Clinical trial NCT03400852
Conditions: Muscular Dystrophy, Duchenne
Keywords: Muscular Dystrophy DMD Duchenne
Sponsor: Mallinckrodt ARD LLC
Start date: 2018-07-27; Completion date: 2020-02-25
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, double blind, placebo controlled, multiple dose study to examine the safety and efficacy of MNK-1411 in male subjects 4 to 8 years of age (inclusive) with Duchenne Muscular Dystrophy (DMD).

Detailed description:
The main purpose of this study is to determine the effect of MNK-1411 on motor function in participants with Duchenne Muscular Dystrophy (DMD). Information is collected only from caretakers who are fluent in English, using the Pediatric Outcomes Data Collection Instrument (PODCI).

The PODCI is a validated 86-question instrument completed by the parent or legal guardian of children 2 to 10 years of age to assess a variety of health outcome measures (Uzark et al, 2012). This study will only collect information for the PODCI domains of sports and physical functioning and transfer/basic mobility.

Arms: arm 1: Participants receive MNK-1411 at a dosing volume appropriate to body weight during Period 1 arm 2: Participants receive placebo at a volume appropriate to body weight during Period 1 arm 3: All participants receive MNK-1411 at a dosing volume appropriate to body weight during Period 2
Interventions: intervention 1: MNK-1411 intervention 2: Placebo
Intervention descriptions: intervention 1: MNK-1411 (1 mg/mL suspension) for subcutaneous injection intervention 2: Placebo suspension for subcutaneous injection

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Parallel Group, Double Blind, Multiple Dose, 
Placebo Controlled Study to Assess the Efficacy and Safety of MNK-1411 in 
Male Subjects 4 to 8 Years of Age With Duchenne Muscular Dystrophy 
Protocol Number: MNK14112096 
Date of Original Protocol: 22 August 2017 
Date of Protocol Amendment 1: 16 November 2017 
Date of Protocol Amendment 2: 22 August 2018 
Date of Protocol Amendment 3: 23 May 2019 
Mallinckrodt ARD LLC 
1425 US Route 206 
Bedminster, NJ 07921 
United States of America 
               NCT03400852
Summary adjusted for disclosure


MNK-1411 (Cosyntropin) 
 
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PROTOCOL AMENDMENT 3 
SUMMARY OF CHANGES 
In order to accommodate subject needs, Protocol Amendment 3 was developed primarily to 
extend the Open Label Extension Period beyond Week 52 (to continue until the subject chooses 
to discontinue treatment, the investigator feels that treatment is no longer indicated, MNK-1411 
is approved and marketed, or the sponsor ceases development of this compound for Duchenne 
Muscular Dystrophy [DMD]). Open label visits will continue every 12 weeks, with dispensing of 
study drug every 12 weeks. Along with this change, text has been added stating that if a subject 
requires a switch in dose during the Open Label Extension Period (eg, switch to low dose due to 
being unable to tolerate high dose, or switch to high dose based on increased weight [eg, as 
subject grows with age]), the investigator should consult with the medical monitor. Since 
subjects will be participating in the study longer, measurements of height have been added to all 
study visits. 
Additional major protocol changes are summarized below and a more comprehensive Summary 
of Changes document, including minor protocol changes, is provided separately: 
 To accommodate the needs of study sites in Israel, the combination of Sunday and 
Wednesday has been added as possible visit and/or dosage administration days. 
 Text has been added specifying that subjects who have a hypersensitivity reaction to 
the study drug are not required to undergo the 2-week taper, or standard cosyntropin 
stimulation test (250 μg) at the follow-up visit.  
 Varicella zoster testing has been added along with an inclusion criterion (Inclusion 
criterion 6) requiring subjects to test positive prior to study entry (since such 
infections may be serious in patients who are immunosuppressed). 
 Pharmacokinetic analysis text has been corrected. 
 Additional guidance regarding the administration of motor tests (10 Meter Walk/Run, 
Time to Climb 4 Standardized Stairs, Time to Stand from a Supine Position, North 
Starr Ambulatory Assessment [NSAA]) has been provided, along with modification 
of Exclusion criterion 7 to require that subjects be able to complete the 10 Meter 
Walk/Run test in 10 seconds or less at the Screening and Baseline Visits. 
 
 
 


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PROTOCOL AMENDMENT 2 
SUMMARY OF CHANGES 
Protocol Amendment 2 was developed to address the following considerations: 
 In a randomized, double-blind, placebo controlled crossover study in patients ages 
5 to 8 with Duchenne muscular dystrophy Beenakker et al, 2005 utilized a 2 month 
washout period between treatment periods with prednisone and placebo and this 
washout period appeared to be effective. Subsequently a Medical Advisory Board 
evaluated the current study design and based on their clinical experience 
recommended allowing the enrollment of subjects who have not received a 
therapeutic dose of corticosteroids within 2 months prior to the start of the study. 
 Subjects with asthma are excluded from the study. Therefore, the concomitant use of 
inhaled corticosteroids (whose approved indication is for asthma) should not be 
permitted. 
 
