The study primary goal is to determine the effectiveness of a single infusion of 1 x 10E13 DRP MYDICAR® in the coronary arteries in addition to an optimal HF regimen in patients with ischemic or non-ischemic cardiomyopathy and moderate to advanced…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to recurrent events (HF-related hospitalizations, ambulatory worsening HF)
in the presence of terminal events (all-cause death, heart transplant, LVAD
implantation).
Secondary outcome
Time to terminal event in the presence of recurrent events.
Background summary
Celladon Corporation (Celladon) is investigating MYDICAR® (AAV1/SERCA2a) in the
treatment of subjects with moderate to advanced chronic systolic heart failure.
SERCA2a is a protein that is important in regulating calcium metabolism and
contractility of the normal human heart. SERCA2a levels drop in all forms of
late-stage heart failure (HF) resulting in a reduced ability of the heart to
pump blood. In a variety of animal models of HF, it was shown that increases in
SERCA2a protein can help to improve heart contraction and function. Celladon is
investigating a vector called AAV1/SERCA2a, or MYDICAR, based on
adeno-associated virus (AAV) that delivers the SERCA2a gene to the cells of the
heart to allow it to produce the same protein that is found in normal human
heart cells. MYDICAR is delivered in a single dose by a procedure which is
similar to an angiogram. AAV is a naturally occurring virus not associated with
any disease in humans. Many people have been infected by the naturally
occurring type of AAV without realizing it, as AAV does not cause disease.
Heart Failure (HF) is a clinical syndrome defined as a chronic inadequate
contraction of the heart muscle resulting in insufficient blood flow to the
body. HF leads to about 280,000 deaths annually. The most common symptoms of HF
are shortness of breath, feeling tired and swelling in the ankles, feet, legs
and sometimes the abdomen. There is no cure. HF is an epidemic with an
estimated 23 million people currently living with HF worldwide. In the United
States alone, nearly 6 million patients are diagnosed with HF and another
700,000 cases are diagnosed every year. In the UK there are an estimated
900,000 people with HF and an equal number of people with damaged hearts but
who show no symptoms. Worldwide occurrence of HF in the general population
ranges from 2*3% and increases significantly with age, up to 8.4-13% in persons
aged 75*84 years. In North America and Europe, the lifetime risk of developing
HF is approximately one in five for a 40- year-old. Prevalence of HF appears to
have increased over time due to the aging population, improved management of
cardiovascular (CV) and non-CV disease, and higher number of patients with risk
factors such as hypertension, diabetes, dyslipidemia and obesity in
industrialized societies. Disease outcome is poor. Based on the Framingham
Heart Study, around 10% of the patients die within 30 days, 20-30% die within 1
year and 45*60% die within 5 years. Similar poor long-term disease outcome is
reported in Europe. Treatment of HF is different for each patient and is based
on the underlying causes, presence of other diseases, the patient*s stage at
diagnosis and NYHA functional classification. HF patients are also broadly
categorized as having either systolic failure (lowered pump function of the
heart) or diastolic failure (failure of the heart to relax). Treatment goals
are to reduce symptoms, prolong survival, improve the quality of life, and slow
or prevent disease progression. Despite optimal medical therapy using a wide
range of pharmacologic, device, and surgical therapeutic options, over the
long-term, most patients experience a HF worsening refractory to optimal
medical therapy, ultimately succumbing to the syndrome or one of the underlying
contributing conditions. The annual cost of HF was estimated to be nearly $40
billion in the United States in 2010, half of which was related to repeated
hospitalizations. The 6-month readmission rate for congestive HF is close to
50%. Despite extensive efforts to reduce hospitalizations in HF, overall
hospitalizations with any mention of HF have tripled from 1.3 million in 1979
to 3.9 million in 2004. In the UK, HF accounted for 1 million hospitalizations
in 2002, which will increase with 50% by 2038 (largely as a result of the aging
population). Thus, the frequent hospitalizations seen in chronic HF are largely
contributing to the increasing public health crisis. So there is an urgent need
for new treatments for HF aimed at reducing hospitalization.
