E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne Muscular Dystrophy |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013801 |
E.1.2 | Term | Duchenne muscular dystrophy |
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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 |
The primary objective of this Phase 1b study is to assess the safety of escalating doses of AVI-4658 when administered by 12 weekly doses in boys with Duchenne muscular dystrophy (DMD). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to explore, after i.v. administration: 1) the pharmacokinetics (PK) of AVI-4658 in patients, and 2) the efficacy of AVI-4658 over 12 weeks of dosing.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Candidates will be included in the study only if all of the following conditions are met:
1. Has provided written informed assent (as required by Ethics Committee) and parents/guardians have provided written informed consent. 2. Has an out of frame deletion(s) that could be corrected by skipping exon 51 [45-50; 47 50; 48-50; 49-50; 50; 52; 52-63], based on DNA sequencing data. 3. Is male and between the ages of ≥ 5 years and ≤ 15 years. 4. Has a muscle biopsy analysis showing < 5% revertant fibers present. 5. DNA sequencing of exon 51 confirms that no DNA polymorphisms occur that could compromise PMO duplex formation or there is confirmation of in vitro dystrophin production after AVI-4658 exposure to fibroblast or myoblast in vitro cultures. 6. Has intact right and left biceps muscles or alternative arm muscle group. 7. Is able to walk independently for at least 25 meters. 8. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen. 9. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD. 10. The parent(s) or legal guardian and subject have undergone counselling about the expectations of this protocol and agree to participate. 11. The parent(s) or legal guardian and subject intend to comply with all study evaluations and return for all study activities.
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E.4 | Principal exclusion criteria |
Candidates will be excluded from the study if any one of the following conditions are present:
1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation. 2. Known antibodies to dystrophin. 3. Lacks intact right and left biceps muscles or alternative arm muscle group. 4. A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockroft and Gault Formula. 5. A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening < 25% based on echocardiography (ECHO) during screening. 6. A history of respiratory insufficiency as defined by a need for intermittent or continuous supplemental oxygen. 7. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol. 8. Any known immune deficiency or autoimmune disease. 9. A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry. 10. Receipt of pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz., growth hormone and/or anabolic steroids). 11. Surgery within 3 months of study entry or planned for anytime during the duration of the study. 12. Another clinically significant illness at time of study entry. 13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances, recent significant emotional loss, and/or history of depressive or anxiety disorder that might interfere with protocol completion or compliance. 14. Use of any experimental treatments, has participated in any DMD interventional clinical trial within 4 weeks of study entry or participation in the AVI-4658-33 i.m. trial.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measures are measures of safety and tolerability.
Safety will be assessed by a series of physical examinations, safety laboratory tests, pulmonary function tests (notably forced vital capacity [FVC]), ECGs, and echocardiography (notably ejection fraction [EF]) by comparison to baseline status for each subject.
Tolerability will be assessed by passive reporting, i.e., from the subject and/or parent or guardian) and elicitation of SAEs and AEs by the study staff.
Additional safety evaluations: To rule out an immunological inflammatory response biopsied muscles will be studied for immune cell infiltration. In particular, the presence of cytotoxic T-cells will be assessed. Verification will be performed via examination of serial sections. All subjects will be monitored for anti-dystrophin antibodies.
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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 | No |
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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Safety, with exploratory PK and efficacy |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |