Becker Muscular Dystrophy
Conditions
Keywords
Givinostat, Becker Dystrophy
Brief 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.
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.
Interventions
DRUGGivinostat
suspension of Givinostat (10 mg/mL)
DRUGPlacebo
suspension manufactured to mimic Givinostat
Sponsors
Italfarmaco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo was indistinguishable from the active product in color, appearance, smell and taste. Personnel involved in the study (Investigators, nurses, all other site personnel, clinical research associates \[CRA\], medical monitors, project managers, data managers and statisticians) were blinded at all times unless knowledge of the study treatment was necessary for the patient's safety.
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies | after 12 months of treatment (at Visit 11) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | 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. |
| Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | 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) |
| Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | 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. |
| Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA | 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. |
| Mean Change From Baseline to Visit 11 in Percentage for the Following Histology Parameters: Fibers With Nuclear Centralizations (%), Total Number of Fibers (%), Regenerative Fibers (%). | 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). |
| Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%) | 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. |
| Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%) | 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. |
| Mean Change From Baseline to Visit 11 in Other Histological Structures | 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. |
| Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) | 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). |
| Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters | 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. |
| Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps | 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. |
| Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus | 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. |
| Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean) | 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. |
| Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment. | 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. |
| Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12) | 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) |
| Percentage of Patients Who Fell During the 6MWT | 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. |
| Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | 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. |
| Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | 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. |
| Number of Patients Experiencing Any Kind of Severity of TEAEs, Serious and Non Serious) From Baseline Through End of Study (EOS). | Throughout the study, till week 52 +/-7 days | 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. |
| Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log) | 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. |
| Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log) | 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. |
| Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log) | 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. |
| 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) | 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). |
| Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor | 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. |
Countries
Italy, Netherlands
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Givinostat Givinostat oral suspension (10 mg/mL) twice daily in a fed state
givinostat: suspension of givinostat (10 mg/mL) | 34 |
| Placebo Placebo oral suspension (10 mg/mL) twice daily in a fed state
placebo: suspension manufactured to mimic givinostat | 17 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 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
| Characteristic | Total | Givinostat | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants | 34 Participants | 17 Participants |
| Age, Continuous | 37.4 years STANDARD_DEVIATION 10.99 | 36.5 years STANDARD_DEVIATION 11.56 | 39.2 years STANDARD_DEVIATION 9.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 1 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 33 Participants | 33 Participants | 0 Participants |
| Region of Enrollment Italy | 45 participants | 31 participants | 14 participants |
| Region of Enrollment Netherlands | 6 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 51 Participants | 34 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 17 |
| other Total, other adverse events | 30 / 34 | 9 / 17 |
| serious Total, serious adverse events | 0 / 34 | 0 / 17 |
Outcome results
Primary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 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] |
| Placebo | Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies | -0.054 log[percentage of total fibrosis] |
Comparison: total fibrosis at visit 11p-value: 0.828295% CI: [-0.3, 0.38]ANCOVA
