Safety Study of Eteplirsen to Treat Advanced Stage Duchenne Muscular Dystrophy

• Sponsor: Sarepta Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02286947
• Collaborator: (none)
• Enrollment: 24
• Locations: 9
• Arm: 1
• Actual Duration (Months): 40.7
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to explore safety and tolerability of eteplirsen in participants with advanced stage Duchenne muscular dystrophy (DMD) who are amenable to exon 51 skipping.

Condition or Disease	Intervention/Treatment	Phase
Muscular Dystrophy, Duchenne	Drug: Eteplirsen	Phase 2

Detailed Description

This is an open-label, multi-center study to explore the safety and tolerability of eteplirsen injection in participants with advanced stage DMD with confirmed genetic mutations amenable to treatment by exon 51 skipping.

Participants will be evaluated for inclusion during a Screening/Baseline period of up to 4 weeks. Eligible participants will receive once weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for 96 weeks, followed by a safety extension (not to exceed 48 weeks).

Safety will be regularly assessed throughout the study via the collection of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Study to Evaluate the Safety and Tolerability of Eteplirsen in Patients With Advanced Stage Duchenne Muscular Dystrophy
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Apr 21, 2017
• Actual Study Completion Date: Mar 23, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eteplirsen 30 mg/kg Participants will receive eteplirsen 30 mg/kg/week intravenous (IV) infusions, weekly, for up to 96 weeks.	Drug: Eteplirsen; Eteplirsen solution for IV infusion; Other Names: AVI-4658 EXONDYS 51®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events [From first dose of drug up to 100 weeks]

   An adverse event (AE) was any untoward medical occurrence in a participant that did not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events that developed or worsened during the on-treatment period (defined as time from first dose of study drug and up to 28 days after last dose of study drug (up to 100 weeks) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

Secondary Outcome Measures

1. Number of Participants With Potentially Clinically Significant Laboratory Abnormalities [Baseline up to 100 weeks]

   Laboratory parameters included hematology, clinical chemistry, urinalysis and coagulation. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal findings. Incr=increase; LLN=lower limit of normal; ULN=upper limit of normal; GGT=gamma glutamyl transferase

2. Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs [Baseline up to 100 weeks]

   Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal vital sign findings.

3. Number of Participants With at Least One Potentially Clinically Significant Abnormalities in Physical Examinations [Baseline up to 100 weeks]

   Physical examinations, full and brief, were performed by the Investigator, a physician Sub-Investigator, or a Nurse Practitioner (if licensed in the state or province to perform physical examinations). Full physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; skin; lymph nodes; and musculoskeletal and neurological systems. Brief physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; and skin.

4. Number of Participants With Abnormalities in Electrocardiograms (ECGs) [Baseline up to 100 weeks]

   Twelve-lead ECGs and Holter ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the patient was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. The Investigator reviewed the results of the centrally read ECG report and determined if the findings were clinically significant. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal ECG findings. msec=milliseconds; QTcF=QT interval corrected with Fridericia's method

5. Number of Participants With Abnormalities in Echocardiograms (ECHO) [Baseline up to 100 weeks]

   Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. The ECHO was reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. Ejection fraction was noted. The Investigator reviewed the results of the ECHO report and determined if the findings were clinically significant. LEVF=left ventricular ejection fraction

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 21 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male 7 - 21 years of age

• Diagnosis of DMD with a mutation that is amenable to exon 51 skipping, confirmed by a genetic report

• Stable dose of oral corticosteroids for at least 24 weeks or has not received corticosteroids for at least 24 weeks

• Non-ambulatory, or incapable of walking ≥300 meters on the 6-Minute Walk Test (6MWT).

• Score of ≤4 on the Brooke Score for Arms and Shoulders.

• Stable cardiac and pulmonary function

• Use of contraceptives for sexually active males throughout the study

• Willing to provide consent and comply with the study

Exclusion Criteria:

• Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks that may have an effect on muscle strength or function (e.g., growth hormone, anabolic steroids).

• Previous treatment with SMT C1100/BMN 195 at any time.

• Previous treatment with drisapersen (PRO051) within the last 6 months.

• Participation in any other DMD interventional clinical study within 12 weeks

• Major change in physiotherapy regimen within the past 3 months

• Major surgery within 3 months

• Presence of other clinically significant illness

• Use of an aminoglycoside antibiotic within 12 weeks or the need for this antibiotic or statin during study

• Forced vital capacity % predicted [FVC % predicted] <40%, or requiring daytime ventilation.

• Require antiarrhythmic and/or antidiuretic therapy for heart failure.

• Have a left ventricular ejection fraction (LVEF) of <40%.

