Phase 3 Trial of Pamrevlumab or Placebo in Combination With Systemic Corticosteroids in Participants With Ambulatory DMD

Phase 3

Terminated

Conditions: Duchenne Muscular Dystrophy

Interventions: Drug: Pamrevlumab
Drug: Placebo
Drug: Corticosteroids

Registration Number: NCT04632940

Lead Sponsor: FibroGen

Brief Summary: To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with systemic corticosteroids administered every 2 weeks in ambulatory participants with Duchenne muscular dystrophy (DMD) (age 6 to \<12 years).

Detailed Description: This is a global, randomized, double-blind, trial of pamrevlumab or placebo in combination with systemic corticosteroids in participants with DMD, aged 6 to \<12 years (ambulatory participants only). Approximately 70 participants will be randomized at a 1:1 ratio to Arm A (pamrevlumab + systemic deflazacort or equivalent potency of corticosteroids administered orally) or Arm B (placebo+ systemic deflazacort or equivalent potency of corticosteroids administered orally), respectively. Randomization will be stratified by exon 44 deletion for analysis. Stratification has no impact upon treatment assignment nor dosage.

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

The main study has 3 study periods:

* Screening period: Up to 4 weeks

* Treatment period: 52 weeks

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

Each participant will receive pamrevlumab or placebo at 35 mg/kg every 2 weeks for up to 52 weeks. Participants who complete 52 weeks of treatment may be eligible for an open-label extension (OLE), offering extended treatment with pamrevlumab.

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: 73

Inclusion Criteria

Age, and consent:

Males at least 6 to <12 years of age 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

DMD diagnosis:
Medical history includes diagnosis of DMD and confirmed Duchenne mutation, including status of exon 44 using a validated genetic test.

Pulmonary criteria:
Average (of screening and Day 0) percent predicted forced vital capacity (FVC) above 45%
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.

Performance criteria:
Able to complete 6-minute walking distance (6MWD) test with a distance of at least 270 meters but no more than 450 meters on two occasions within 3 months prior to randomization with ≤10% variation between these two tests.
Able to rise (TTSTAND) from floor in <10 seconds (without aids/orthoses) at screening visit.
Able to undergo magnetic resonance imaging (MRI) test for the lower extremities vastus lateralis muscle.

Vaccination:
Agreement to receive annual influenza vaccinations during the conduct of the study.

Laboratory criteria:
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

General Criteria:

Concurrent illness other than DMD that can cause muscle weakness and/or impairment of motor function
Severe intellectual impairment (for example, severe autism, severe cognitive impairment, severe behavioral disturbances) preventing the ability to perform study assessments in the Investigator's judgment
Previous exposure to pamrevlumab
Body mass index (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
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, ataluren, golodirsen, casimersen) within 5 half-lives of screening, whichever is longer with the exception of the systemic corticosteroids, including deflazacort

Pulmonary and Cardiac criteria:
Requires ≥16 hours continuous ventilation
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
Hospitalization due to respiratory failure within the 8 weeks prior to screening
Severe uncontrolled heart failure (New York Heart Association [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
Any other evidence of clinically significant structural or functional heart abnormality

Clinical judgment:
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, surgical or psychiatric conditions

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
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
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
Placebo	Placebo	Matching placebo 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 North Star Ambulatory Assessment (NSAA) Total Score at Week 52	Baseline, Week 52	The NSAA consisted of 17 activities, each scored as 0 (activity could not be performed), 1 (modified method but achieved goal without physical assistance from another), or 2 (normal, achieved goal without assistance). The sum of these 17 scores was used to form a total score ranging from 0 (worst) to 34 (fully independent function). If fewer than 15 of the 17 activities were performed, the total score was considered missing. If 15 to 16 activities were performed, the total score was calculated by multiplying the sum of the scores in the x activities that were performed by 17/x. If an activity could not be performed due to disease progression/loss of ambulation, a score of 0 was assigned. Higher scores indicated better functioning. Least square (LS) mean and standard error (SE) were analyzed using a mixed model for repeated measure (MMRM).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Time to Stand (TTSTAND) at Week 52	Baseline, Week 52	The time (in sec) required for a participant to stand from supine position has been reported. A longer time taken reflected a worse outcome.
Time to Loss of Ambulation (LoA) From Baseline to Week 52	Baseline to Week 52	Time (days) to LoA was defined as the number of days from randomization to the date of LoA, or all-cause death based on observed data, whichever occurred earlier during the on-study period. Median time (days) to LoA was calculated using Kaplan Meier Survival Estimates.
Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52	Baseline, Week 52	The 4SCV (centimeters \[cm\]/second \[sec\]) was calculated as the ratio of the total height (cm) of stairs climbed divided by the number of seconds taken to complete the 4-stair climb.
Change From Baseline in the 10-Meter Walk/Run Test at Week 52	Baseline, Week 52	The time (in sec) required for a participant to run or walk a distance of 10 meters as quickly as possible was calculated as velocity (meters/sec).

