CTRI Number	CTRI/2021/04/032498 [Registered on: 01/04/2021] Trial Registered Prospectively
Last Modified On:	01/03/2022
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug
Study Design	Randomized, Parallel Group, Active Controlled Trial
Public Title of Study Modification(s)	A clinical trial to study the effects of Antisense Oligonucleotide in boys with Duchenne Muscular Dystrophy.
Scientific Title of Study	A Double Blind, Placebo-Controlled, Multicentre Study with an Open-Label Extension to Evaluate the Efficacy and Safety of 2’O Methyl Antisense Oligonucleotide in Patients with Duchenne Muscular Dystrophy
Secondary IDs if Any Modification(s)	Secondary ID  Registry  DART_CT_DMD-001 vesion 03 dated 15-06-2020  Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)	Name  Dr Surinder Kher  Address  Vaswani Presidio 3rd Floor Panathur Main Road Outer Ring Road Bengaluru Bangalore KARNATAKA 560103 India  Phone  9900503671   Fax     Email  skher@vibranceclinical.com
Details Contact Person Scientific Query	Name  Dr Surinder Kher  Address  Vaswani Presidio 3rd Floor Panathur Main Road Outer Ring Road Bengaluru Bangalore KARNATAKA 560103 India  Phone  9900503671   Fax     Email  skher@vibranceclinical.com
Details Contact Person Public Query	Name  Dr Arun Shastry  Address  295, 14th Cross, Dollars Colony, RMV II Sanjay Nagar, Bangalore Bangalore KARNATAKA 560094 India  Phone  9840219833   Fax     Email  arunshastry@dartindia.in
Source of Monetary or Material Support	DART India Bangalore
Primary Sponsor	Name  Dystrophy Annihilation Research Trust  Address  295, 14th Cross, Dollars Colony, RMV II Sanjay Nagar, Bangalore 560094 Karnataka  Type of Sponsor  Other [NGO]
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study Modification(s)	No of Sites = 4   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Madhulika Kabra  All India Institute of Medical Sciences  Ansari Nagar New Delhi   9891543958 madhulikakabra@hotmail.com  Dr Sanjeeva GN  Indra Gandhi Institute of Child Health  South Hospital Complex, Dharamraj College Post Bengaluru-560029 Bangalore   9945657034 sanju.gn26@gmail.com  Dr Renu Suthar  PGIMER Chandigarh  Madhya Marg, Sector 12, Chandigarh, 160012 Chandigarh   9855483969 suthar.renu@pgimer.edu.in  Dr I C Verma  Sir Ganga Ram Hospital  Old Rajinder Nagar New Delhi New Delhi   9818659921 bijarnia@gmail.com
Details of Ethics Committee Modification(s)	No of Ethics Committees= 4   Name of Committee  Approval Status  AIIMS Institute Ethics Committee New Delhi  Approved  Indra Gandhi Institute of Child Health Ethics Committee  Approved  Institutional Ethics Committee Post Graduate Institute of Medical Education and Research Chandigarh  Approved  Sir Ganga Ram Hospital Ethics Committee  Approved
Regulatory Clearance Status from DCGI	Status  Approved/Obtained
Health Condition / Problems Studied	Health Type  Condition  Patients  Administration  Patients  Muscular dystrophy
Intervention / Comparator Agent Modification(s)	Type  Name  Details  Intervention  2 O Antisense Oligonucleotide  Active Arm- 2 O antisense oligonucleotide plus current underlying standard of care  Comparator Agent  Placebo  Arm 2 Placebo plus current underlying standard of care
Inclusion Criteria Modification(s)	Age From  5.00 Year(s) Age To  25.00 Year(s) Gender  Male  Details  A patient must meet all of the following criteria to be eligible for this study. 1) An established clinical diagnosis of DMD with mutation amenable for Exon 45 or 51 or 53 skipping confirmed by state-of-the-art DNA diagnostic technique like Next Generation Sequencing (NGS) 2) Male, at least 5 years of age at randomization 3) Able to rise from floor in ≤7 seconds (without aids/orthoses) 4) Able to complete the 6MWD test with a distance of at least 75m 5) should be on glucocorticoids for a minimum of six months immediately prior to screening, with no significant change in total daily dosage or dosing regimen for a minimum of 3 months immediately prior to screening and a reasonable expectation that total daily dosage and dosing regimen will not change significantly for the duration of the study (unless clinically indicated) 6) Has stable pulmonary function (FVC % of predicted ≥50% and no requirement for nocturnal ventilation) that, in Investigator’s opinion, is unlikely to decompensate over the duration of the study 7) Echo with EF>45% 8) Life expectancy of at least 1 year 9) No previous treatment with investigational medicinal treatment within six months prior to the study 10) Willing and able to comply with all study requirements and (self or through parent/ guardian) procedures (with the exception of those assessments requiring a subject to be ambulant, for those subjects who have lost ambulation) 11) Able to give informed assent and/or consent in writing by the subject and/or parent(s)/legal guardian (according to local regulations)
