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

Italfarmaco51 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Eligibility

Sex: MALEMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

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

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

Secondary Outcomes

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)

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)

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)

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

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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

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)

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)

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)

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

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

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

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

Time frame: after 12 months of treatment

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

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

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)

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

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes