ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD)

Sponsor

Sarepta Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT02500381

Collaborator

(none)

222

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main objective of this study is to evaluate the efficacy of SRP-4045 (casimersen) and SRP-4053 (golodirsen) compared to placebo in participants with DMD with out-of-frame deletion mutations amenable to skipping exon 45 and exon 53, respectively.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Drug: SRP-4045 Drug: SRP-4053 Drug: Placebo	Phase 3

Detailed Description

This is a double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of SRP-4045 and SRP-4053. Eligible participants with out-of-frame deletion mutations amenable to exon 45 or 53 skipping will be randomized to receive once weekly intravenous (IV) infusions of 30 milligrams/kilograms (mg/kg) SRP-4045 or 30 mg/kg SRP-4053 respectively (combined-active group) or placebo for up to 96 weeks (the placebo-controlled period of the trial). This will be followed by an open-label extension period in which all participants will receive open-label active treatment for 48 weeks (up to Week 144 of study).

The study will enroll approximately 222 participants. Twice as many participants will be randomized to receive active treatment as will receive placebo (2:1 randomization).

Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests, such as the 6-minute walk test (6MWT). All participants will undergo a muscle biopsy at baseline and a second muscle biopsy either at Week 48 or Week 96.

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

Blood samples will be taken periodically throughout the study to assess the pharmacokinetics of both drugs.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

222 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Part 1 is double-blind and randomized; Part 2 is open-label.

Primary Purpose:

Treatment

Official Title:

A Double-Blind, Placebo-Controlled, Multi-Center Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy

Actual Study Start Date :

Sep 28, 2016

Anticipated Primary Completion Date :

Apr 30, 2024

Anticipated Study Completion Date :

Apr 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SRP-4045 Participants amenable to exon 45 skipping will receive SRP-4045 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045 SRP-4045 solution for IV infusion Other Names: Casimersen AMONDYS 45
Experimental: SRP-4053 Participants amenable to exon 53 skipping will receive SRP-4053 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4053 SRP-4053 solution for IV infusion Other Names: Golodirsen VYONDYS 53
Placebo Comparator: Placebo followed by SRP-4045 or SRP-4053 Participants amenable to exon 45 or 53 skipping will receive SRP-4045 or SRP-4053 placebo-matching IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 or SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).	Drug: SRP-4045 SRP-4045 solution for IV infusion Other Names: Casimersen AMONDYS 45 Drug: SRP-4053 SRP-4053 solution for IV infusion Other Names: Golodirsen VYONDYS 53 Drug: Placebo SRP-4045 or SRP-4053 placebo-matching solution for IV infusion

Arm

Intervention/Treatment

Experimental: SRP-4045

Participants amenable to exon 45 skipping will receive SRP-4045 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).

Drug: SRP-4045

SRP-4045 solution for IV infusion

Other Names:

Casimersen

AMONDYS 45

Experimental: SRP-4053

Participants amenable to exon 53 skipping will receive SRP-4053 IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).

Drug: SRP-4053

SRP-4053 solution for IV infusion

Other Names:

Golodirsen

VYONDYS 53

Placebo Comparator: Placebo followed by SRP-4045 or SRP-4053

Participants amenable to exon 45 or 53 skipping will receive SRP-4045 or SRP-4053 placebo-matching IV infusions, weekly, at 30 mg/kg for up to 96 weeks in the double-blinded period. This will be followed by an open-label extension period in which all participants will receive open-label active treatment of SRP-4045 or SRP-4053 at 30 mg/kg/week IV infusions for 48 weeks (up to Week 144 in the study).