ExclusionCriteria	Details  • A patient who meets any of the following criteria will be excluded from this study. • Aberrant RNA splicing and/or aberrant response to Exon Skipping • FVC <50% of predicted percentage • Current or history of liver or renal disease • Acute illness within 4 weeks prior to treatment which may interfere with the measurements • Severe mental retardation which in the opinion of the investigator prohibits participation in this study • Severe cardiac myopathy which in the opinion of the investigator prohibits participation in this study • Need for mechanical ventilation • Creatinine concentration above 1.5 times the upper limit of normal (age corrected) • Serum ASAT and/or ALAT concentration(s) which suggest hepatic impairment • Use of anticoagulants, anti-thrombotic or anti-platelet agents • Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test at screening, • History of significant medical disorder which may confound the interpretation of safety data (e.g. current or history of renal or liver disease/impairment, history of inflammatory illness) • Symptomatic cardiomyopathy. If subject has a left ventricular ejection fraction <25% at start of this study, the investigator should discuss inclusion of subject in this study with the Medical Monitor • A platelet count under the lower limit of normal (LLN) at start of this study. A re-test is possible at a later stage, and if within normal range, the subject may enter the study • Current or history of drug and/or alcohol abuse
Method of Generating Random Sequence	Computer generated randomization
Method of Concealment	On-site computer system
Blinding/Masking	Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome	Outcome  TimePoints  Primary Endpoints: Efficacy • Change from Baseline at Week 24 in 6MWT. • NSAA total score Safety The safety and tolerability of 2’O Methyl Antisense Oligonucleotide will be assessed through a review and evaluation of AEs, serious adverse events (SAEs), deaths and discontinuations due to AEs; laboratory testing including hematology, coagulation, chemistry and urinalysis, Echo, ECG; vital signs; and physical examination findings.   24 weeks safety and efficacy 48 weeks safety and efficacy 52 weeks safety follow up
Secondary Outcome	Outcome  TimePoints  Secondary Endpoints: • Ability to rise independently from the floor (without external support) at Week 24 • Time to Loss of Ambulation (LOA) from randomization through Week 24. • Change from Baseline at Week 24 in: o forced vital capacity percent (FVC%) predicted o Frequency of falls o LVEF   Baseline vs 24 weeks and 48 weeks
Target Sample Size	Total Sample Size="117" Sample Size from India="117"
Phase of Trial	Phase 2/ Phase 3
Date of First Enrollment (India)	15/06/2021
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="1" Months="9" Days="0"
Recruitment Status of Trial (Global)	Not Applicable
Recruitment Status of Trial (India)	Not Yet Recruiting
Publication Details	Nil
Brief Summary Modification(s)	The purpose of this study is to evaluate the efficacy and safety of 2’O Methyl Antisense Oligonucleotide administration in DMD patients with deletion mutations amenable to treatment by exon skipping.  DMD is a progressive disease that leads to relentless deterioration of muscle function and is ultimately fatal. As there is no approved therapy for DMD patients in India with mutations amenable to treatment by exon skipping there is a high unmet medical need for effective treatments. 2’O Methyl Antisense Oligonucleotide has the potential to be disease-modifying therapy for such patients as has been proven in earlier clinical studies outside India. This study   is designed to investigate the efficacy and safety of 2’O Methyl Antisense Oligonucleotide in DMD patients. No therapies are currently available for these DMD patients. 2’O Methyl Antisense Oligonucleotide is designed to promote alternative splicing of the dystrophin transcript to restore the reading frame, permitting production of an internally truncated form of dystrophin protein. This is a randomized, double-blind, parallel group, placebo-controlled, multi-centre study to assess the efficacy and safety of 2’O Methyl Antisense Oligonucleotide compared to Placebo in Duchenne Muscular Dystrophy ambulant boys. Approximately 54 patients with genotypically confirmed DMD with mutation amenable for Exon 45 or 51 or 53 skipping as determined by genetic testing. A placebo group will be employed, and patients will be randomized in a double-blind fashion in a 1:1 ratio of active drug to placebo respectively.   The total duration of the blinded treatment  is  48 weeks. Post completion of the 48 week blinded treatment all patients will enter an open label treatment period of 24 weeks.  In the open-label extension part of the study, all the subjects (irrespective of whether they received placebo in the double-blind phase) will receive the active treatment. At the end of the treatment period, all patients will be followed up for a minimum of 4 weeks after receiving the last dose of the study drug. Patients   will continue their baseline current standard steroid therapy in both groups. An independent Data Safety and Monitoring Committee  will review  the safety and data quality and the integrity of the study conduct.