Study objective
The study primary goal is to determine the effectiveness of a single infusion
of 1 x 10E13 DRP MYDICAR® in the coronary arteries in addition to an optimal HF
regimen in patients with ischemic or non-ischemic cardiomyopathy and moderate
to advanced symptoms of HF by reducing the frequency and/or delaying HF-related
hospitalizations compared to placebo-treated patients. Secondary goals will
include assessing the safety of MYDICAR® by determining the frequency and
severity of side effects and changes in laboratory parameters. In addition, an
independent company will assess the resource utilization, health related
quality of life and cost effectiveness of MYDICAR® treatment compared to
standard-of-care alone.
Study design
This is a phase 2b, multinational, multicenter, double-blind,
placebo-controlled, randomized study of a single intracoronary administration
of either 1 x 10E13 DRP MYDICAR® versus placebo in addition to an optimal HF
regimen. Subjects will be divided in parallel in 2 groups in a ratio of 1:1.
Intervention
One of the two groups will receive a single intracoronary administration of
MYDICAR® during a coronary angiography. The other control group will receive a
single intracoronary administration of placebo during a coronary angiography.
Study burden and risks
Subjects will be screened for the presence of AAV neutralizing antibodies to
determine their eligibility prior to randomization and enrollment into the
study. On Day 0, patients will undergo cardiac catheterization and angiography,
followed by infusion of investigational product unless contraindicated. At
Months 1, 3, 6, 9 and 12, subjects will undergo several safety, effectiveness
and economic assessments. This 12-Month Active Observation Period is followed
by visits every 3 months (at months 15, 18, 21, 24, etc.) for the collection of
information on clinical side effects and resource utilization. This Long-Term
Follow-Up will be performed until the last participating patient completes the
12-Month Active Observation Period and at least 180 adjudicated HF-related
hospitalizations have occurred (whichever comes later). This time point is then
defined as the End of Study. If a subject terminates or discontinues within
the 12-Month Active Observation Period, this subject will be rolled over into
the Long-Term Follow-Up for collection of information on clinical side effects
until the End of Study. All patients will be observed and followed-up for a
minimum of 24 months. These 24 months include the amount of time in the
12-Month Active Observation Period plus the amount of time in Long-Term
Follow-Up.
Following procedures will be performed in context of the study:
* Physical exam of body, recording of temperature, weight, height, pulse, and
breathing rate. The medical history and physical examination will be part of
all visits.
* Blood draws: 8x
* Urine test: 7x
* Coronary angiography (including administration of the investigational product
or placebo and IV nitroglycerine): 1x
* Chest X-Ray: 1x
* Day hospitalization and telemetry (day of the angiography): 1x
* ECG: 7x
* Questionnaires: 14x
* Echo-cardio: 1x
* 6-minutes* walk test: 5x
MYDICAR® is administered via antegrade epicardial coronary artery infusion
using the B Braun Perfusor®
Space Syringe Pump. Potential procedure-related events are similar to those
associated with standard
coronary intervention procedures. rAAV1 capsid proteins is unlikely to cause
adverse side effects. The SERCA2a gene is unlikely to cause adverse effects.
These adverse events occurred the most often (*5%) in order of frequency
(highest to lowest): ventricular tachycardia, an abnormal heart rhythm; low
level of potassium in the blood; too much fluid in the blood; nasal congestion;
low blood pressure; ventricular fibrillation, an abnormal heart rhythm; fall;
low level of sodium in the blood; muscle spasms, sudden, involuntary
contractions of a muscle; decrease in kidney function; shortness of breath;
shortness of breath upon exertion; clicking, rattling or crackling noises in
the lungs; arrhythmia; cardiogenic shock cardiogenic shock (failure of the
heart to pump effectively); abnormal manner in walking; herpes; viral
infection; flu; eye injury; increased bilirubin which might indicate damage to
the liver or a blood disorder; increased creatine phosphokinase which might
indicate a breakdown of muscle; groin pain; fainting; productive cough; nose
bleeds; and bruising.
