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| ID | Type | Description | Link |
|---|---|---|---|
| 2007-002809-48 | EudraCT Number |
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Early termination following Trial Steering Committee recommendation
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| Name | Class |
|---|---|
| British Heart Foundation | OTHER |
| Leducq Foundation | OTHER |
| Celladon Corporation | INDUSTRY |
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The aim of the study is to determine the safety and feasibility of giving an adeno-associated viral vector expressing the sarcoplasmic reticulum calcium ATPase (SERCA2a), driven by the CMV promoter (AAV1-CMV-SERCA2a), to heart failure patients that have received a left ventricular assist device (LVAD) for an accepted clinical indication.
It is a randomised, double-blind study of 24 patients that will be randomised to receive either the study drug (AAV1.SERCA2a) or placebo.
The purpose of gene transfer of SERCA2a is to improve systolic and diastolic function of the failing ventricle. Studies show that reduction of SERCA2a in failing ventricle is a key factor in depression of contraction, and that restoration of SERCA2a levels can improve function to near normal levels. The vector will be delivered during a cardiac catheterisation procedure by a 10-minute infusion into the coronary arteries.
Myocardial tissue is obtained at the time of LVAD placement, as a routine part of device implantation. Further samples will be obtained when the heart is transplanted or the LVAD removed. Measures of tissue inflammation as well as efficacy of gene transfer will be made by comparing these two samples. Recovery of contractile function of the heart will be assessed during attempts to wean patients from the LVAD using standard protocols.
The results will be assessed in conjunction with two companion studies which will start earlier in the US, one performing SERCA2a gene transfer with the same vector, but delivered by direct injection into the myocardium during LVAD insertion, and one using AAV1-CMV-SERCA2a delivered percutaneously in heart failure patients. The latter has both a dose-ranging and placebo-controlled arm.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AAV1/SERCA2A | Active Comparator | SERCA gene therapy |
|
| Placebo | Placebo Comparator | Placebo (saline solution) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AAV1/SERCA2a | Genetic | AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients | Safety is defined as the incidence of patients experiencing death and major adverse cardiovascular events, and out of range laboratory values. Both AAV1/SERCA2a treated cohorts (NAb+ and NAb-) will be compared to the placebo group. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA | The trial was terminated early with only 5 subjects enrolled. As a result full statistical analysis for both primary and secondary outcomes was impossible and a more pragmatic approach was undertaken to assess product safety. | 6 months |
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Inclusion criteria
Exclusion criteria
<18 or >70 years of age at the time of consent
Pregnancy or within 6 months of giving birth
Women of child-bearing potential not using an effective method of contraception
Men not using an effective method of contraception
Suspected or active viral, fungal or parasitic infection within 48 hours prior to administration of IMP, in the opinion of the investigator*.
Patients at a high risk of thrombosis in the opinion of the investigator
Patients with a previous episode of LVAD thrombosis
Patients with persistently raised lactate dehydrogenase (LDH >2.5 ULN)
Patients requiring triple anticoagulation i.e. warfarin and dual anti-platelet
Patients participating in another clinical trial
Patients unable to comply with the protocol mandated procedures for social or other reasons, in the opinion of the investigator and primary care physician
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| Name | Affiliation | Role |
|---|---|---|
| Sian Harding | Imperial College London | Principal Investigator |
| Alexander Lyon | Imperial College London | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Papworth Hospital | Cambridge | CB23 3RE | United Kingdom | |||
| Harefield Hospital, Royal Brompton and Harefiled NHS Trust |
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| ID | Title | Description |
|---|---|---|
| FG000 | AAV1/SERCA2A | SERCA gene therapy AAV1/SERCA2a: AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles) |
| FG001 | Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Placebo | Drug | Placebo aliquots will be of the same composition as the investigational medicinal product with the absence of the active ingredient and will be visually indistinguishable from the medicinal product. Placebo is prepared and handled exactly as above in a blinded fashion. |
|
| Left Ventricular Function (LVEF) | Left ventricular function assessed by echocardiography and exercise capacity (6MWT, MVO2) during minimal LVAD support (low/no flow settings depending upon device) LVEF expressed as % | 6 months |
| Levels of SERCA2a Protein | 6 months |
| Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger. | 6 months |
| Function of Isolated Myocytes | 6 months |
| Middlesex |
| UB9 6JH |
| United Kingdom |
Placebo (saline solution)
Placebo: Placebo aliquots will be of the same composition as the investigational medicinal product with the absence of the active ingredient and will be visually indistinguishable from the medicinal product. Placebo is prepared and handled exactly as above in a blinded fashion.
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | AAV1/SERCA2A | SERCA gene therapy AAV1/SERCA2a: AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles) |
| BG001 | Placebo | Placebo (saline solution) Placebo: Placebo aliquots will be of the same composition as the investigational medicinal product with the absence of the active ingredient and will be visually indistinguishable from the medicinal product. Placebo is prepared and handled exactly as above in a blinded fashion. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
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| 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 | Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients | Safety is defined as the incidence of patients experiencing death and major adverse cardiovascular events, and out of range laboratory values. Both AAV1/SERCA2a treated cohorts (NAb+ and NAb-) will be compared to the placebo group. | The trial was terminated early with only 5 subjects enrolled. As a result full statistical analysis for both primary and secondary outcomes was impossible and results have been presented taking a descriptive approach instead | Posted | Count of Participants | Participants | No | 6 months |
|
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| Secondary | Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA | The trial was terminated early with only 5 subjects enrolled. As a result full statistical analysis for both primary and secondary outcomes was impossible and a more pragmatic approach was undertaken to assess product safety. | Posted | Count of Participants | Participants | 6 months |
|
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| Secondary | Left Ventricular Function (LVEF) | Left ventricular function assessed by echocardiography and exercise capacity (6MWT, MVO2) during minimal LVAD support (low/no flow settings depending upon device) LVEF expressed as % | Note: The trial was terminated early with only 5 subjects enrolled. As a result, full statistical analysis for both primary and secondary outcomes was impossible and results have been presented using a descriptive approach | Posted | Count of Participants | Participants | 6 months |
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| Secondary | Levels of SERCA2a Protein | Data not collected due to early termination of the trial | Posted | 6 months |
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| Secondary | Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger. | Data not collected due to early termination of the trial | Posted | 6 months |
| ||||||||||||||||||||||||||||||||||
| Secondary | Function of Isolated Myocytes | Data not collected due to early termination of the trial | Posted | 6 months |
|
6 Months
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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 | AAV1/SERCA2A | SERCA gene therapy AAV1/SERCA2a: AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles) | 1 | 4 | 2 | 4 | 4 | 4 |
| EG001 | Placebo | Placebo (saline solution) Placebo: Placebo aliquots will be of the same composition as the investigational medicinal product with the absence of the active ingredient and will be visually indistinguishable from the medicinal product. Placebo is prepared and handled exactly as above in a blinded fashion. | 0 | 1 | 0 | 1 | 1 | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| LVAD Alarm | Product Issues | MedDRA (19.1) | Systematic Assessment | LVAD Alarm and power increase with hospital admission |
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| Worsening heart failure | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Heart transplantation | Surgical and medical procedures | MedDRA (19.1) | Systematic Assessment |
| |
| Death | General disorders | MedDRA (19.1) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vessel puncture, site haematoma | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Myocarditis | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Atrial Flutter | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
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| Iron deficiency - Anaemia | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Rhinitis | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Site Bleeding | General disorders | MedDRA (19.1) | Systematic Assessment |
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| Malaise | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Skin Lesion | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
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| Device Alarm Issue | Product Issues | MedDRA (19.1) | Systematic Assessment |
| |
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Device related infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Alexander Lyon | Imperial College London | +442075943409 | a.lyon@imperial.ac.uk |
| Male |
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| Black |
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