2 Interval -0.42 to 0.933	-0.287 centimeters^2 Interval -1.133 to 0.559

SECONDARY outcome

Timeframe: After 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA CSA type II fibers	-25.320 micrometers^2 Interval -1438.395 to 1387.755	593.875 micrometers^2 Interval -1177.854 to 2365.604
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA Total CSA	642.505 micrometers^2 Interval -603.081 to 1888.092	1215.047 micrometers^2 Interval -359.764 to 2789.857

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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).

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). Fibers with nuclear centralizations	0.196 percentage of fibers Interval -0.183 to 0.576	0.463 percentage of fibers Interval 0.006 to 0.921
Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). Total number of fibers (Slide II)	-24.573 percentage of fibers Interval -59.132 to 9.986	-22.346 percentage of fibers Interval -64.799 to 20.106
Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). Total number of fibers (Slide III)	-9.804 percentage of fibers Interval -22.511 to 2.904	-14.521 percentage of fibers Interval -30.335 to 1.293

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%)	0.422 percentage of muscle fiber area Interval -10.2 to 11.043	-2.028 percentage of muscle fiber area Interval -16.254 to 12.199

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%)	0.088 percentage of total tissue Interval -0.364 to 0.54	0.226 percentage of total tissue Interval -0.346 to 0.798

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Other Histological Structures	-0.297 percentage of total tissue Interval -0.832 to 0.238	0.045 percentage of total tissue Interval -0.611 to 0.701

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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).

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) Total Score	-0.011 score on a scale Interval -0.025 to 0.002	-0.026 score on a scale Interval -0.044 to -0.008
Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) Standing and transfers (D1)	-0.038 score on a scale Interval -0.087 to 0.011	-0.100 score on a scale Interval -0.165 to -0.035
Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) Axial and proximal motor function (D2)	-0.004 score on a scale Interval -0.012 to 0.004	-0.007 score on a scale Interval -0.018 to 0.003
Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) Distal motor function (D3)	-0.003 score on a scale Interval -0.013 to 0.006	-0.001 score on a scale Interval -0.014 to 0.011

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters	0.013 sec Interval -0.1 to 0.125	0.078 sec Interval -0.072 to 0.228

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=32 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=15 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps	-0.144 sec Interval -0.339 to 0.051	-0.123 sec Interval -0.396 to 0.149

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=29 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=10 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor	1.392 sec Interval -0.968 to 3.753	0.774 sec Interval -3.014 to 4.562

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean)	-0.058 log [meters] Interval -0.118 to 0.002	-0.046 log [meters] Interval -0.128 to 0.036

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment.	7 Participants	1 Participants

SECONDARY outcome

Timeframe: from baseline to the end of month 12

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

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Percentage of Patients Who Fell During the 6MWT	1 Participants	1 Participants

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=3 # of measurements Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=3 # of measurements Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion Left Knee Extension (N)	-1.479 Newton Interval -10.208 to 7.251	-5.051 Newton Interval -15.952 to 5.851
Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion Left Elbow Flexion (N)	1.551 Newton Interval -10.046 to 13.148	-2.373 Newton Interval -17.487 to 12.742
Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion Right Elbow Flexion (N)	-1.277 Newton Interval -13.384 to 10.83	-5.381 Newton Interval -21.27 to 10.508
Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion Right Knee Extension (N)	0.703 Newton Interval -5.212 to 6.618	-0.460 Newton Interval -7.705 to 6.784

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

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.

