| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Duchenne Muscular Dystrophy | |
| E.1.1.1 | Medical condition in easily understood language | | Duchenne Muscular Dystrophy | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10013801 | | E.1.2 | Term | Duchenne muscular dystrophy | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | Blinded phase: To evaluate the effect of ATL1102 on upper limb muscle function in non-ambulant participants with DMD, as assessed by change in the Performance of Upper Limb Module for DMD 2.0 (PUL 2.0) score compared to placebo.
OLE phase: To evaluate the continued safety and tolerability of ATL1102 administered once weekly by subcutaneous injection, in non-ambulant participants with DMD.
For Primary Combined Blinded and OLE Phases objectives please see section 4.3 of Protocol | |
| E.2.2 | Secondary objectives of the trial | Blinded phase: 1.To evaluate the effects of ATL1102 using several additional endpoints for assessment of muscle function, strength, respiratory function and Quality of Life
2.To evaluate the safety and tolerability of ATL1102 administered once weekly, by subcutaneous injection in non-ambulant participants with DMD including events associated with the Safety Monitoring Plan and Stopping Rules.
3.To evaluate the pharmacokinetic (PK) profile of ATL1102 at the different dose levels, administered once weekly by subcutaneous injection in non-ambulant participants with DMD.
OLE Phase:1.To evaluate the of effect of ATL1102 on upper limb muscle function in non-ambulant participants with DMD as assessed by change in the Performance of Upper Limb Module for DMD 2.0 (PUL 2.0) score.
2.To evaluate the effects of ATL1102 using several additional endpoints for assessment of muscle function, strength, respiratory function and Quality of Life
Full list of secondary obj. refer in sec. 4 of protocol | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | A participant will be entered into this study only if they meet all of the following criteria:
1.Has a parent/guardian who is capable of understanding the purposes and risks of the study and is able to provide voluntary written informed consent for the participant to participate in the study and assent will be documented.
2.Where required by law or if the Investigator determines the potential participant is of sufficient maturity and has the ability to understand the nature and consequence of the study, participant consent will be obtained. Otherwise, assent will be documented.
3.Has a clinical diagnosis of DMD confirmed by validated genetic testing (i.e., documented deletion, duplication or point mutation in the dystrophin gene).
4.Is considered to be non-ambulatory, defined as unable to walk 10 meters without assistance or help at Screening
5.Male aged 10 to less than 18 years, at the time of screening and informed consent for participation in the study.
6.Body weight of at least 25 kg at Screening.
7.If receiving corticosteroid therapy, therapy was initiated at least six months prior to the baseline visit and a stable daily dose for at least 3
months prior to baseline and, there is currently no clinical intent to alter the dose during the study period, except for adaption for body weight.
8.On study entry (Screening and Baseline), the participant has a Performance of Upper Limb Module for DMD 2.0 (PUL 2.0) Entry Item A score ≥2.
9.Able to perform spirometry and has sufficient Respiratory function defined as reproducible percent predicted FVC ≥50%. Ability to provide reliable and reproducible repeat FVC with the best of three attempts assessed at Baseline being within 20% of the best of three attempts assessed at Screening.
10.Has adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥45% by echocardiogram and if receiving cardiac medication, must be currently on a stable regimen and doses of cardiac therapy (at least 3 months prior to baseline Day 1) including angiotensin converting enzyme inhibitors (ACEi), angiotensin 2 receptor antagonists (A2RA), aldosterone receptor antagonists (ARA) or beta blockers (BB).
11.Participant who is post pubertal and sexually active must agree to use approved methods of contraception (condoms or abstinence) for the duration of the study and until 4 months after administration of the last dose of the study medication. Female sexual partner must also agree to use a medically acceptable form of contraception.
12.Participant and their parent/guardian are willing and able to comply with scheduled visits, study medication administration and study procedures. | |
| E.4 | Principal exclusion criteria | A participant who meets any of the following criteria will be excluded from participating in the study:
1.Participation in another clinical trial (non-interventional) or administration of any investigational product or experimental product within 12 weeks or 5 half-lives (whichever is longer) preceding Day 1.
2.Exposure to more than 3 investigational products within the 12 months prior to Day 1.
3.Has the following abnormal haematology values during the Screening period:
a.Lymphocytes <1.2 x 109/L
b.Neutrophils <1.8 x 109/L
c.Platelets <150 x 109/L.
4.Has the following liver function test values during the Screening period:
a.Gamma glutamyl transpeptidase (GGT) levels >2.0 x the upper limit of normal (ULN) or
b.Total bilirubin concentrations greater than 1.5 x ULN or
c.Glutamate dehydrogenase (GLDH) levels greater than 2.0 x ULN.
