Phase 3 Trial of Pamrevlumab or Placebo With Systemic Corticosteroids in Participants With Non-ambulatory Duchenne Muscular Dystrophy (DMD)

Phase 3

Terminated

Conditions: Duchenne Muscular Dystrophy

Interventions: Drug: Placebo
Drug: Pamrevlumab
Drug: Corticosteroids

Registration Number: NCT04371666

Lead Sponsor: FibroGen

Brief Summary: To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with systemic corticosteroids in participants with non-ambulatory Duchenne muscular dystrophy (age 12 years and older).

Detailed Description: This is a global, Phase 3, randomized, double-blind trial of pamrevlumab or placebo in combination with systemic corticosteroids in participants with non-ambulatory Duchenne muscular dystrophy, aged 12 years and older. Approximately 90 male participants will be randomized at a 1:1 ratio to Arm A (pamrevlumab + systemic corticosteroid) or Arm B (placebo+ systemic corticosteroid), respectively.

Participants must be fully informed of the potential benefits of approved products and make an informed decision that they prefer to participate in a clinical trial in which they could be randomized to placebo.

This trial has 3 study periods:

* Screening period: Up to 4 weeks

* Treatment period: 52 weeks

* Safety Follow-up period/End of Study (EOS): A visit 28 days (+/- 3 Days) and a final safety follow-up phone call 60 days (+ 3 Days) after the last dose

In the screening period, participants will be evaluated per the protocol inclusion/exclusion criteria to determine eligibility for participation in this trial.

During the treatment period, each participant will receive pamrevlumab or placebo at 35 mg/kg every 2 weeks for up to 52 weeks.

Participants who complete the 52-week study (either arm) may be eligible for rollover into an open-label extension treatment (OLE) with pamrevlumab + systemic corticosteroids.

Participants who discontinue study treatment for any reason should be encouraged to return to the investigative site to complete final safety and efficacy assessments.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 98

Inclusion Criteria

Males at least 12 years of age, non-ambulatory at screening initiation
Written consent by participant and/or legal guardian as per regional/ country and/or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements
Male participants with partners of childbearing potential must use contraception during the conduct of the study, and for 12 weeks after the last dose of study drug.
Medical history includes diagnosis of DMD and confirmed Duchenne mutation using a validated genetic test
Brooke Score for Arms and Shoulders ≤5
Able to undergo MRI test for the upper arm extremities (Biceps Brachii muscle) and cardiac muscle
Able to perform spirometry
Average (of Screening and Day 0) percent predicted forced vital capacity (FVC) between 45 and 85, inclusive
Left ventricular ejection fraction ≥50% as determined by local cardiac MRI read at screening or within 3 months prior to randomization (Day 0)
If participants have a history of cardiomyopathy, then participant must be on a stable dose of cardiomyopathy/ heart failure medications (for example, angiotensin converting enzyme inhibitors, aldosterone receptors blockers, angiotensin-receptor blockers, and betablockers) for at least 1 month prior to screening. If participants have no diagnosis of cardiomyopathy, then no dose of cardiomyopathy/heart failure medication is required for eligibility.
On a stable dose of systemic corticosteroids for a minimum of 6 months, with no substantial change in dosage for a minimum of 3 months (except for adjustments for changes in body weight) prior to screening. Corticosteroid dosage should be in compliance with the DMD Care Considerations Working Group recommendations (for example, prednisone or prednisolone 0.75 mg/kg per day or deflazacort 0.9 mg/kg per day) or stable dose. A reasonable expectation is that dosage and dosing regimen would not change significantly for the duration of the study.
Agreement to receive annual influenza vaccinations during the course of the study.
Adequate renal function: cystatin C ≤1.4 mg/liter (L)
Adequate hematology and electrolytes parameters:
1. Platelets >100,000/microliter (μL)
2. Hemoglobin >12 grams (g)/deciliter (dL)
3. Absolute neutrophil count >1500/μL
4. Serum calcium (Ca), potassium (K), sodium (Na), magnesium (Mg) and phosphorus (P) levels are within a clinically accepted range for DMD participants.
Adequate hepatic function:
1. No history or evidence of liver disease
2. Gamma glutamyl transferase (GGT) ≤3x upper limit of normal (ULN)
3. Total bilirubin ≤1.5xULN

Exclusion Criteria

Previous exposure to pamrevlumab
BMI ≥40 kg/square meter (m^2) or weight >117 kg
History of:
1. allergic or anaphylactic reaction to human, humanized, chimeric or murine monoclonal antibodies
2. hypersensitivity to study drug or any component of study drug
3. hypersensitivity reaction to Gadolinium-based Contrast Agents (GBCA) required for MRI acquisition
Exposure to any investigational drug (for DMD or not), in the 30 days prior to screening initiation or use of approved DMD therapies (for example, eteplirsen [exondys 51], ataluren, golodirsen [vyondys 53], casimersen [amondys 45]) within 5 half-lives of screening, whichever is longer, with the exception of the systemic corticosteroids, including deflazacort
Severe uncontrolled heart failure (NYHA Classes III-IV), or renal dysfunction, including any of the following:
1. Need for intravenous diuretics or inotropic support within 8 weeks prior to screening
2. Hospitalization for a heart failure exacerbation or arrhythmia within 8 weeks prior to screening
3. Participants with glomerular filtration rate (GFR) of less than 30 mL/minute (min)/1.73 m^2 or with other evidence of acute kidney injury as determined by investigator
Arrhythmia requiring anti-arrhythmic therapy
Requires ≥16 hours continuous ventilation
Hospitalization due to respiratory failure within the 8 weeks prior to screening
Poorly controlled asthma or underlying lung disease such as bronchitis, bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the investigator might impact respiratory function
The Investigator judges that the participant will be unable to fully participate in the study and complete it for any reason, including inability to comply with study procedures and treatment, or any other relevant medical or psychiatric conditions