Trial Locations

Locations (52): Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
University of California San Diego Health
🇺🇸
San Diego, California, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Oxford University Hospitals NHS Foundation Trust
🇬🇧
Oxford, England, United Kingdom
Leeds Teaching Hospitals NHS Trust
🇬🇧
Leeds, England, United Kingdom
Universitair Ziekenhuis Leuven - Campus Gasthuisberg
🇧🇪
Leuven, Flemish Brabant, Belgium
Hôpital Hautepierre
🇫🇷
Strasbourg, Bas-Rhin, France
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
🇨🇳
Beijing, China
Shriners Hospital for Children
🇺🇸
Portland, Oregon, United States
Children's Wisconsin Corporate Center
🇺🇸
Milwaukee, Wisconsin, United States
Klinik Favoriten
🇦🇹
Wien, Vienna, Austria
Rare Disease Research - Tampa
🇺🇸
Tampa, Florida, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Rare Disease Research Center
🇺🇸
Atlanta, Georgia, United States
University of Iowa Hospitals and Clinics
🇺🇸
Iowa City, Iowa, United States
University of Kansas Medical Center Research Institute
🇺🇸
Fairway, Kansas, United States
University of Massachusetts Memorial Center
🇺🇸
Worcester, Massachusetts, United States
Kennedy Krieger Institute
🇺🇸
Baltimore, Maryland, United States
Spectrum Health Hospitals Helen DeVos Children's Hospital
🇺🇸
Grand Rapids, Michigan, United States
Washington University School of Medicine in St. Louis
🇺🇸
Saint Louis, Missouri, United States
Penn State Health Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Texas Children's Hospital
🇺🇸
Houston, Texas, United States
University of Virginia Children's Hospital
🇺🇸
Charlottesville, Virginia, United States
University of Utah Health
🇺🇸
Salt Lake City, Utah, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Murdoch Children's Research Institute
🇦🇺
Parkville, Victoria, Australia
Centre Hospitalier Régional de la Citadelle
🇧🇪
Liège, Liege, Belgium
Children's Hospital of Chongqing Medical University
🇨🇳
Chongqing, Chongqing, China
The 1st Affiliated Hospital, Sun Yat-sen University
🇨🇳
Guangzhou, Guangdong, China
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
Universitair Ziekenhuis Gent
🇧🇪
Gent, Oost-Vlaanderen, Belgium
Xiangya Hospital Central South University
🇨🇳
Changsha, Hunan, China
West China Second University Hospital, Sichuan University
🇨🇳
Chengdu, Sichuan, China
Centre Hospitalier Universitaire Nantes - Hôtel Dieu
🇫🇷
Nantes, France
IRRCS Ospedale San Raffaele
🇮🇹
Milano, Milan, Italy
Association Institut de Myologie
🇫🇷
Paris, France
Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea - Lombardia
🇮🇹
Bosisio ParIni, Italy
Centro Clinico NeMO
🇮🇹
Milano, Italy
Fondazione Policlinico Universitario Agostino Gemelli
🇮🇹
Roma, Italy
Ospedale Pediatrico Bambino Gesù - Roma - Gianicolo
🇮🇹
Roma, Italy
Leiden Universitair Medisch Centrum
🇳🇱
Leiden, Netherlands
Radboud Universitair Medisch Centrum
🇳🇱
Nijmegen, Netherlands
Hospital Universitari Vall d'Hebrón
🇪🇸
Barcelona, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸
Valencia, Spain
C.S. Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
University of California Davis Children's Hospital
🇺🇸
Sacramento, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
University of Florida Health Shands Hospital
🇺🇸
Gainesville, Florida, United States