5.History of clinically significant bleeding or coagulation abnormalities.
6.Clinically significant abnormal coagulation parameters.
7.Currently receiving antiplatelet or anticoagulant therapy or has taken medication with an antiplatelet or anticoagulant effect within 4 weeks prior Day 1 (e.g., aspirin).
8.History of hypersensitivity to ATL1102 or to any of the excipients in the ATL1102 drug product formulation.
9.Any evidence of clinically significant structural or functional heart abnormality (cardiomyopathy that is managed by ACEi or beta blockers is acceptable provided the LVEF inclusion criterion is met).
10.Known history of or a positive test for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibodies, human immunodeficiency virus (HIV) antibodies at Screening.
11.Evidence of renal impairment and/or cystatin C >1.4 mg/L.
12.Received a live vaccine (including intranasal influenza vaccine) within 4 weeks prior to Day 1 or planned live vaccination during the study period.
13.Planned or expected surgery during the study period (as judged by the Investigator).
14.Asthma (if requiring regular medication), bronchitis/chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, pneumonia or the presence of any non-DMD respiratory illness that affects PEF and FVC or other respiratory measures.
15.Requires day-time assisted mechanical or non-invasive ventilation (NIV) (night-time NIV is permitted).
16.Unable to form a mouth seal to allow precise respiratory flow measurements and mouth pressure.
17.Chronic use (daily intake >14 days), within one month of Day 1, of beta-2 agonists or any use of other bronchodilating medication (e.g., inhaled steroids, sympathomimetics, anticholinergics).
18.Used carnitine, creatine, glutamine, oxatomide, idebenone or other forms of coenzyme Q10 or vitamin E or any other nutritional or antioxidant supplements or herbal medicines or anabolic steroids other than standard corticosteroids or puberty testosterone supplementation within 4 weeks of Day 1. NOTE: daily multivitamin, Vitamin D or calcium supplements are permitted.
Used ataluren, eteplirsen, casimersen, golodirsen (or other exon skipping antisense oligonucleotide drugs), and vamorolone within 6
months prior to Day 1.
Used systemic immunosuppressants treatment (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, TNFɑ inhibitors) within the 3 months prior to Day 1.
Used intravenous immunoglobulin (IVIg) within 6 months prior to Day 1.
Refer Section 7.6.2 Prohibited Medication.
19.Other than the condition under study, has a history of or current active medical condition including allergic, skin, cardiovascular, psychiatric disease, drug or alcohol abuse, severe behavioural or cognitive deficits, or laboratory finding, that in the opinion of the Investigator precludes participation in the study, or may interfere with the study objectives/results.
20.Has an increased risk for opportunistic infections or systemic medical conditions resulting in significantly compromised immune system function (e.g., HIV, organ transplant, active malignancy).
21.An employee of the Sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Blinded Phase: Change of Performance of Upper Limb (PUL 2.0) score from baseline to Week 25.
OLE Phase (Efficacy): Change of Performance of Upper Limb (PUL 2.0) score from Week 25 to Week 49.
OLE Phase (Safety):
1.Frequency and severity of AEs, SAEs and SUSARs.
2.Clinical Laboratory Tests
i.Haematology
ii.Coagulation (including fibrinogen)
iii.Complement
iv.Biochemistry (including haptoglobin)
v.Urinalysis (including weekly dipsticks)
3.Cardiac function (ECG, echocardiogram)
4.Respiratory function (as above in efficacy)
5.Physical examination
6.Vital Signs (blood pressure, heart rate, respiratory rate, tympanic temperature)
7.Events associated with the Safety Monitoring Plan and Stopping Rules
i.number, total frequency and percentage of participants overall who experience events defined in the Safety Monitoring Plan and in whom dosing is halted on a temporary basis or on a permanent basis.
ii.Number, total frequency and percentage of participants who experience events defined in each category in the Safety Monitoring Plan (Liver Function Tests [LFTs], Renal Function tests [RFTs], Platelets, CRP, A/G ratio, Complement C3, haematology, haptoglobin, fibrinogen, MCP-1, opportunistic infections, cardiac function and JCV antibodies/PML) and in whom dosing is halted on a temporary basis or on a permanent basis.
Combined Blinded and Open Label Phase: 1.Change of Performance of Upper Limb (PUL 2.0) score from baseline to Week 25 compared to the change from Week 25 to Week 49.
2.Change of Performance of Upper Limb (PUL 2.0) score from baseline to Week 49 (for those that remained on the same ATL1102 treatment dose over the blinded and OLE phases of the study). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | Blinded Phase: From baseline to week 25
OLE Phase (Efficacy): From week 25 to week 49
OLE Phase (Safety): throughout the study
Combined Blinded and Open Label Phase:
1. from week 25 to week 49
2. from baseline to week 49 | |
| E.5.2 | Secondary end point(s) | Blinded Phase (Efficacy):
1.Percentage of treatment responders at Week 25, where a treatment responder is defined as no decline from baseline in Performance of Upper Limb (PUL 2.0).
