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| Name | Class |
|---|---|
| British Medical Research Council | OTHER_GOV |
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The specific aim of this Phase I/II study is to assess the safety of intravenous administered Morpholino oligomer directed against exon 51 (AVI-4658 PMO).
Primary outcome is safety, tolerability and dose selection for future studies.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 - 0.5 mg/kg/wk | Experimental | Subjects in this group will receive a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
|
| Cohort 2 - 1.0 mg/kg/wk | Experimental | Subjects in this group will receive a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
|
| Cohort 3 - 2.0 mg/kg/wk | Experimental | Subjects in this group will receive a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
|
| Cohort 4 - 4.0 mg/kg/wk | Experimental | Subjects in this group will receive a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
|
| Cohort 5 - 10.0 mg/kg/wk | Experimental | Subjects in this group will receive a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AVI-4658 for Injection | Drug | AVI-4658 for Injection, is packaged as 100 mg/mL in phosphate buffered saline with 1 mL per vial. Study dosages will be infused over a 1 hour period with Normal saline in 6 dose cohorts. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability | Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug | Baseline to 6 months |
| Treatment Emergent Adverse Events | Number of Patients with Treatment Emergent Adverse Events | from Baseline to Follow up (27 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration | Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data. | Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Austen Eddy, MSM | AVI BioPharma, Director, Clinical Operations | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Great Ormond Street Hospital | London | England | WC1N 3JH | United Kingdom | ||
| Royal Victoria Infirmary |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21784508 | Result | Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011 Aug 13;378(9791):595-605. doi: 10.1016/S0140-6736(11)60756-3. Epub 2011 Jul 23. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 - 0.5 mg/kg/wk | Subjects in this group received a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| FG001 | Cohort 2 - 1.0 mg/kg/wk | Subjects in this group will receive a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| FG002 | Cohort 3 - 2.0 mg/kg/wk | Subjects in this group will receive a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| FG003 | Cohort 4 - 4.0 mg/kg/wk | Subjects in this group will receive a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| FG004 | Cohort 5 - 10.0 mg/kg/wk | Subjects in this group will receive a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| FG005 | Cohort 6 - 20.0 mg/kg/wk | Subjects in this group will receive a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 - 0.5mg/kg/wk | Subjects in this group received a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| BG001 | Cohort 2 - 1.0mg/kg/wk |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Safety and Tolerability | Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug | Safety Population - Any patient who received at least one dose of the study drug. | Posted | Number | participants | Baseline to 6 months |
|
Adverse Event data for this study was collected from Baseline to Follow-up (27 Weeks)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1 - 0.5 mg/kg/wk | Subjects in this group received a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Post-Operative Nausea and Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rhinitis | Infections and infestations | Non-systematic Assessment |
Due to the small number of study participants, a single adverse event (AE) in 1 patient exceeds the reporting threshold of 5%. Refer to the "Post-Hoc Outcome Measures" #5 for a summary of frequent and related AEs.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Edward M. Kaye, MD, Interim CEO, SVP & Chief Medical Officer | Sarepta Therapeutics | 617-274-4003 | EKaye@Sarepta.com |
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| ID | Term |
|---|---|
| D020388 | Muscular Dystrophy, Duchenne |
| ID | Term |
|---|---|
| D009136 | Muscular Dystrophies |
| D020966 | Muscular Disorders, Atrophic |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| C000611335 | eteplirsen |
| D007267 | Injections |
| ID | Term |
|---|---|
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
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|
| Cohort 6 - 20.0 mg/kg/wk | Experimental | Subjects in this group will receive a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
|
|
| Efficacy of Eteplirsen Over 12 Weeks of Dosing | Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers. | Biopsies were taken at Baseline and Week 14 |
| Newcastle upon Tyne |
| England |
| NE2 4LP |
| United Kingdom |
Subjects in this group received a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period
| BG002 | Cohort 3 - 2.0mg/kg/wk | Subjects in this group received a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| BG003 | Cohort 4 - 4.0mg/kg/wk | Subjects in this group received a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| BG004 | Cohort 5 - 10.0mg/kg/wk | Subjects in this group received a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| BG005 | Cohort 6 - 20.0mg/kg/wk | Subjects in this group received a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period |
| BG006 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Body Weight | Mean | Standard Deviation | kilograms |
|
