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    Clinical Trial Results:
    Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure and a left ventricular assist device

    Summary
    EudraCT number
    2007-002809-48
    Trial protocol
    GB  
    Global end of trial date
    19 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Oct 2016
    First version publication date
    05 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRO782
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00534703
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Funder reference: SP/09/007/27920
    Sponsors
    Sponsor organisation name
    Imperial College London/ Joint Research Compliance Office
    Sponsor organisation address
    Medical School Building, London, United Kingdom, W2 1PG
    Public contact
    Dr. Alexander Lyon , Imperial College London, +44 (0)207 351 8164, t.sasikaran@imperial.ac.uk
    Scientific contact
    Dr. Alexander Lyon , Imperial College London, +44 (0) 207 351 8164, a.lyon@imperial.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Sep 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the safety and feasibility of increasing the level of SERCA2a protein by viral gene transfer into patients with advanced heart failure who have had a mechanical pump (left ventricular assist device) that assists heart function implanted.
    Protection of trial subjects
    Patients are diagnosed with advanced heart failure and have undergone recent LVAD insertion and it is possible they will have comprehension difficulties. Study staff ensured that a full understanding of the protocol and its implications was reached during the consent process.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Regulatory reason
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    5
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    4
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Potentially eligible patients have been identified by staff involved in managing advanced heart failure and transplantation in the collaborating institution. The patients who have agreed to take part in the study have signed the consent forms prior to taking part in the study.

    Pre-assignment
    Screening details
    Patients with prior LVAD implantation have undergone screening assessments including a test to look for presence of AAV NAbs.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AAV1/SERCA2A
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    MYDICAR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracoronary use
    Dosage and administration details
    1 x 10^13 DRP (dnase resistant particles). AAV1/SERCA2a is given as a single intracoronary infusion lasting approximately 10 minutes. Patients are followed up for 6 months (end of study) and there is an additional annual followup for 10 years for safety purposes.

    Arm title
    PLACEBO
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    PLACEBO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracoronary use
    Dosage and administration details
    Placebo is given as a single intracoronary infusion lasting approximately 10 minutes.

    Number of subjects in period 1
    AAV1/SERCA2A PLACEBO
    Started
    4
    1
    Completed
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AAV1/SERCA2A
    Reporting group description
    -

    Reporting group title
    PLACEBO
    Reporting group description
    -

    Reporting group values
    AAV1/SERCA2A PLACEBO Total
    Number of subjects
    4 1 5
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    3 1 4
        From 65-84 years
    1 0 1
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    41 (29 to 69) 49 (49 to 49) -
    Gender categorical
    Units: Subjects
        Female
    1 0 1
        Male
    3 1 4
    Ethnicity
    Units: Subjects
        White
    4 0 4
        Black
    0 1 1
        Not Recorded
    0 0 0
    Smoking History
    Units: Subjects
        Never
    4 1 5
        Not Recorded
    0 0 0
    Alcohol Consumption
    Units: Subjects
        None
    1 0 1
        ≤1 alcoholic drink p/w
    3 1 4
        Not Recorded
    0 0 0
    Type of Heart Failure
    Units: Subjects
        Dilated cardiomyopathy
    1 1 2
        Familial cardiomyopathy
    2 0 2
        Valvular Heart Disease
    1 0 1
        Not Recorded
    0 0 0
    Type of LVAD
    Units: Subjects
        Heartware HVAD
    3 1 4
        Thoratec Heartmate 2
    1 0 1
        Not Recorded
    0 0 0
    Cardiac Transplant Waiting List?
    If the patient on the waiting list for a heart transplant
    Units: Subjects
        Yes
    4 1 5
        Not Recorded
    0 0 0
    Subject History of Dislipidemia
    IF the patient has a history of dislipidemia
    Units: Subjects
        No
    4 1 5
        Not Recorded
    0 0 0
    Subject History of Thyroid Disorders
    If the patient has a history of thyroid disorders
    Units: Subjects
        No
    4 1 5
        Not Recorded
    0 0 0
    Subject History of Thoracic Radiation
    If the patient has a history of thoracic radiation
    Units: Subjects
        No
    4 1 5
        Not Recorded
    0 0 0
    Subject History of Hypertension
    If the patient has a history of hypertension
    Units: Subjects
        No
    4 1 5
        Not Recorded
    0 0 0
    Strata
    Units: Subjects
        AAV -ve
    3 1 4
        AAV +ve
    1 0 1
        Not Recorded
    0 0 0
    Height
    Height of Patient in cm
    Units: cm
        arithmetic mean (full range (min-max))
    174.75 (164 to 185) 173 (173 to 173) -
    Weight
    Weight of patient in cm
    Units: kg
        arithmetic mean (full range (min-max))
    73.05 (62 to 87.7) 102.5 (102.5 to 102.5) -
    BMI
    BMI of patient in kg/m2
    Units: kg/m2
        arithmetic mean (full range (min-max))
    23.795 (21.45 to 27.07) 34.25 (34.25 to 34.25) -
    Duration of Optimal HF Regime
    Units: months
        arithmetic mean (full range (min-max))
    9.25 (1 to 19) 27 (27 to 27) -
    LDH
    Units: U/L
        arithmetic mean (full range (min-max))
    593.5 (416 to 835) 395 (395 to 395) -
    Creatinine
    Units: micromole(s)/litre
        arithmetic mean (full range (min-max))
    85.75 (62 to 130) 128 (128 to 128) -
    6MWT
    Six-minute walk test
    Units: metres
        arithmetic mean (full range (min-max))
    531.75 (397 to 627) 563 (563 to 563) -
    Peak VO2
    Units: mls/kg/min
        arithmetic mean (full range (min-max))
    20.95 (15.6 to 28.3) 13.5 (13.5 to 13.5) -