2.Change in muscle strength as assessed by percent predicted MyoGrip (using the Myoset System) from baseline to Week 25.
3.Change in muscle strength as assessed by percent predicted MyoPinch (using the Myoset System) from baseline to Week 25.
4.The extent of response in a total arm functional score from baseline to Week 25 will be assessed by the cumulative distribution of the number of the components of total arm functional score (PUL2.0, dominant hand and non-dominant hand MyoGrip and MyoPinch) that do not decline. The endpoint variable will be the count of the number of components with stabilisation yielding a count ranging from 0 to 5.
5.Change of Performance of Upper Limb (PUL 2.0) score from baseline to Week 25 for each of the dimensions of the PUL2.0; high level shoulder, mid-level elbow and distal level wrist and hand.
6.Respiratory function assessed by percent predicted PEF and percent predicted FVC from baseline to Week 25.
7.Quality of Life assessed by percentage of change in the Paediatric quality of life instrument, PedsQL™ Duchenne Muscular Dystrophy (DMD) Module Patient Report and Parent Report scores (at baseline [Day 1/Week 0], Weeks 12, 24 and pre-dose Week 25).
OLE Phase (Efficacy):
1.Percentage of treatment responders at Week 49, where a treatment responder is defined as no decline from baseline at entry into this extension study in Performance of Upper Limb (PUL 2.0).
2.Change in Muscle strength as assessed by and percent predicted MyoGrip (using the Myoset System) from Week 25 to Week 49.
3.Change in Muscle strength as assessed by percent predicted MyoPinch (using the Myoset System) from Week 25 to Week 49.
4.The extent of response in a total arm functional score from Week 25 to Week 49 will be assessed by the cumulative distribution of the number of the components of total arm functional score (PUL2.0, right hand and left hand MyoGrip and MyoPinch) that do not decline. The endpoint variable will be the count of the number of components with stabilisation yielding a count ranging from 0 to 5.
5.Change of Performance of Upper Limb (PUL 2.0) score from Week 25 to Week 49 for each of the dimensions of the PUL2.0; high level shoulder, mid-level elbow and distal level wrist and hand.
6.Respiratory function assessed by percent predicted PEF and percent predicted FVC from Week 25 to Week 49.
7.Quality of Life assessed by percentage of change in the Paediatric quality of life instrument PedsQL™ Duchenne Muscular Dystrophy (DMD) Module Patient Reports and Parent Reports scores (at Weeks 25, 37 and 49 and at Week 65).
Combined Blinded and Open Label Phase:
1.Percentage of treatment responders in the OLE phase compared to the blinded phase in each of the 4 treatment groups; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
2.Change in Muscle strength as assessed by percent predicted MyoGrip (using the Myoset System) from baseline to Week 25 compared to the change from Week 25 to Week 49; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
3.Change in Muscle strength as assessed by percent predicted MyoPinch (using the Myoset System) from baseline to Week 25 compared to the change from Week 25 to Week 49; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
4.The extent of response in total arm functional score from OLE phase compared to the blinded phase in each of the 4 treatment groups; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
5.Change of Performance of Upper Limb (PUL 2.0) score for each of the dimensions of the PUL2.0; high level shoulder, mid-level elbow and distal level wrist and hand. from baseline to Week 25 compared to the change from Week 25 to Week 49; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
6.Respiratory function assessed by percent predicted PEF and, percent predicted FVC from baseline to Week 25 compared to the change from Week 25 to Week 49; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
7.Quality of Life assessed by percentage of change in the Paediatric Quality of Life instrument PedsQLTM Duchenne Muscular Dystrophy (DMD) Module Patient Reports and Parent Reports scores from baseline (Day1/Week 0) through to Week 25 and Week 25 through to Week 49; and from baseline to Week 49 for those that remained on the same dose of ATL1102.
For complete list of endpoints please refer to section 5.4 of protocol | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Blinded Phase:
1. Week 25
2.-6. from baseline to Week 25
7. at baseline [Day 1/Week 0], Weeks 12, 24 and pre-dose Week 25
OLE Phase:
1. Week 49
2.-6. from Week 25 to Week 49
7. at Weeks 25, 37 and 49 and at Week 65
Combined Blinded and Open Label Phase:
1.-7. from baseline to Week 49 | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | | Double blind study with open label extension | |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 | The trial involves single site in the Member State concerned | Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Serbia | | United Kingdom | | Bulgaria | | Türkiye | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