The following changes were made: 
Section 12.2, Exclusion criterion 2 was revised to: 
2. Subject has had previous systemic treatment with corticosteroids within 2 months 
prior to the Screening Visit. Exception: In subjects who were down-titrated to a 
physiological dose of corticosteroids (ie, 3 mg/m2 of prednisone or deflazacort) a 
maximum of 1 month of no greater than a physiological dose followed by 1 month 
completely off corticosteroids prior to the Screening Visit will be acceptable for study 
entry. Transient previous use of corticosteroids will be evaluated on a case-by-case 
basis by the sponsor or designee. The use of topical or intra-articular corticosteroids is 
permitted during the study. 
Section 13.1, the exception for inhaled corticosteroids was deleted. 
 
 
 


MNK-1411 (Cosyntropin) 
 
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PROTOCOL AMENDMENT 1 
SUMMARY OF CHANGES 
Protocol Amendment 1 was developed to address issues raised by the central institutional review 
board including adding a study drug taper followed by a cosyntropin stimulation test and 
clarifying parent and/or legal guardian consent.  
Additional minor changes that do not impact study conduct or subject safety were also made.  
The major protocol changes are summarized below:  
 A mandatory study drug taper has been added. All subjects will complete a 2-week 
taper after their last full dose of study drug. In the first week of the taper, each subject 
will receive one-half of their original dose administered 2 times per week for 1 week, 
followed by one-half of their original dose administered 1 time per week for 1 week.  
 All subjects will have a standard cosyntropin stimulation test (250 μg) at their 
Follow-up Visit. 
 References to “legally authorized representative” have been removed from the 
protocol. Only a parent or legal guardian can give consent for subjects to participate. 
 The listing of chemistry laboratory tests in Attachment 1, Section 32.1 has been 
clarified (creatine updated to creatine phosphokinase). 
 


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5. 
ABBREVIATIONS  
Abbreviation 
Term 
2x/week 
2 times per week 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the concentration time curve 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CL/F 
Apparent clearance 
Cmax 
Peak drug concentration 
eCRF 
Electronic case report form 
DMD 
Duchenne muscular dystrophy 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FVC 
Forced vital capacity 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HCV 
Hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IGRA 
Interferon gamma release assay 
IM 
Intramuscular, intramuscularly 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IXRS 
Interactive Phone/Web Response System 
MCR 
Melanocortin receptor 
mITT 
Modified Intent-to-Treat 
MM 
Medical monitor 
NSAA 
North Star Ambulatory Assessment 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 


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Abbreviation 
Term 
PK 
Pharmacokinetics 
PODCI 
Pediatric Outcomes Data Collection Instrument 
SAE 
Serious adverse event 
SC 
Subcutaneous, subcutaneously 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TFT 
Timed function tests 
US 
United States 
V 
Volume of distribution 
WTDMD 
Weight in kg of the DMD subject 
 
 
 


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6. 
SYNOPSIS  
Study Title: A Multicenter, Randomized, Parallel Group, Double Blind, Multiple Dose, Placebo Controlled 
Study to Assess the Efficacy and Safety of MNK-1411 in Male Subjects 4 to 8 Years of Age With Duchenne 
Muscular Dystrophy 
Protocol Number: MNK14112096 
Type: Phase 2 
Condition/Disease:  
Duchenne Muscular Dystrophy 
Approximate Number of Subjects: 132 
 
Approximate Duration of Subject Participation: 24 weeks for the 
Blinded Treatment Period, Open Label Extension Period until 
study termination. 
Approximate Number of Study Centers:  
50 globally 
Approximate Duration of Study: The Blinded Treatment Period 
portion of the study is estimated to be 3 years. 
Design:  
This is a multicenter, double blind, placebo controlled, multiple dose study to examine the safety and efficacy of 
MNK-1411 in male subjects 4 to 8 years of age (inclusive) with Duchenne Muscular Dystrophy (DMD). 
Approximately 150 subjects will be screened in order to randomize 132 (44 per treatment group).  
Following a screening period of up to 28 days, subjects will be randomized on a 2:2:1:1 basis to receive 24 weeks 
of treatment with 2 weight based doses of MNK-1411 or volume matched placebo administered 2x/week. 
Subjects will return to the clinic for visits at 4, 8, 12, 16, and 24 weeks after their first dose of study drug. 
Subjects who complete the 24-week Blinded Treatment Period will be eligible to enter an Open Label Extension 
Period where all subjects will receive treatment with MNK-1411. Participation in the Open Label Extension 
Period will continue until the subject chooses to discontinue treatment, the investigator feels that treatment is no 
longer indicated, MNK-1411 is approved and marketed, or the sponsor ceases development of this compound for 
DMD. All subjects will complete a 2-week drug taper after their last full dose of study drug and a follow-up visit 
28 (± 7) days after their last full dose of study drug. The taper is not required for any subject who has a 
hypersensitivity reaction to the study drug. 
Objectives: 
Primary Objective 
To determine the effect of MNK-1411 on motor function in subjects with DMD. 
Secondary Objectives 
To assess the effect of MNK-1411 on motor skills and strength. 
To determine the safety and tolerability of MNK-1411 in subjects with DMD. 
Exploratory Objectives 
 