These adverse events occurred less often (3%): chest pain, abnormal heart
rhythms, heart and kidney failure, blood clot in the heart, cardiac aneurysm
(thinning, stretching or bulging of the wall of the heart), palpitations
(skipped beat or rapid beating of heart), bloating or increased pressure in
stomach, stomach pain, build-up of fluid in the abdomen, stomach discomfort,
ulcer, bleeding ulcer, blood in stool, inflammation of the pancreas, jaundice
(yellow color of skin), yeast infection, skin infection, central line
infection, infection in stomach with bacteria that causes ulcers, herpes,
pneumonia, upper respiratory infection (infection in nose, throat and lungs),
excessive weight loss, decreased appetite, dehydration, diabetes, water
retention, high level of lipids/cholesterol in the blood, bone disorder,
bursitis (swelling of the fluid-filled sac that lies between a tendon and skin
or bone), wrist tremor, stroke, worsening brain function from liver not working
properly, reduced sense of touch, neurological symptoms, involuntary eye
movement, restless leg syndrome, drowsiness and mini-stroke, alcoholism,
clenching or grinding teeth, mental status changes, sleepwalking, kidney
failure, asthma; chronic obstructive pulmonary disease (narrowing of the
airways, leading to limitation of flow of air to and from the lungs and causing
shortness of breath); coughing up blood from the lungs; sore or painful throat;
respiratory failure, sleep apnea (pauses in breathing during sleep), bleeding
underneath the skin, skin ulcer, Stevens-Johnson syndrome, blood clots in a
deep vein, high blood pressure, fluid around a testicle, blurred vision, blood
leaking from blood vessel to surrounding tissue, jittery feeling, swelling near
injection or catheter site, swelling in hands and feet, sudden death, blood
clot at site of injection or blood draw, head injury, mouth injury, discharge
from injection site, tendon injury, certain abnormal blood tests (increased
uric acid which might indicate arthritis or gout, increase in clotting time of
blood, increase in red blood cell volume which might indicate a type of anemia,
increase in Prostate Specific Antigen (PSA) which might indicate inflammation
or cancer of the prostate gland in men, increase in liver enzymes which might
indicate damage to the liver, and decrease in vitamin D), weight increase,
breast disorder, breast enlargement in males, enlarged or twisted veins in the
scrotum.
12760 High Bluff Drive STE 240
San Diego CA 92130-2019
US
12760 High Bluff Drive STE 240
San Diego CA 92130-2019
US
Listed location countries
Age
Inclusion criteria
1. Negative AAV1 NAb (titer <1:2 or equivocal) within 90 days of screening.
2. 18-80 years of age, inclusive, at the time of signing the informed consent.
3. Chronic systolic HF due to ischemic or non-ischemic cardiomyopathy.
Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with TIMI grade 3 flow. If a subject has not undergone coronary angiography with 2 months, this criterion may be assessed after the subject is randomized and undergoes angiography just prior to the planned infusion of IMP.
a. Hypertrophic cardiomyopathy is excluded.
b. Toxic and alcoholic cardiomyopathies are allowed as long as toxin or alcohol exposure has been eliminated and a sufficient amount of time has elapsed to rule-out spontaneous recovery.
4. Left ventricular ejection fraction (LVEF) *35% anytime during the 60-day window prior to administration of IMP.
5. Diagnosis of NYHA class II, III or IV heart failure for a minimum of 90 days prior to screening.
6. Individualized, maximal, optimized heart failure therapy consistent with American College of Cardiology/American Heart Association and European Society of Cardiology practice guidelines for the treatment of chronic heart failure (ACC/AHA/ESC HF guidelines) and as updated from time to time:
a. Medical therapy as appropriate to the individual subject including oral diuretic, angiotensin-converting enzyme (ACE) inhibitor (or angiotensinreceptor blocker (ARB) if ACE intolerant) and as tolerated, beta blocker at approved dosages as labeled in the respective package insert. The choice
of beta blocker is limited to those approved for heart failure in all participating countries (bisoprolol, carvedilolor sustained release metoprolol succinate). Unless contraindicated or not tolerated, the
addition of an aldosterone antagonist should be considered in the absence of hyperkalemia and significant renal dysfunction and according to evolving standards; the final decision is at the discretion of the investigator.