Comparison: A Mixed Model was fitted to the data in order to evaluate the difference in total fibrosis between biopsy sitesp-value: 0.646595% CI: [-0.59, 0.37]Mixed Models Analysis
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 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] |
| Placebo | Change From Baseline to Visit 11 in Distance Performed Via 6-minute Walk/Run Test (6MWT, Expressed as Log Least Square Mean) | -0.046 log [meters] |
Comparison: Maximum distance walked after 6 minutes at Visit 11p-value: 0.810695% CI: [-0.11, 0.08]Mixed Models Analysis
Secondary
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
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Givinostat | Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12) | 0 Participants |
| Placebo | Count of Participant Who Lose Ambulation During the Study (From Baseline to Month 12) | 0 Participants |
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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 |
| Givinostat | 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 |
| Placebo | Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA | CSA type II fibers | 593.875 micrometers^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA | Total CSA | 1215.047 micrometers^2 |
Comparison: CSA Type II at Visit 11p-value: 0.32495% CI: [-1872.37, 633.98]ANCOVA
Comparison: Total CSA at Visit 11p-value: 0.30795% CI: [-1690.73, 545.64]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 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] |
| Placebo | Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA (Log) | 0.246 log [micrometers^2] |
Comparison: CSA Type Ip-value: 0.949395% CI: [-0.29, 0.3]ANCOVA
Secondary
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
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Quadriceps | 0.139 centimeters^2 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| 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 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Pelvis Girdle | -0.287 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Whole Thigh | -1.057 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Quadriceps | -0.493 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Medial Thigh | -0.197 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) | Contractile Area in the Triceps Surae | -1.291 centimeters^2 |
Comparison: Whole Thigh at Visit 11p-value: 0.037595% CI: [0.08, 2.65]ANCOVA
Comparison: Quadriceps at Visit 11p-value: 0.052895% CI: [-0.01, 1.27]ANCOVA
Comparison: Medial Thigh at Visit 11p-value: 0.201295% CI: [-0.2, 0.91]ANCOVA
Comparison: Triceps Surae at Visit 11p-value: 0.467695% CI: [-1.33, 2.83]ANCOVA
Comparison: Pelvis Girdle at Visit 11p-value: 0.154995% CI: [-0.21, 1.3]ANCOVA
Secondary
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
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log) | 0.025 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI) (Log) | -0.022 centimeters^2 |
Comparison: Hamstrings at Visit 11p-value: 0.193995% CI: [-0.02, 0.12]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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 |
| Givinostat | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | quadriceps | 0.997 centimeters^2 |
| Givinostat | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | medial thigh | 0.669 centimeters^2 |
| Givinostat | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | hamstrings | 1.103 centimeters^2 |
| Givinostat | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | triceps surae | -0.033 centimeters^2 |
| Givinostat | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | pelvic girdle | 1.284 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | triceps surae | 0.183 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | whole thigh | 2.377 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | hamstrings | 0.994 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | quadriceps | 1.082 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | pelvic girdle | 0.965 centimeters^2 |
| Placebo | Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles | medial thigh | 0.321 centimeters^2 |
Comparison: Whole Thigh at visit 11p-value: 0.77795% CI: [-2.45, 3.26]ANCOVA
Comparison: Quadriceps at Visit 11p-value: 0.892695% CI: [-1.35, 1.18]ANCOVA
Comparison: Medial Thigh at Visit 11p-value: 0.57295% CI: [-0.88, 1.58]ANCOVA
Comparison: Hamstrings at Visit 11p-value: 0.838695% CI: [-0.97, 1.18]ANCOVA
Comparison: Triceps Surae at Visit 11p-value: 0.859195% CI: [-2.68, 2.25]ANCOVA
Comparison: Pelvis Girdle at Visit 11p-value: 0.739295% CI: [-1.6, 2.24]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| 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 |
| Placebo | Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) | Total Score | -0.026 score on a scale |
| Placebo | Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) | Standing and transfers (D1) | -0.100 score on a scale |
| Placebo | Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) | Distal motor function (D3) | -0.001 score on a scale |
| Placebo | Mean Change From Baseline to Visit 11 in Motor Function Measurement (MFM, Expressed as Log Least Square Mean) | Axial and proximal motor function (D2) | -0.007 score on a scale |
Comparison: Standing and transfers (D1) at Visit 11p-value: 0.060295% CI: [0, 0.13]Mixed Models Analysis
Comparison: Axial and proximal motor function (D2) at Visit 11p-value: 0.590695% CI: [-0.01, 0.01]Mixed Models Analysis