 
 
 
Entry Criteria:  
Male subjects 4 to 8 years of age (inclusive) with a diagnosis of DMD confirmed by complete dystrophin 
deficiency, an identifiable mutation of the DMD gene, or complete dystrophin gene sequencing consistent with 
DMD, and a clinical profile consistent with DMD. Subjects should have serum potassium within the reference 
range at screening.  Subjects taking approved treatments that target gene mutation (eg, eteplirsen or ataluren) may 
be enrolled in the study if they have been on a stable dose for 30 days prior to the first dose of study drug, and 
plan to remain on that dose throughout the study. Subjects will be excluded if they have symptomatic 
cardiomyopathy; have had any previous systemic treatment with corticosteroids within 2 months prior to the 
Screening Visit; or treatment with immunosuppressants or mineralocorticoids in the 3 months prior to the 
Screening Visit. Subjects must be able to complete the 10 Meter Walk/Run test in 10 seconds or less at the 
Screening and Baseline Visits. 


MNK-1411 (Cosyntropin) 
 
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Study Title: A Multicenter, Randomized, Parallel Group, Double Blind, Multiple Dose, Placebo Controlled 
Study to Assess the Efficacy and Safety of MNK-1411 in Male Subjects 4 to 8 Years of Age With Duchenne 
Muscular Dystrophy 
Protocol Number: MNK14112096 
Type: Phase 2 
Condition/Disease:  
Duchenne Muscular Dystrophy 
Concomitant Medications and Treatments: Subjects are not permitted to receive live or live-attenuated 
vaccines (with the exception of the varicella zoster vaccine, if needed per Inclusion criterion 6), systemic 
corticosteroids (eg, prednisone or deflazacort) for DMD, mineralocorticoids, or immunosuppressants during the 
study. All medications and nondrug therapies (eg, physical therapy, blood transfusions, oxygen supplementation, 
etc) taken from 30 days prior to the Screening Visit and throughout the study will be recorded.  
Study Drug and Treatment Administration:  
The following treatments will be administered during the 24 week Blinded Treatment Period: 
 
Treatment A: MNK-1411 0.5 mg (0.5 mL, for subjects weighing more than 20 kg) or 0.4 mg (0.4 mL, 
for subjects weighing less than or equal to 20 kg) administered SC 2 times per week (2x/week) 
(administered on either Sunday and Wednesday, Monday and Thursday, Tuesday and Friday, or 
Wednesday and Saturday). 
 
Treatment B: MNK-1411 0.25 mg (0.25 mL, for subjects weighing more than 20 kg) or 0.2 mg 
(0.2 mL, for subjects weighing less than or equal to 20 kg) administered SC 2x/week (administered on 
either Sunday and Wednesday, Monday and Thursday, Tuesday and Friday, or Wednesday and 
Saturday). 
 
Treatment C: Volume matched placebo (0.5 mL for subjects weighing more than 20 kg or 0.4 mL for 
subjects weighing less than or equal to 20 kg) administered SC 2x/week (administered on either Sunday 
and Wednesday, Monday and Thursday, Tuesday and Friday, or Wednesday and Saturday). 
 