Dosing of the above medications must be stable for a minimum of 30 days prior to screening, although up- or down-titration of diuretics, as medically indicated, is permitted. Enrollment of any subject with any deviation from this combination must be reviewed and approved by the
medical monitor.
b. Resynchronization therapy, if clinically indicated according to ACC/AHA/ESCHF guidelines, must have been implanted at least 6 months prior to screening.
c. Implantable cardioverter defibrillator (ICD), if clinically indicated, according to ACC/AHA/ESC HF guidelines, must have been implanted a minimum of 30 days prior to screening.
d. Cardiac rehabilitation, if ongoing, should be consistent with the Agency for Health Care Policy and Research Clinical Practice Guideline, Number 17, Cardiac Rehabilitation. This does not imply that the potential candidate must be enrolled in a cardiac rehabilitation program now or in
the future.
7. All women of childbearing potential must have a negative urine pregnancy test prior to administration of IMPand agree to use adequate contraception (defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization or a combination of a condom and spermicide) or limit sexual activity to vasectomized partner for 3 months after administration of IMP. Men capable of fathering a child must agree to use barrier contraception(combination of a condom and spermicide) or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of IMP.
8. Ability to understand and comply with study requirements as evidenced by providing signed written informed consent form and Release of Medical Information Form.
9. Presence of at least one of the following risk factors:
a. Hospitalization for heart failure within 6 months of screening, or in lieu of hospitalization, at least 2 outpatient interventions for the intended treatment of signs and symptoms of worsening heart failure (e.g., intravenous diuretics, peripheral ultrafiltration)
b. NT-proBNP >1200 pg/mL (BNP >225 pg/mL) within 30 days of screening; if subject is in atrial fibrillation, NT-proBNP >1600 pg/mL (BNP >275 pg/mL) within 30 days of screening
Exclusion criteria
1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening.;2. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete LV aneurysm.;3. Cardiac surgery, percutaneous coronary intervention or valvuloplasty within 30 days prior to screening.;4. Myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined >3x ULN for CKMB or >5x ULN for troponin.;5. Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap* Cardiac Support Device), surgically implanted LVAD or cardiac shunt.;6. Likely need for an immediate heart transplant or LVAD implant due to hemodynamic instability.;7. Prior CABG is not considered ideal for inclusion in the study; however, a potential candidate can be reviewed on a case-by-case basis. Ideally, the orifice of the graft should be easy to engage with a catheter and the graft should perfuse a significant amount of potentially viable myocardium.;8. Known hypersensitivity to contrast agents used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography.;9. Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis.;10. Liver function tests (ALT, AST, alkaline phosphatase) > 3x Upper Limit of Normal (ULN) within 30 days prior to IMP administration or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection).;11. Current or likely need for hemodialysis within 12 months following enrollment or current GFR *20 mL/minute/1.73 m2 estimated by MDRD calculation.;12. Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/*L.;13. Anemia defined as hemoglobin <9 g/dL, provided that there is no evidence of bleeding.;14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3.;15. Diagnosis of, or treatment for, any cancer other than basal cell carcinoma within the last 5 years. (Past medical history of cancer is not exclusionary as long as subject has been disease-free for at least 5 years since the time of diagnosis and treatment).;16. Previous participation in a study of gene transfer; however, if the study was unblinded or documentation otherwise exists that the subject was randomized to the placebo control group and did not receive active gene transfer agent, the subject may be considered for this study.;17. Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment.;18. Pregnant or breast-feeding.;19. Recent history of psychiatric disease, including drug or alcohol abuse, that is likely to impair, in the opinion of the investigator, the subject*s ability to comply with protocol-mandated procedures.;20. Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the subject or objectives of the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001700-37-NL |
| ClinicalTrials.gov | NCT01643330 |
| CCMO | NL40872.000.12 |