Drug: SRP-4045

SRP-4045 solution for IV infusion

Other Names:

Casimersen

AMONDYS 45

Drug: SRP-4053

SRP-4053 solution for IV infusion

Other Names:

Golodirsen

VYONDYS 53

Drug: Placebo

SRP-4045 or SRP-4053 placebo-matching solution for IV infusion

Outcome Measures

Primary Outcome Measures

Change From Baseline in the Total Distance Walked During 6MWT at Week 96 [Baseline, Week 96]

Secondary Outcome Measures

Change from Baseline in the Total Distance Walked During 6MWT at Week 144 (Week 48 of the Open-Label Extension Period) [Baseline, Week 144]
Change from Baseline in Dystrophin Protein Levels Determined by Western Blot at Weeks 48 or 96 [Baseline, Week 48 or Week 96]
Change from Baseline in Dystrophin Intensity Levels Determined by Immunohistochemistry (IHC) at Weeks 48 or 96 [Baseline, Week 48 or Week 96]
Participant's Ability to Rise Independently From the Floor, as indicated by a North Star Ambulatory Assessment (NSAA) Subscore [Week 96, Week 144]
The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, the participant's ability to rise independently from the floor (without external support) will be reported as an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver).
Time to Loss of Ambulation (LOA) [Baseline, Week 96, and Week 144]
Change From Baseline in the NSAA Total Score at Week 96 and Week 144 [Baseline, Week 96 and Week 144]
The NSAA is a clinician administered scale that rates the participant's performance on various functional activities. During this assessment, participants will be asked to perform 17 different functional activities, including a 10 meter walk/run, rising from a sit to standing, standing on 1 leg, climbing a box step, descending a box step, rising from lying to sitting, rising from the floor, lifting the head, standing on heels, and jumping. Participants will be graded as follows: 2 = achieves goal without any assistance; 1 = modified method but achieves goal independent of physical assistance from another person; and 0 = unable to achieve goal independently. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function.
Change From Baseline in Forced Vital Capacity Percent (FVC%) Predicted at Week 96 and Week 144 [Baseline, Week 96 and Week 144]

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 13 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Genotypically confirmed DMD, with genetic deletion amenable to exon 45 or exon 53 skipping
Stable dose of oral corticosteroids for at least 24 weeks prior to Week 1, and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight).
Intact right and left biceps or 2 alternative upper muscle groups
Mean 6MWT ≥300 meters and ≤450 meters
Stable pulmonary function: forced vital capacity (FVC) ≥50% predicted

Exclusion Criteria:

Treatment with gene therapy at any time
Previous treatment with SMT C1100 within 1 week prior to Week 1 and previous treatment with PRO045 (BMN 045), PRO053 (BMN 053), or PRO051 (BMN 051) within 24 weeks prior to Week 1
Current or previous treatment with any other experimental treatment within 12 weeks prior to Week 1
Major surgery within 3 months prior to Week 1
Presence of other clinically significant illness