    End points

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    End points reporting groups
    Reporting group title
    AAV1/SERCA2A
    Reporting group description
    -

    Reporting group title
    PLACEBO
    Reporting group description
    -

    Primary: Safety of administering AAV1/SERCA2a to LVAD patients

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    End point title
    Safety of administering AAV1/SERCA2a to LVAD patients [1]
    End point description
    Safety is defined as incidence of death and major adverse cardiovascular events, and out of range laboratory values.
    End point type
    Primary
    End point timeframe
    From Baseline to 6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: 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.
    End point values
    AAV1/SERCA2A PLACEBO
    Number of subjects analysed
    4
    1
    Units: events
        Death
    1
    0
    No statistical analyses for this end point

    Secondary: Presence of SERCA DNA - Transplant

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    End point title
    Presence of SERCA DNA - Transplant
    End point description
    AAV1/SERCA2a vector DNA presence in the heart by qPCR. Greatest value between the 4 samples per subject to be counted. BLOD = Below Limit of Detection
    End point type
    Secondary
    End point timeframe
    From Baseline to 6 Months
    End point values
    AAV1/SERCA2A PLACEBO
    Number of subjects analysed
    4
    1
    Units: subjects
        No Sample Available
    2
    1
        BLOD
    1
    0
        20.0 - 49.9 ss DNA copy numbers/ µg human gDNA
    0
    0
        50.0 - 99.9 ss DNA copy numbers/ µg human gDNA
    1
    0
        ≥ 100 ss DNA copy numbers/ µg human gDNA
    0
    0
    No statistical analyses for this end point

    Secondary: Presence of SERCA DNA - Biopsy

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    End point title
    Presence of SERCA DNA - Biopsy
    End point description
    AAV1/SERCA2a vector DNA presence in the heart by qPCR: highest reading per subject to be used. BLOD = Below Limit of Detection
    End point type
    Secondary
    End point timeframe
    From Baseline to 6 Months
    End point values
    AAV1/SERCA2A PLACEBO
    Number of subjects analysed
    4
    1
    Units: subjects
        No sample taken
    3
    1
        BLOD
    0
    0
        20.0 - 49.9 ss DNA copy numbers/ µg human gDNA
    1
    0
        50.0 - 99.9 ss DNA copy numbers/ µg human gDNA
    0
    0
        ≥ 100 ss DNA copy numbers/ µg human gDNA
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent to 6 months follow-up
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    AAV1/SERCA2A
    Reporting group description
    -

