Trial of Pamrevlumab (FG-3019), in Non-Ambulatory Participants With Duchenne Muscular Dystrophy (DMD)

• ClinicalTrials.gov Identifier: NCT02606136
• Recruitment Status: Active, not recruiting
• First Posted: November 17, 2015
• Results First Posted: December 30, 2021
• Last Update Posted: December 30, 2021
• Sponsor: FibroGen
• Information provided by (Responsible Party): FibroGen

Study Description

Brief Summary:

This is a Phase 2, open-label, single arm trial of pamrevlumab (FG-3019) to estimate pamrevlumab's safety and efficacy in non-ambulatory participants with DMD.

Condition or disease	Intervention/treatment	Phase
Duchenne Muscular Dystrophy	Drug: Pamrevlumab	Phase 2

Detailed Description:

The study will include a screening period, main study period, open-label extension (OLE) period, and follow-up period 4 weeks after the last dose. All participants who complete the main portion of the study for a minimum of 104 weeks (2 years) will be rolled over to an OLE for up to an additional 208 weeks (4 years).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Trial of Pamrevlumab (FG-3019), a Monoclonal Antibody to Connective Tissue Growth Factor, in Non-Ambulatory Subjects With Duchenne Muscular Dystrophy
• Actual Study Start Date: January 4, 2016
• Actual Primary Completion Date: May 7, 2020
• Estimated Study Completion Date: January 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pamrevlumab; Participants will receive pamrevlumab 35 milligrams (mg)/kilogram (kg) by intravenous (IV) infusion every 2 weeks for a minimum of 104 weeks.	Drug: Pamrevlumab; Pamrevlumab, 10 milligrams (mg)/milliliter (mL), single dose vials; Other Name: Monoclonal Antibody to Connective tissue growth factor (CTGF), FG-3019

Outcome Measures

Primary Outcome Measures :

1. Annual Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 104 [ Time Frame: Baseline, Week 104 ]
   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 a random coefficient model (RCM), which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.

Secondary Outcome Measures :

1. Change From Baseline in Percent Predicted Forced Expiratory Volume at 1 Second (ppFEV1) at Week 104 [ Time Frame: Baseline, Week 104 ]
   FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Predicted FEV1 is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FEV1= (observed value)/(predicted value) * 100%. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
2. Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 104 [ Time Frame: Baseline, Week 104 ]
   Percent predicted PEF 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. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
3. Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF%) at Week 104 [ Time Frame: Baseline, Week 104 ]
   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). Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
4. Change From Baseline in Performance of Upper Limb (PUL) Total Score at Week 104 [ Time Frame: Baseline, Week 104 ]
   The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into shoulder level (4 items), elbow level (9 items), and distal level (8 items) dimensions. Scoring options per item may not be uniform and may vary from 0-1 and 0-6, according to the performance, with higher values corresponding to better performance. Each dimension was scored separately with a maximum score of 16 for shoulder level, 34 for elbow level, and 24 for distal level. Total score was calculated by adding the 3 level scores, with a maximum global score of 74 (total score range = 0-74). Higher score = better outcome. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
5. Change From Baseline in Grip Strength by Hand, as Measured by Hand Held Myometry (HHM) at Week 104 [ Time Frame: Baseline, Week 104 ]
   The HHM was used to measure distal upper arm strength (grip strength). Data has been presented by dominant and non-dominant hand. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
6. Change From Baseline in Pinch Strength, as Measured by HHM at Week 104 [ Time Frame: Baseline, Week 104 ]
   The HHM was used to measure distal upper arm strength (pinch strength). Data has been presented by dominant and non-dominant hand. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
7. Change From Baseline in Cardiac Fibrosis (Scar Mass), as Measured by Magnetic Resonance Imaging (MRI) at Week 104 [ Time Frame: Baseline, Week 104 ]
   Cardiac MRI was used to assess the cardiac fibrosis by detecting the presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.
8. Change From Baseline in Upper Arm (Biceps Brachii MRI) Muscle Fat and Fibrosis Score, as Measured by MRI at Week 104 [ Time Frame: Baseline, Week 104 ]
   T2-mapping with MRI was conducted to measure upper arm muscle fibrosis and fat in the biceps brachii muscle. Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect. The visual score for muscle fat and fibrosis will be assessed using a modified 5-point Mercuri score in which 0 = normal muscle appearance and 5 = complete replacement of muscle by connective tissue and fat, where a lower score indicated visually healthier muscle. Change from baseline was calculated as the score at Week 104 - the score at baseline.
9. Change From Baseline in Fat Fraction Percentage (%F), as Measured by MRI at Week 104 [ Time Frame: Baseline, Week 104 ]
   Analysis was done using an RCM, which included visit in years (as a continuous variable), and baseline efficacy as fixed effects, the intercept and the linear slope of visit as random effect, and individual participants as participant effect.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Written consent/assent by participant and/or legal guardian as per regional and/or institutional review board (IRB) requirements
• Non-ambulatory
• Brooke Score for Arms and Shoulders ≤5
• Diagnosis of DMD by medical history and confirmed Duchenne mutation in available genetic testing using a validated genetic test
• Able to perform spirometry
• Able to undergo cardiac and extremity (upper arm) MRI
• Percent predicted FVC between 40 and 90, inclusive
• At least one historical ppFVC predicted value within 18 months of baseline
• Left ventricular ejection fraction ≥ 45% as determined by cardiac MRI at screening or within 3 months prior to Day 0
• Participants currently receiving heart failure cardiac medications (for example, angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, and beta-blockers) must achieve a stable regimen for at least 3 months prior to screening
• On a stable dose of corticosteroids for a minimum of 6 months prior to screening with no substantial change in dosage for a minimum of 3 months (except for adjustments for changes in body weight) prior to screening and no foreseen change in corticosteroid use during the course of study participation
• Received pneumococcal vaccine and is receiving annual influenza vaccinations
• Adequate renal function: cystatin C ≤1.4 mg/liter (L)