• Prior or ongoing medical condition that could adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
2	University of California, Davis Medical Center	Sacramento	California	United States	95817
3	University of Iowa Children's Hospital	Iowa City	Iowa	United States	52242
4	Kennedy Krieger Institute	Baltimore	Maryland	United States	21205
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
7	University of Rochester Medical Center	Rochester	New York	United States	14642
8	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
9	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Sarepta Therapeutics, Inc.

Investigators

• Study Director: Medical Director, Sarepta Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Jul 5, 2016
• Statistical Analysis Plan - Apr 20, 2017

More Information

Publications

None provided.

• Responsible Party: Sarepta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02286947
• Other Study ID Numbers: 4658-204
• First Posted: Nov 10, 2014
• Last Update Posted: Mar 30, 2020
• Last Verified: Mar 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sarepta Therapeutics, Inc.: DMD; exon 51; dystrophin; dystrophy; eteplirsen; Duchenne
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne

Study Results

Participant Flow

Pre-assignment Detail	The study was conducted at 9 sites in the United States from November 2014 to March 2018.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg intravenous (IV) infusions, once weekly, for 96 weeks.
Period Title: Overall Study
STARTED	24
COMPLETED	22
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.9 (3.30)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	24 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 12.5%
Not Hispanic or Latino	20 83.3%
Unknown or Not Reported	1 4.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	21 87.5%
More than one race	2 8.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	An adverse event (AE) was any untoward medical occurrence in a participant that did not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events that developed or worsened during the on-treatment period (defined as time from first dose of study drug and up to 28 days after last dose of study drug (up to 100 weeks) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
Time Frame	From first dose of drug up to 100 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population included all participants who received at least 1 dose of eteplirsen.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
Measure Participants	24
Count of Participants [Participants]	24 100%

2. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Laboratory Abnormalities
Description	Laboratory parameters included hematology, clinical chemistry, urinalysis and coagulation. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal findings. Incr=increase; LLN=lower limit of normal; ULN=upper limit of normal; GGT=gamma glutamyl transferase
Time Frame	Baseline up to 100 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population included all participants who received at least 1 dose of eteplirsen.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
Measure Participants	24
Sodium: Decrease of 8 or more	3 12.5%
Sodium: Increase of 8 or more	3 12.5%
Potassium: Decrease of 1.1 or more	2 8.3%
Potassium: Increase of 1.0 or more	2 8.3%
Potassium: Value > 5.5 or < 3.0	1 4.2%
Calcium: Decrease of 0.30 or more	1 4.2%
Glucose: Decrease of 3.1 or more	1 4.2%
Glucose: Increase of 3.2 or more	6 25%
Albumin: Value < LLN or > ULN	4 16.7%
Bilirubin: Incr of 10 or more	1 4.2%
Bilirubin: Value > 1.5 x ULN	1 4.2%
Alanine Aminotransferase: Value >= 2 x Baseline	1 4.2%
GGT: value > 3*Baseline or > ULN	2 8.3%
Lactate Dehydrogenase: Value >= 2 x Baseline	1 4.2%
Creatine Kinase: Value >= 2 x Baseline	5 20.8%
Hemoglobin: Value < LLN	5 20.8%
Hematocrit: Value < LLN	7 29.2%
Red Blood Cell: Value < LLN	4 16.7%
White Blood Cell: Value < LLN or > 1.5 x ULN	5 20.8%
Platelets: Value < 150 or < 200	1 4.2%
Neutrophils: Value > 1.5 x ULN or < 1000	7 29.2%
Lymphocytes: Value < LLN	6 25%
Monocytes: Value < LLN	14 58.3%
Eosinophils: Value > 1.5 x ULN or < LLN	2 8.3%
Basophils: Value < LLN or > ULN	2 8.3%
Urine Protein: Value > 1+	5 20.8%

3. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
Description	Vital sign parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and body temperature. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal vital sign findings.
Time Frame	Baseline up to 100 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population included all participants who received at least 1 dose of eteplirsen.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
Measure Participants	24
DBP: Less than 40 mmHG	1 4.2%
DBP: Greater than 90 mmHg	12 50%
SBP: Less than 80 mmHg	4 16.7%
SBP: Greater than 130 mmHG	17 70.8%
HR: Less than 50 beats per minute (bpm)	1 4.2%
HR: Greater than 130 bpm	15 62.5%

4. Secondary Outcome

Title	Number of Participants With at Least One Potentially Clinically Significant Abnormalities in Physical Examinations
Description	Physical examinations, full and brief, were performed by the Investigator, a physician Sub-Investigator, or a Nurse Practitioner (if licensed in the state or province to perform physical examinations). Full physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; skin; lymph nodes; and musculoskeletal and neurological systems. Brief physical examinations included examination of general appearance; head, ears, eyes, nose, and throat; heart; lungs; chest; abdomen; and skin.
Time Frame	Baseline up to 100 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
Measure Participants	24
Count of Participants [Participants]	23 95.8%