    Reporting group title
    PLACEBO
    Reporting group description
    -

    Serious adverse events
    AAV1/SERCA2A PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Heart transplant
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Product issues
    Device alarm issue
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AAV1/SERCA2A PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    Injury, poisoning and procedural complications
    Vessel puncture site haematoma
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Myocarditis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Atrial flutter
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Medical device site bleeding
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Product issues
    Device alarm issue
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2010
    Protocol Version 8 The following sections in the trial protocol have been amended. Section 1. Investigators, Section 2. Background and Rationale, Section 5. Eligibility Criteria, Section 6.1 Screening and enrolment of patients, Section 7.2 Delivery of the vector, Section 7.3.2. Hazards related to the AAV6 vector, Section 9. Study related investigations and follow-up, Section 12.3 Study funding, Section 12.4, Section 13.2 Data Collection and Section 14. Pharmacovigilance.
    20 Dec 2012
    Protocol version 9 The following sections in the protocol have been updated. Abbreviations, Section 1. Investigators, Section 3. Background and Rationale, Section 4. Aims of the study, Section 5. Trial design, Section 6. Eligibility Criteria, Section 7. Randomisation, Section 8. Delivery of the IMP, Section 10. IMP composition, Section 12. Study related Investigations, Section 13. Outcome measures, Section 13. Scientific studies after LVAD insertion, Section 14. Statistics, Section 15.4 Study funding, Section 16. Regulatory Issues and Section 17. Expected Serious Adverse Events/clinical outcomes
    21 Aug 2013
    Protocol version 10. Following advice from the Principal Investigators at each of the participating centres, additional exclusion criteria have been added to the protocol to account for patients that are at a high risk of left ventricular assist device (LVAD) thrombosis and the effect of altering or temporarily stopping anticoagulation prior to administration of the gene therapy. Weekly visits during the month after gene transfer have been amended to reduce the need for patients to travel to hospital so frequently. Visits in week 1 and 3 will be conducted as home visits by a trained member of the study team at each hospital and weeks 2 and 4 will remain as visits to hospital.
    29 May 2014
    Protocol version 11 Protocol version 10 has been updated.
    24 Mar 2015
    Protocol version 12 Reasons for amendment • Clarification regarding trial samples including size of myocardial tissue samples, transfer and analysis • Update to IMPD to include clarification regarding manufacturing process, updated information on packaging operations and QP release • Change to IMP labelling due to extension of expiry date • Minor amendments have been made to the protocol and patient information sheet to correct typographical errors and administrative details
    15 May 2015
    The amendment is to temporarily halt recruitment to the trial . Results of the CUPID2 trial were announced by Celladon Corporation at the end of April in the form of a press release. Celladon Corporation is the IMP supplier for the SERCA-LVAD trial and the CUPID2 trial used the same IMP and administration protocol. The results of CUPID2 were negative, indicating that there is no evidence of benefit of AAV1/SERCA2a compared to placebo control. No safety concerns were raised for AAV1/SERCA2a (MYDICAR). The TSC advised a temporary halt to the trial as it is considered that the risk/benefit ratio is altered in light of the CUPID2 results.
    02 Sep 2015
    The Investigators and Trial Steering Committee have decided the following: • Recruitment to the trial will not recommence • Trial assessments that do not introduce an additional risk to patients will continue for existing patients (only one patient out of five still requires their 6-month follow-up visit). This is considered to be important for safety, scientific and ethical reasons as this is a safety trial and the data could be important for the individual patients and the study in general. • The end of the trial will be declared after the final patient’s 6-month follow-up visit which is estimated to take place by the end of September

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 May 2015
    The trial was temporarily halted following the announcement of the CUPID 2 trial in May 2015. The results of CUPID2 were negative, indicating that there is no evidence of benefit of AAV1/SERCA2a compared to placebo control. No safety concerns were raised for AAV1/SERCA2a (MYDICAR). The Trial Steering Committee recommended that recruitment to the trial should be halted and that all existing patients (N=5) should be followed up until the 6-month follow-up visit, excluding any invasive tests and investigations.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was terminated early with all existing patients (N=5) followed up until the 6-month follow-up visit, excluding any invasive tests and investigations. Full statistical analysis for both primary and secondary outcomes is no longer possible.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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