| Height | Mean | Standard Deviation | centimeters |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration | Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data. | PK Evaluable Population: Included all patients who provided at least 1 PK sample. The reportable PK population included those patients with at least Cmax, Tmax, and AUC0-24 computed from 1 or more of the 3 sampling days (1st, 6th, 12th dose [Weeks 1, 6, and 12]). | Posted | Mean | Standard Deviation | ng/mL | Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12 |
|
|
|
| Secondary | Efficacy of Eteplirsen Over 12 Weeks of Dosing | Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers. | Per Protocol Population - Included all patients who received all 12 doses of study treatment. | Posted | Number | participants | Biopsies were taken at Baseline and Week 14 |
|
|
|
| Primary | Treatment Emergent Adverse Events | Number of Patients with Treatment Emergent Adverse Events | Safety Population | Posted | Number | participants | from Baseline to Follow up (27 weeks) |
|
|
|
| Post-Hoc | Adverse Events >15% | Adverse events that occurred in >15% of overall patient population across dose level arms. | Safety Population | Posted | Number | Events | 27 Weeks |
|
|
|
| 0 |
| 4 |
| 4 |
| 4 |
| EG001 | Cohort 2 - 1.0 mg/kg/wk | Subjects in this group received a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period | 0 | 2 | 2 | 2 |
| EG002 | Cohort 3 - 2.0 mg/kg/wk | Subjects in this group received a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period | 1 | 2 | 2 | 2 |
| EG003 | Cohort 4 - 4.0 mg/kg/wk | Subjects in this group received a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period | 1 | 3 | 3 | 3 |
| EG004 | Cohort 5 - 10.0 mg/kg/wk | Subjects in this group received a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period | 0 | 4 | 4 | 4 |
| EG005 | Cohort 6 - 20.0 mg/kg/wk | Subjects in this group received a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60 minute period | 0 | 4 | 4 | 4 |
| Fracture of Left Medial Malleolus | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | Non-systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Influenza like illness | General disorders | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Platelet anisocytosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Cardiomyopathy | Cardiac disorders | Non-systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Ear Pain | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Abdominal pain - Upper | Gastrointestinal disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Enteritis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Lip dry | Gastrointestinal disorders | Non-systematic Assessment |
|
| Abasia | General disorders | Non-systematic Assessment |
|
| Application site rash | General disorders | Non-systematic Assessment |
|
| Catheter Site Pain | General disorders | Non-systematic Assessment |
|
| Disease progression | General disorders | Non-systematic Assessment | One subject had a reduction in fractional shortening due DMD progression One subject had a deterioration of clinical signs of DMD |
|
| Fatigue | General disorders | Non-systematic Assessment |
|
| Infusion related reaction | General disorders | Non-systematic Assessment |
|
| Pyrexia | General disorders | Non-systematic Assessment |
|
| Vaccination site pain | General disorders | Non-systematic Assessment |
|
| Vessel puncture site haematoma | General disorders | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | Non-systematic Assessment |
|
| Hordeolum | Infections and infestations | Non-systematic Assessment |
|
| Incision site infection | Infections and infestations | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | Non-systematic Assessment |
|
| Respiratory tract infection viral | Infections and infestations | Non-systematic Assessment |
|
| Tinea infection | Infections and infestations | Non-systematic Assessment |
|
| Viral Infection | Infections and infestations | Non-systematic Assessment |
|
| Ankle Fracture | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Arthropod bite | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Arthropod sting | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Excoriation | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Head Injury | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Heat Stroke | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Lumbar vertebral fracture | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Post procedural haematoma | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Procedural Pain | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Vaccination complication | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Decreased appetitie | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Coccydynia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Osteopenia | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Enuresis | Renal and urinary disorders | Non-systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Drug eruption | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Skin irritation | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Haematoma | Vascular disorders | Non-systematic Assessment |
|
| Pallor | Vascular disorders | Non-systematic Assessment |
|
The PI required written permission to publish any information relating to the trial and if given permission to acknowledge the sponsor's contribution and ownership of the materials.
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Tachycardia |
|
| Abdominal Pain |
|
| Nausea |
|
| Vomiting |
|
| Influenza like illness |
|
| Rhinitis |
|
| Upper respiratory tract infection |
|
| Fall |
|
| Arthralgia |
|
| Back Pain |
|
| Myalgia |
|
| Dizziness |
|
| Headache |
|