Comparison: Distal motor function (D3) at Visit 11p-value: 0.779995% CI: [-0.01, 0.01]Mixed Models Analysis
Comparison: Total Score at Visit 11p-value: 0.111695% CI: [0, 0.03]Mixed Models Analysis
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Left Knee Extension (N) | -1.479 Newton |
| Givinostat | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Right Knee Extension (N) | 0.703 Newton |
| Givinostat | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Left Elbow Flexion (N) | 1.551 Newton |
| Givinostat | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Right Elbow Flexion (N) | -1.277 Newton |
| Placebo | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Right Elbow Flexion (N) | -5.381 Newton |
| Placebo | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Left Knee Extension (N) | -5.051 Newton |
| Placebo | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Left Elbow Flexion (N) | -2.373 Newton |
| Placebo | Mean Change From Baseline to Visit 11 in Muscle Strength Evaluated by Knee Extension, Elbow Flexion | Right Knee Extension (N) | -0.460 Newton |
Comparison: Left Knee Extension (N) at Visit 11p-value: 0.509995% CI: [-7.27, 14.41]ANCOVA
Comparison: Right Knee Extension (N) at Visit 11p-value: 0.735595% CI: [-5.73, 8.06]ANCOVA
Comparison: Left Elbow Flexion (N) at Visit 11p-value: 0.603795% CI: [-11.22, 19.06]ANCOVA
Comparison: Right Elbow Flexion (N) at Visit 11p-value: 0.617895% CI: [-12.35, 20.55]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Other Histological Structures | -0.297 percentage of total tissue |
| Placebo | Mean Change From Baseline to Visit 11 in Other Histological Structures | 0.045 percentage of total tissue |
p-value: 0.149895% CI: [-0.81, 0.13]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%) | 0.422 percentage of muscle fiber area |
| Placebo | Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameter MFA(%) | -2.028 percentage of muscle fiber area |
p-value: 0.63495% CI: [-7.87, 12.77]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%) | 0.088 percentage of total tissue |
| Placebo | Mean Change From Baseline to Visit 11 in Percentage for the Biopsy Histology Parameters Adipose Tissue (%) | 0.226 percentage of total tissue |
p-value: 0.489395% CI: [-0.54, 0.26]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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 (%). | Total number of fibers (Slide III) | -9.804 percentage of fibers |
| 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 |
| 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 (%). | Total number of fibers (Slide II) | -24.573 percentage of fibers |
| Placebo | 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) | -14.521 percentage of fibers |
| Placebo | 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 | 0.463 percentage of fibers |
| Placebo | 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) | -22.346 percentage of fibers |
Comparison: Fibers with nuclear centralizations (%) at Visit 11p-value: 0.105595% CI: [-0.59, 0.06]ANCOVA
Comparison: Total number of fibers at Visit 11 (slide II)p-value: 0.884695% CI: [-33.05, 28.59]ANCOVA
Comparison: Total number of fibers (Slide III)p-value: 0.405495% CI: [-6.62, 16.06]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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] |
| 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) | Regenerative fibers | 0.667 log[percentage of fibers] |
| Placebo | 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) | -0.257 log[percentage of fibers] |
| Placebo | 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 | 1.104 log[percentage of fibers] |
Comparison: Total number of Fibers at Visit 11 (slide I)p-value: 0.626595% CI: [-0.16, 0.26]ANCOVA
Comparison: Regenerative Fibers (%) at Visit 11p-value: 0.156295% CI: [-1.05, 0.17]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | Pelvis Girdle | 1.471 percentage of fat in muscle |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | Whole Thigh | 1.996 percentage of fat in muscle |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | Quadriceps | 2.572 percentage of fat in muscle |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | Hamstrings | 1.455 percentage of fat in muscle |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles | Triceps Surae | 1.317 percentage of fat in muscle |
Comparison: Whole thigh at visit 11p-value: 0.014995% CI: [-2.43, -0.28]ANCOVA
Comparison: Quadriceps at visit 11p-value: 0.002295% CI: [-3.18, -0.75]ANCOVA
Comparison: Hamstrings at visit 11p-value: 0.486995% CI: [-2.24, 1.08]ANCOVA
Comparison: Triceps Surae at Visit 11p-value: 0.093995% CI: [-3.47, 0.29]ANCOVA
Comparison: Pelvis girdle at visit 11p-value: 0.157995% CI: [-2.13, 0.36]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 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] |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles (Log) | 0.038 log[percentage of fat in muscle] |
Comparison: Medial Thigh at visit 11p-value: 0.116595% CI: [-0.06, 0.01]ANCOVA
Secondary
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)
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.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 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] |
| Givinostat | 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] |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus | Vastus Lateralis | 0.064 log[percentage of fat in muscle] |
| Placebo | Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus | Soleus | -4.021 log[percentage of fat in muscle] |
Comparison: Vastus lateralisp-value: 0.199195% CI: [-0.12, 0.03]ANCOVA
Comparison: Soleusp-value: 0.784995% CI: [-2.22, 1.69]ANCOVA
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters | 0.013 sec |
| Placebo | Mean Change From Baseline to Visit 11 in Time Function Test (TFT): Time to Walk/Run 10 Meters | 0.078 sec |
Comparison: Time to Walk/Run 10 meters at Visit 11p-value: 0.434695% CI: [-0.23, 0.1]Mixed Models Analysis
Secondary
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)
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. Please consider the data are showed in Log Least Square Mean
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps | -0.144 sec |
| Placebo | Mean Change From Baseline to Visit 11 in Time Function Test (TFT) Via Time to Climb 4 Standard Steps | -0.123 sec |
Comparison: Time to climb 4 standard steps (sec) at visit 11p-value: 0.891495% CI: [-0.32, 0.28]Mixed Models Analysis
Secondary
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)
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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Givinostat | Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor | 1.392 sec |
| Placebo | Mean Change From Baseline to Visit 11 in Time Function Test Via Time to Rise From Floor | 0.774 sec |
Comparison: Time to rise from floor at Visit 11p-value: 0.762995% CI: [-3.51, 4.75]Mixed Models Analysis
Secondary
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)
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Givinostat | 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 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Bodily Pain | 2.12 units on a scale | Standard Deviation 15.227 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Physical Component Summary | -1.20 units on a scale | Standard Deviation 5.535 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Mental Component Summary | 3.70 units on a scale | Standard Deviation 7.177 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Physical Functioning | -5.00 units on a scale | Standard Deviation 11.989 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Role-Physical | 0.37 units on a scale | Standard Deviation 16.006 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Mental Health | 4.41 units on a scale | Standard Deviation 13.793 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | General Health | 1.47 units on a scale | Standard Deviation 13.267 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Vitality | 3.68 units on a scale | Standard Deviation 12.705 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Social Functioning | 8.82 units on a scale | Standard Deviation 20.139 |
| Placebo | Mean Changes From Baseline to Visit 11 in Quality of Life (QoL, Assessed by the 36-item Short Form Survey [SF36]) | Role-Emotional | 4.90 units on a scale | Standard Deviation 15.607 |
Secondary
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
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 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 |
| 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 moderate TEAEs | 12 Participants |
| 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 fatal TEAEs | 0 Participants |
| 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 severe TEAEs | 5 Participants |
| 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 TEAEs leading to interruption of study treatment | 11 Participants |
| 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 TEAEs related to study treatment | 29 Participants |
| 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 mild TEAEs | 30 Participants |
| 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 TEAEs not related to study treatment | 25 Participants |
| 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 any TEAEs | 30 Participants |
| Placebo | 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 | 8 Participants |
| Placebo | 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 | 9 Participants |
| Placebo | 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 |
| Placebo | 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 | 1 Participants |
| Placebo | 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 |
| Placebo | 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 | 9 Participants |
| Placebo | 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 | 1 Participants |
| Placebo | 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 | 0 Participants |
| Placebo | 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 | 4 Participants |
Secondary
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)
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Givinostat | Percentage of Patients Who Fell During the 6MWT | 1 Participants |
| Placebo | Percentage of Patients Who Fell During the 6MWT | 1 Participants |
Secondary
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)
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. Patients with missing data such that \<10% worsening cannot be determined are included in the analysis as having worsened
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Givinostat | Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment. | 7 Participants |
| Placebo | Percentage of Patients With < 10% Worsening in 6MWT After 12 Months of Treatment. | 1 Participants |
Comparison: \<10% worsening at visit 11p-value: 0.1626Cochran-Mantel-Haenszel