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matching placebo IV every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks
Pamrevlumab	Corticosteroids	Pamrevlumab 35 milligrams (mg)/kilogram (kg) intravenously (IV) every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks
Pamrevlumab	Pamrevlumab	Pamrevlumab 35 milligrams (mg)/kilogram (kg) intravenously (IV) every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks
Placebo	Corticosteroids	Matching placebo IV every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks

Primary Outcome Measures

Name	Time	Method
Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at Week 52	Baseline, Week 52	The PUL module is an observer-administered performance battery of upper extremity mobility tasks for the shoulder (upper, 6 items, 12 points), elbow (middle, 9 items, 17 points) and wrist/hand (distal, 7 items, 13 points). Higher scores indicate higher level of function. Total score ranges from 0-42 points and is the sum of the scores for the 3 subscales. Analysis was done using a random coefficient model (RCM), which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline ordinal PUL entry score as covariate.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI)	Baseline, Week 52	LVEF% is an important measure of cardiac function. LVEF is a fraction of blood (in percent) pumped out of the left ventricle of the heart (the main pumping chamber). The LVEF% was analyzed using an analysis of covariance (ANCOVA) model with treatment and baseline value.
Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry	Baseline, Week 52	FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Analysis was done using an RCM, which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline value as covariate.
Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry	Baseline, Week 52	The ppPEF is a measure of the maximal or peak flow produced during an exhalation with maximal effort and, as such, is the most effort-dependent measure of lung function. The ppFEV1 was analyzed using an RCM including fixed effects of time, treatment, and treatment-by-time interaction, with baseline as covariate.
Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM)	Baseline, Week 52	The HHM was used to measure distal upper arm strength (grip strength). Data has been presented by dominant and non-dominant hand. Grip Strength was analyzed using a MMRM with fixed effects for treatment, visit (as a factor), treatment-by-visit interaction, and covariates (baseline values).

Trial Locations

Locations (53): Rare Disease Research, LLC
🇺🇸
Atlanta, Georgia, United States
Kennedy Krieger Institute
🇺🇸
Baltimore, Maryland, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
University of Utah Health
🇺🇸
Salt Lake City, Utah, United States
University of California Los Angeles Medical Center
🇺🇸
Los Angeles, California, United States
UC Davis Health
🇺🇸
Sacramento, California, United States
University of Iowa
🇺🇸
Iowa City, Iowa, United States
Spectrum Health Hospitals Helen DeVos Children's Hospital
🇺🇸
Grand Rapids, Michigan, United States
Washington University School of Medicine in Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Carolinas HealthCare System Neurosciences Institute-Neurology - Charlotte
🇺🇸
Charlotte, North Carolina, United States
Shriners Hospital for Children
🇺🇸
Portland, Oregon, United States
Penn State Health Children's Hospital
🇺🇸
Hershey, Pennsylvania, United States
Children's Health Dallas/UTSW
🇺🇸
Dallas, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Murdoch Children's Research Institute
🇦🇺
Parkville, Victoria, Australia
CHU de Nantes - Hotel Dieu
🇫🇷
Nantes, France
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
🇨🇳
Beijing, China
West China Second University Hospital, Sichuan University
🇨🇳
Chengdu, Sichuan, China
Hopital Hautepierre
🇫🇷
Strasbourg cedex, France
Ospedale Pediatrico Bambino Gesù - Roma - Gianicolo
🇮🇹
Rome, Italy
Hospital General Universitario de Alicante
🇪🇸
Alicante, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸
Valencia, Spain
Hospital Universitari Vall d'Hebrón
🇪🇸
Barcelona, Spain
Leeds Teaching Hospitals NHS Trust
🇬🇧
Leeds, United Kingdom
University College London Hospitals NHS Foundation Trust
🇬🇧
London, United Kingdom
Oxford University Hospitals NHS Foundation Trust
🇬🇧
Oxford, United Kingdom
Fakultní Nemocnice Brno - Dětská Nemocnice
🇨🇿
Brno, Czechia
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
UMASS Med School
🇺🇸
Worcester, Massachusetts, United States
C.S. Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
The Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Specialty Group - Medical Center Office
🇺🇸
Norfolk, Virginia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Children's Hospital of Chongqing Medical University
🇨🇳
Chongqing, Chongqing, China
Klinika dÄ>tské neurologie, Neuromuskulární centrum
🇨🇿
Prague, Czechia
Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea - Lombardia
🇮🇹
Lecco, Italy
Association Institut de Myologie
🇫🇷
Paris, France
IRRCS Ospedale San Raffaele
🇮🇹
Milan, Italy
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹
Rome, Italy
Universitair Ziekenhuis Leuven - Campus Gasthuisberg
🇧🇪
Leuven, Belgium
Inselspital Universitätsspital Bern
🇨🇭
Bern, Switzerland
Klinik Favoriten
🇦🇹
Vienna, Austria
Universitair Ziekenhuis Gent
🇧🇪
Gent, Belgium
The Chaim Sheba Medical Center
🇮🇱
Tel Aviv, Israel
The Edith Wolfson Medical Center
🇮🇱
Tel Aviv, Israel
Leiden Universitair Medisch Centrum
🇳🇱
Leiden, Netherlands
Centre Hospitalier Régional de la Citadelle
🇧🇪
Liège, Belgium
Arkansas Children's
🇺🇸
Little Rock, Arkansas, United States
Radboud Universitair Medisch Centrum
🇳🇱
Nijmegen, Gelderland, Netherlands
University of Kansas Medical Center
🇺🇸
Fairway, Kansas, United States