Other inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neuromuscular Research Center	Phoenix	Arizona	United States	85028
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	David Geffen School of Medicine, UCLA	Los Angeles	California	United States	90095
4	UC Davis Medical Center	Sacramento	California	United States	95817
5	Rady Children's Hospital San Diego/ UCSD	San Diego	California	United States	92123
6	Stanford University School of Medicine/Medical Center	Stanford	California	United States	94305
7	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
8	University of Florida	Gainesville	Florida	United States	32610
9	NW Florida Clinical Research Group, LLC	Gulf Breeze	Florida	United States	32561
10	Center for Integrative Rare Disease Research (CIRDR)	Atlanta	Georgia	United States	30318
11	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
12	University of Iowa Children's Hospital	Iowa City	Iowa	United States	52242
13	University of Kansas, Medical Center	Kansas City	Kansas	United States	66160
14	Boston Children's Hospital	Boston	Massachusetts	United States	02115
15	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
16	Las Vegas Clinic	Las Vegas	Nevada	United States	89145
17	University of Rochester Clinical Research Center	Rochester	New York	United States	14642
18	Cincinnati Children's Hospital Medical Center (CCHMC)	Cincinnati	Ohio	United States	45229
19	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
20	Shriners Hospital for Children	Portland	Oregon	United States	97239
21	Childrens Hospital of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
22	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
23	Children's Medical Center Dallas	Dallas	Texas	United States	75235
24	University of Utah	Salt Lake City	Utah	United States	84132
25	Children's Hospital of the King's Daughters	Norfolk	Virginia	United States	23507
26	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
27	DOM Centro de Reumatologia	Ciudad Autonoma de Buenos Aires		Argentina	1111
28	Royal Children's Hospital Melbourne	Parkville	Victoria	Australia	3052
29	Queensland Children's Hospital	South Brisbane		Australia	4101
30	Children's Hospital at Westmead	Westmead		Australia	2145
31	Universitair Ziekenhuis Gent	Ghent		Belgium	9000
32	Universitair Ziekenhuis Leuven	Leuven		Belgium	3000
33	CHR de la Citadelle	Liège		Belgium	4000
34	University Multiprofile Hospital for Active Treatment Aleksandrovska EAD	Sofia	Sofia-Grad	Bulgaria	1431
35	Alberta Childrens Hospital	Calgary	Alberta	Canada	T3B 6A8
36	Children's and Women's Health Centre of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
37	London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
38	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
39	University Hospital Brno	Brno		Czechia	61300
40	Fakultni nemocnice v Motole	Praha		Czechia	15008
41	Rigshospitalet Copenhagen University Hospital	København Ø		Denmark	2100
42	Hôpital Des Enfants	Toulouse	Haute-Garonne	France	31059
43	Reference Centre for Neuromuscular Diseases	Nantes		France	44093
44	Hôpital Armand Trousseau	Paris		France	75012
45	Charité - Universitätsmedizin Berlin	Berlin		Germany	13353
46	Universitätsklinikum Essen	Essen		Germany	45122
47	University Hospital Freiburg	Freiburg		Germany	79106
48	IASO Children's Hospital	Maroussi		Greece	15123
49	Ippokratio General Hospital of Thessaloniki	Thessaloniki		Greece	54642
50	Semmelweis Egyetem Genomikai Medicina és Ritka Betegsegek Intezete	Budapest		Hungary	1083
51	The Children's University Hospital	Dublin		Ireland	D1
52	Schneider Children's Medical Center of Israel	Petah Tikvah		Israel	49102
53	Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant' Anna	Ferrara		Italy	44124
54	Istituto Giannina Gaslini	Genoa		Italy	16147
55	Az Ospedaliera Universitaria Policlinico G Martino	Messina		Italy	98125
56	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano		Italy	20133
57	Policlinico Universitario A Gemelli	Rome		Italy	00168
58	Neurociencias Estudios Clínicos S.C	Culiacán		Mexico	80020
59	Instituto de Investigaciones Clínicas para la Salud A.C	Durango		Mexico	34000
60	Samodzielny Publiczny Centralny Szpital Kliniczny	Warsaw	Mazowieckie	Poland	02-097
61	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
62	Federal state budget educational institution of higher education "Russian national research medical university n.a. N.I. Pirogov" of Ministry of healthcare of Russian Federation	Moscow		Russian Federation	125412
63	State Autonomous Healthcare Institution of Sverdlovsk Region Children's Clinical Hospital No. 9 City of Ekaterinburg	Yekaterinburg		Russian Federation
64	Clinic for Neurology and Psychiatry for Children and Youth	Belgrade		Serbia	11000
65	Hospital de La Santa Creu i Sant Pau	Barcelona		Spain	08041
66	Hospital Sant Joan de Deu	Barcelona		Spain	08950
67	Hospital Universitari i Politecnic La Fe de Valencia	Valencia		Spain
68	Drottning Silvias Barn Och Ungdomssjukhus	Göteborg		Sweden	SE-41685
69	Royal Hospital for Children (Glasgow)	Glasgow		United Kingdom	G51 4TF
70	Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom	LS1 3EX
71	Alder Hey Childrens Hospital	Liverpool		United Kingdom	L12 2AP
72	Great Ormond Street Hospital (GOSH)	London		United Kingdom	WC1N 1EH
73	Royal Victoria Infirmary	Newcastle upon Tyne		United Kingdom	NE1 4LP
74	John Radcliffe Hospital	Oxford		United Kingdom	OX3 9DU