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

Trial of Pamrevlumab (FG-3019), a Monoclonal Antibody to Connective Tissue Growth Factor, in Non-Ambulatory Subjects With Duchenne Muscular Dystrophy

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02606136

Acronym

MISSION

Enrollment

Registered

2015-11-17

Start date

2016-01-04

Completion date

2023-08-09

Last updated

2024-08-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Duchenne Muscular Dystrophy

Keywords

Duchenne, muscular, dystrophy, DMD, non-ambulatory

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.

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).

Interventions

DRUGPamrevlumab

Pamrevlumab, 10 milligrams (mg)/milliliter (mL), single dose vials

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

12 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Annual Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 104	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

Measure	Time frame	Description
Change From Baseline in Percent Predicted Peak Expiratory Flow (PEF) at Week 104	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.
Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF%) at Week 104	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.
Change From Baseline in Performance of Upper Limb (PUL) Total Score at Week 104	Baseline, Week 104	The PUL module is an observer-administered performance battery of upper extremity mobility tasks for the shoulder (upper, 6 items: maximum score = 12), elbow (middle, 9 items: maximum score = 17) and wrist/hand (distal, 7 items: maximum score = 13). Higher scores of each item indicate higher level of function. Total score was calculated by adding the 3 level scores, with a maximum global score of 42 (total score range = 0-42; with higher score indicating 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.
Change From Baseline in Grip Strength by Hand, as Measured by Hand Held Myometry (HHM) at Week 104	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.
Change From Baseline in Percent Predicted Forced Expiratory Volume at 1 Second (ppFEV1) at Week 104	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.
Change From Baseline in Cardiac Fibrosis (Scar Mass), as Measured by Magnetic Resonance Imaging (MRI) at Week 104	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.
Change From Baseline in Upper Arm (Biceps Brachii MRI) Muscle Fat and Fibrosis Score, as Measured by MRI at Week 104	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.
Change From Baseline in Fat Fraction Percentage (%F), as Measured by MRI at Week 104	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.
Change From Baseline in Pinch Strength, as Measured by HHM at Week 104	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.

Countries

United States

Participant flow

Pre-assignment details

All participants who completed the main portion of the study for a minimum of 104 weeks (2 years) were rolled over to an open-label extension (OLE) for up to an additional 208 weeks (4 years). Some participants remained in the main study for up to 206 weeks before rolling over to the OLE.

Participants by arm

Arm	Count
Pamrevlumab Participants received pamrevlumab 35 mg/kg by IV infusion every 2 weeks for a minimum of 104 weeks in the main study. Participants who completed the main study, continued to receive pamrevlumab 35 mg/kg by IV infusion every 2 weeks for a minimum of up to 208 weeks in the OLE.	21
Total	21

Withdrawals & dropouts

Period	Reason	FG000
Main Study (104 Weeks)	Participant/Legal Guardian Decision	5
Main Study (104 Weeks)	Withdrawal by Subject	1
OLE (Up to 208 Weeks)	Participant/Legal Guardian Decision	1
OLE (Up to 208 Weeks)	Sponsor Decision to Terminate Study	14

Baseline characteristics

Characteristic	Pamrevlumab
Age, Continuous	15.99 years STANDARD_DEVIATION 3.277
Cardiac Fibrosis Score (Scar Mass), as Measured by Magnetic Resonance Imaging (MRI)	24.100 grams
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Fat Fraction Percentage (%F), as Measured by MRI	22.07 percentage of fat
Grip Strength by Hand, as Measured by HHM Dominant Grip Best Result	45.861 newton
Grip Strength by Hand, as Measured by HHM Non-Dominant Grip Best Result	41.977 newton
Left Ventricular Ejection Fraction Percentage (LVEF%)	56.992 percentage of LVEF
Percent Predicted Forced Expiratory Volume at 1 Second (ppFEV1)	53.815 percentage of predicted FEV1
Percent Predicted Forced Vital Capacity (ppFVC)	54.15 percentage of predicted FVC
Percent Predicted Peak Expiratory Flow (PEF)	54.66 percentage of predicted PEF
Performance of Upper Limb (PUL) Total Score	24.4 unit on a scale
Pinch Strength, as Measured by Hand Held Myometry (HHM) Dominant Pinch Best Result	17.003 newton
Pinch Strength, as Measured by Hand Held Myometry (HHM) Non-Dominant Pinch Best Result	16.607 newton
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	20 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	21 Participants
Upper Arm (Biceps Brachii MRI) Muscle Fat and Fibrosis Score	8.01 unit on a scale

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 21	0 / 15
other Total, other adverse events	21 / 21	15 / 15
serious Total, serious adverse events	6 / 21	5 / 15

Outcome results

Primary

Annual Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at 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.