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

Duchenne Muscular Dystrophy Clinical Trial

— LELANTOS-1  

Official title:

A Phase 3, Randomized, Double-Blind Trial of Pamrevlumab (FG-3019) or Placebo in Combination With Systemic Corticosteroids in Subjects With Non-ambulatory Duchenne Muscular Dystrophy (DMD)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04371666
• Other study ID #: FGCL-3019-093
• Secondary ID: 2020-000698-26
• Status: Terminated
• Phase: Phase 3
• Start date: August 10, 2020
• Est. completion date: August 17, 2023

Study information

• Verified date: February 2024
• Source: FibroGen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Terminated
• Enrollment: 98
• Est. completion date: August 17, 2023
• Est. primary completion date: February 13, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

1. Males at least 12 years of age, non-ambulatory at screening initiation

2. Written consent by participant and/or legal guardian as per regional/ country and/or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements

3. 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.

4. Medical history includes diagnosis of DMD and confirmed Duchenne mutation using a validated genetic test

5. Brooke Score for Arms and Shoulders =5

6. Able to undergo MRI test for the upper arm extremities (Biceps Brachii muscle) and cardiac muscle

7. Able to perform spirometry

8. Average (of Screening and Day 0) percent predicted forced vital capacity (FVC) between 45 and 85, inclusive

9. Left ventricular ejection fraction =50% as determined by local cardiac MRI read at screening or within 3 months prior to randomization (Day 0)

10. 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.

11. 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.

12. Agreement to receive annual influenza vaccinations during the course of the study.

13. Adequate renal function: cystatin C =1.4 mg/liter (L)

14. 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.

15. 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:

1. Previous exposure to pamrevlumab

2. BMI =40 kg/square meter (m^2) or weight >117 kg

3. 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

4. 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

5. 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

6. Arrhythmia requiring anti-arrhythmic therapy

7. Requires =16 hours continuous ventilation

8. Hospitalization due to respiratory failure within the 8 weeks prior to screening

9. 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

10. 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

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Pamrevlumab
Pamrevlumab per dose and schedule specified in the arm description
• Placebo
Matching placebo per schedule specified in the arm description
• Corticosteroids
Systemic deflazacort or equivalent potency of corticosteroids administered orally

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
FibroGen

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  Czechia,  France,  Israel,  Italy,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at 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.	Baseline, Week 52
Secondary	Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry	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.	Baseline, Week 52
Secondary	Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM)	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).	Baseline, Week 52
Secondary	Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI)	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.	Baseline, Week 52
Secondary	Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry	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.	Baseline, Week 52