• Adequate hematological function

  1. Platelets >100,000/microliter (μL)
  2. Hemoglobin >12 grams (g)/deciliter (dL)
  3. Absolute neutrophil count >1500/μL

• Adequate hepatic function

  1. No history or evidence of liver disease
  2. Gamma glutamyl transferase (GGT) ≤3 x upper limit of normal (ULN)
  3. Total bilirubin ≤1.5 x ULN
• If sexually active, will use medically accepted contraceptives during participation in the study and for 3 months after the last dose of study drug

Exclusion Criteria:

• Requires ≥16 hours continuous ventilation
• Prior or ongoing medical condition that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of 156 weeks of treatment and follow-up would be completed, or could impair the assessment of study results
• Anticipated spine surgery within 156 weeks

• Severe uncontrolled heart disease, including any of the following:

  1. Need for intravenous diuretics or inotropic support within 3 months prior to screening
  2. Hospitalization for a heart failure exacerbation or arrhythmia in last 3 months
• Arrhythmia requiring anti-arrhythmic therapy
• Hospitalization due to respiratory failure in the last 6 weeks
• Poorly controlled asthma or underlying lung disease such as bronchopulmonary dysplasia
• Known or suspected active hepatitis B or C or history of human immunodeficiency virus (HIV)
• Body mass index (BMI) ≥40 kilograms (kg)/square meter (m^2) or weight >117 kg
• Exposure to another investigational drug or another approved product for DMD (for example, eteplirsen or golodirsen) within 28 days prior to start of study treatment
• Exposure to another investigational drug or another approved product for DMD (e.g. eteplirsen) within 28 days prior to start of study treatment (or 5 half-lives of the product whichever is longer) prior to first screening visit with the exception of deflazacort. Use of deflazacort, if regarded by the principal investigator as standard of care, is allowed.

Contacts and Locations

Locations

United States, California

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 90095

University of California San Francisco - Benioff Children's Hospital

San Francisco, California, United States, 94143

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Georgia

Rare Disease Research

Atlanta, Georgia, United States, 30318

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Missouri

Washington University in St. Louis School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Oregon

Shriner's Hospital for Children - Portland

Portland, Oregon, United States, 97239

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Children's Medical Center Ambulatory Care Pavilion

Dallas, Texas, United States, 75207

Sponsors and Collaborators

FibroGen

  Study Documents (Full-Text)

Documents provided by FibroGen:

Study Protocol  [PDF] September 27, 2019

Statistical Analysis Plan  [PDF] June 25, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rayego-Mateos S, Morgado-Pascual JL, Lavoz C, Rodrigues-Diez RR, Marquez-Exposito L, Tejera-Munoz A, Tejedor-Santamaria L, Rubio-Soto I, Marchant V, Ruiz-Ortega M. CCN2 Binds to Tubular Epithelial Cells in the Kidney. Biomolecules. 2022 Feb 3;12(2):252. doi: 10.3390/biom12020252.

• Responsible Party: FibroGen
• ClinicalTrials.gov Identifier: NCT02606136
• Other Study ID Numbers: FGCL-3019-079
• First Posted: November 17, 2015
• Results First Posted: December 30, 2021
• Last Update Posted: December 30, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by FibroGen:

Duchenne; muscular; dystrophy; DMD; non-ambulatory

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mitogens; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action