5. Secondary Outcome

Title	Number of Participants With Abnormalities in Electrocardiograms (ECGs)
Description	Twelve-lead ECGs and Holter ECGs were performed at a consistent time of day throughout the study. Electrocardiograms were performed only after the patient was in the supine position, resting, and quiet for a minimum of 15 minutes. The ECG was manually reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. The Investigator reviewed the results of the centrally read ECG report and determined if the findings were clinically significant. Data is only reported for parameters in which at least 1 participant had potentially clinically significant abnormal ECG findings. msec=milliseconds; QTcF=QT interval corrected with Fridericia's method
Time Frame	Baseline up to 100 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population included all participants who received at least 1 dose of eteplirsen.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg intravenous (IV) infusions, weekly, for 96 weeks.
Measure Participants	24
Heart Rate: >120 beats/minute	6 25%
QTcF: Increase of 60 or more msec	1 4.2%

6. Secondary Outcome

Title	Number of Participants With Abnormalities in Echocardiograms (ECHO)
Description	Standard, 2-dimensional ECHOs were performed at a consistent time of day throughout the study. The ECHO was reviewed and interpreted by medically qualified personnel using a central vendor according to prespecified criteria. Ejection fraction was noted. The Investigator reviewed the results of the ECHO report and determined if the findings were clinically significant. LEVF=left ventricular ejection fraction
Time Frame	Baseline up to 100 weeks

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population included all participants who received at least 1 dose of eteplirsen.

Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg intravenous (IV) infusions, once weekly, for 96 weeks.
Measure Participants	24
LEVF: <55%	0 0%
Fractional Shortening: <28%	6 25%

Adverse Events

Time Frame	Baseline up to Week 100
Arm/Group Title	Eteplirsen 30 mg/kg
Arm/Group Description	Participants received eteplirsen 30 mg/kg IV infusions, weekly, for 96 weeks.
All Cause Mortality
	Eteplirsen 30 mg/kg
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	Eteplirsen 30 mg/kg
	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)
Cardiac disorders
Cardiomyopathy	1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Extremity contracture	1/24 (4.2%)
Scoliosis	1/24 (4.2%)
Renal and urinary disorders
Nephrolithiasis	1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Eteplirsen 30 mg/kg
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Gastrointestinal disorders
Vomiting	7/24 (29.2%)
Abdominal pain upper	6/24 (25%)
Diarrhoea	6/24 (25%)
Nausea	4/24 (16.7%)
Abdominal discomfort	3/24 (12.5%)
Constipation	3/24 (12.5%)
General disorders
Catheter site pain	5/24 (20.8%)
Infusion site bruising	4/24 (16.7%)
Catheter site bruise	3/24 (12.5%)
Pyrexia	3/24 (12.5%)
Chest pain	2/24 (8.3%)
Infusion site pain	2/24 (8.3%)
Infections and infestations
Nasopharyngitis	14/24 (58.3%)
Upper respiratory tract infection	6/24 (25%)
Ear infection	3/24 (12.5%)
Gastroenteritis	3/24 (12.5%)
Pharyngitis streptococcal	3/24 (12.5%)
Injury, poisoning and procedural complications
Contusion	6/24 (25%)
Procedural pain	4/24 (16.7%)
Joint injury	3/24 (12.5%)
Ligament sprain	3/24 (12.5%)
Foot fracture	2/24 (8.3%)
Skin abrasion	2/24 (8.3%)
Soft tissue injury	2/24 (8.3%)
Spinal compression fracture	2/24 (8.3%)
Investigations
Breath sounds abnormal	3/24 (12.5%)
Protein urine present	2/24 (8.3%)
Metabolism and nutrition disorders
Dehydration	2/24 (8.3%)
Musculoskeletal and connective tissue disorders
Back pain	9/24 (37.5%)
Pain in extremity	4/24 (16.7%)
Arthralgia	3/24 (12.5%)
Muscle spasms	2/24 (8.3%)
Musculoskeletal pain	2/24 (8.3%)
Osteoporosis	2/24 (8.3%)
Nervous system disorders
Headache	8/24 (33.3%)
Dizziness	2/24 (8.3%)
Psychiatric disorders
Depression	2/24 (8.3%)
Renal and urinary disorders
Renal pain	2/24 (8.3%)
Respiratory, thoracic and mediastinal disorders
Cough	7/24 (29.2%)
Nasal congestion	5/24 (20.8%)
Oropharyngeal pain	5/24 (20.8%)
Rhinorrhoea	5/24 (20.8%)
Throat irritation	2/24 (8.3%)
Skin and subcutaneous tissue disorders
Rash	8/24 (33.3%)
Acne	2/24 (8.3%)
Ecchymosis	2/24 (8.3%)
Rash papular	2/24 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The most restrictive relevant agreement provides that the PI can only publish the study results with the approval of Sponsor.