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Physical Functioning	-1.03 units on a scale Standard Deviation 16.274	-5.00 units on a scale Standard Deviation 11.989
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Role-Emotional	0.00 units on a scale Standard Deviation 20.205	4.90 units on a scale Standard Deviation 15.607
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Role-Physical	-2.21 units on a scale Standard Deviation 19.697	0.37 units on a scale Standard Deviation 16.006
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Bodily Pain	5.12 units on a scale Standard Deviation 19.384	2.12 units on a scale Standard Deviation 15.227
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) General Health	0.82 units on a scale Standard Deviation 14.532	1.47 units on a scale Standard Deviation 13.267
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Vitality	0.55 units on a scale Standard Deviation 11.654	3.68 units on a scale Standard Deviation 12.705
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Social Functioning	2.94 units on a scale Standard Deviation 22.415	8.82 units on a scale Standard Deviation 20.139
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Mental Health	4.12 units on a scale Standard Deviation 15.997	4.41 units on a scale Standard Deviation 13.793
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Physical Component Summary	-0.17 units on a scale Standard Deviation 5.633	-1.20 units on a scale Standard Deviation 5.535
Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) Mental Component Summary	1.41 units on a scale Standard Deviation 7.345	3.70 units on a scale Standard Deviation 7.177

SECONDARY outcome

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

Population: Safety Set: all patients who received at least one dose of study medication. Patients were analyzed according to the study treatment actually received. The safety set was used for the safety analysis.

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.

Outcome measures

Outcome measures
Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with serious TEAEs	0 Participants	0 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with TEAEs leading to interruption of study treatment	11 Participants	1 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with mild TEAEs	30 Participants	9 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with moderate TEAEs	12 Participants	1 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with severe TEAEs	5 Participants	0 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with TEAEs related to study treatment	29 Participants	4 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with TEAEs not related to study treatment	25 Participants	8 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with any TEAEs	30 Participants	9 Participants
Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). Number of patients with fatal TEAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: after 12 months of treatment (at Visit 11)

Outcome measures

Outcome measures
Measure	Givinostat n=5 MRI images for each timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=5 MRI images for each timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log)	0.012 log[percentage of fat in muscle] Interval -0.017 to 0.041	0.038 log[percentage of fat in muscle] Interval 0.003 to 0.073

SECONDARY outcome

Timeframe: after 12 months of treatment

Outcome measures

Outcome measures
Measure	Givinostat n=5 MRI muscle images for each timepoint Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=5 MRI muscle images for each timepoint Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log)	0.025 centimeters^2 Interval -0.042 to 0.092	-0.022 centimeters^2 Interval -0.104 to 0.059

SECONDARY outcome

Timeframe: After 12 months of treatment (Visit 11)

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log)	0.255 log [micrometers^2] Interval -0.069 to 0.579	0.246 log [micrometers^2] Interval -0.166 to 0.658

SECONDARY outcome

Timeframe: after 12 months of treatment (Visit 11)

Outcome measures

Outcome measures
Measure	Givinostat n=4 # fields for each biopsy sample Givinostat oral suspension (10 mg/mL) twice daily in a fed state Givinostat: suspension of Givinostat (10 mg/mL)	Placebo n=4 # fields for each biopsy sample Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat
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) Total number of fibers (Slide I)	-0.207 log[percentage of fibers] Interval -0.446 to 0.032	-0.257 log[percentage of fibers] Interval -0.552 to 0.037
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) Regenerative fibers	0.667 log[percentage of fibers] Interval -0.031 to 1.365	1.104 log[percentage of fibers] Interval 0.248 to 1.961

Adverse Events

Givinostat

Serious events: 0 serious events

Other events: 30 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Maurizio Caserini, MD

Italfarmaco SpA

Phone: + 39 02 64431

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Givinostat n=34 Participants Givinostat oral suspension (10 mg/mL) twice daily in a fed state givinostat: suspension of givinostat (10 mg/mL)	Placebo n=17 Participants Placebo oral suspension (10 mg/mL) twice daily in a fed state placebo: suspension manufactured to mimic givinostat	Total n=51 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	34 Participants n=5 Participants	17 Participants n=7 Participants	51 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	36.5 years STANDARD_DEVIATION 11.56 • n=5 Participants	39.2 years STANDARD_DEVIATION 9.84 • n=7 Participants	37.4 years STANDARD_DEVIATION 10.99 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	17 Participants n=7 Participants	51 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	17 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) White	33 Participants n=5 Participants	0 Participants n=7 Participants	33 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Netherlands	3 participants n=5 Participants	3 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Italy	31 participants n=5 Participants	14 participants n=7 Participants	45 participants n=5 Participants