Treatment D: Volume matched placebo (0.25 mL for subjects weighing more than 20 kg or 0.2 mL for 
subjects weighing less than or equal to 20 kg) administered SC 2x/week (administered on either Sunday 
and Wednesday, Monday and Thursday, Tuesday and Friday, or Wednesday and Saturday). 
During the Open Label Extension Period, subjects will be treated with MNK-1411 at the dose administered 
during the Blinded Treatment Period. If a subject requires a switch in dose (eg, switch to low dose due to being 
unable to tolerate high dose, or switch to high dose based on increased weight [eg, as subject grows with age]), 
the investigator should consult with the medical monitor. No switches in dose are permitted during the Blinded 
Treatment Period. 
All subjects will complete a 2-week taper after their last full dose of study drug. In the first week of the taper, 
each subject will receive one-half of their original dose administered 2x/week for 1 week, followed by one-half of 
their original dose administered 1 time per week for 1 week. The taper is not required for any subject who has a 
hypersensitivity reaction to the study drug. 
Efficacy Evaluations: 
The following efficacy assessments will be evaluated: 10 Meter Walk/Run, North Star Ambulatory Assessment 
(NSAA), Time to Climb 4 Standardized Stairs, Time to Stand from A Supine Position, quantitative muscle 
testing, pulmonary function tests, and biomarkers. 
Pharmacokinetic and Pharmacodynamic Evaluations: 
The pharmacokinetics (PK) of MNK-1411 in DMD patients will be characterized using population PK modeling 
with sparse PK sampling implemented in this study. The exposure response (selected efficacy and/or safety 
endpoints at Week 4) relationship will be explored. 
Safety Evaluations:  
The following safety assessments will be evaluated: adverse events, medical history, physical examinations, 
concurrent medical conditions, height, weight, clinical laboratory tests, vital signs, electrocardiograms, and 
antidrug antibodies. 


MNK-1411 (Cosyntropin) 
 
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Study Title: A Multicenter, Randomized, Parallel Group, Double Blind, Multiple Dose, Placebo Controlled 
Study to Assess the Efficacy and Safety of MNK-1411 in Male Subjects 4 to 8 Years of Age With Duchenne 
Muscular Dystrophy 
Protocol Number: MNK14112096 
Type: Phase 2 
Condition/Disease:  
Duchenne Muscular Dystrophy 
Quality of Life/ Health Outcome Evaluations: 
The following quality of life /health outcome assessment will be evaluated: Pediatric Outcomes Data Collection 
Instrument (PODCI). 
Statistical Methods: 
Analysis Populations 
The following analysis populations are defined for this study: 
 
The Modified Intent-to-Treat (mITT) Population will include all randomized subjects who receive 1 or 
more doses of study drug and who contribute any efficacy data to the study. 
 
The Safety Population will include all subjects who receive 1 or more doses of study drug. 
 
The PK Population will include all subjects who provide at least 1 quantifiable concentration of 
ACTH1-24 following the administration of at least 1 complete dose of study drug, and without any major 
protocol deviations that compromise the PK samples. 
Sample Size  
A total of 132 subjects will be randomized in this study (44 per treatment group). The sample size was 
determined using the change from baseline in the 10 Meter Walk/Run time. With 37 subjects per treatment group 
expected to complete the Blinded Treatment Period, the trial will have an 80% power to detect a 1 second 
treatment difference comparing 2 groups at a significance level of 0.05. Taking into account a dropout rate of 
approximately 15%, the sample size for this study will be 44 subjects per treatment arm. 
Efficacy Analysis  
Unless otherwise specified, all statistical tests will be two-sided with a significance level of 0.05. Summary 
statistics will be provided for all study variables with descriptive statistics (number of observations, mean, SD, 
median, minimum, and maximum) for numerical (or continuous) variables, and frequency and percentages will 
be calculated for categorical variables. All data will be summarized by treatment groups as appropriate. The 
2 placebo groups will be combined for all analyses. Data summary and analyses will be performed with SAS 9.4 
or higher.  
The primary efficacy endpoint is a change from baseline in 10 Meter Walk/Run time at Week 24. The primary 
statistical analysis method for the endpoint will be performed using an analysis of variance (ANOVA) model with 
treatment as a main factor and baseline value as a covariate.  
The secondary efficacy endpoints will be analyzed using the same statistical method as that for the primary 
efficacy endpoint.  
Additional exploratory analyses 
 
 
 
Pharmacokinetic Analysis 
Population PK analysis for MNK-1411 will be conducted using nonlinear mixed effects modeling.  
Safety Analysis 
Treatment-emergent adverse events and serious adverse events will be summarized using the appropriate version 
of MedDRA by preferred term within system organ class. Other safety data will be listed and summarized 
descriptively or graphically, as appropriate. 


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Study Title: A Multicenter, Randomized, Parallel Group, Double Blind, Multiple Dose, Placebo Controlled 
Study to Assess the Efficacy and Safety of MNK-1411 in Male Subjects 4 to 8 Years of Age With Duchenne 
Muscular Dystrophy 
Protocol Number: MNK14112096 
Type: Phase 2 
Condition/Disease:  
Duchenne Muscular Dystrophy 
Quality of Life/Health Outcomes Analysis 
The PODCI (sport and physical functioning domain and transfer/basic mobility domain) will be summarized at 
baseline and each study visit. Change from baseline to Weeks 4, 8, 12, 16, and 24 in PODCI domains also will be 
summarized. The change from baseline data will be analyzed using the same methods as those used for the 
primary efficacy endpoint. 
Open Label Extension Analysis 
In the Open Label Extension Period, efficacy data will be summarized at each visit. Safety data will also be 
summarized as appropriate.