Impact of Bromocriptine on Clinical Outcomes for Peripartum Cardiomyopathy

Study Overview
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Brief Summary
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The study will enroll 200 women newly diagnosed with peripartum cardiomyopathy within 5 months postpartum in a randomized placebo controlled trial of bromocriptine therapy to evaluate its impact on myocardial recovery and clinical outcomes. Given that bromocriptine prevents breastfeeding, an additional 50 women with peripartum cardiomyopathy excluded from the trial due to a desire to continue breastfeeding but meeting all other entry criteria will be followed in an observational cohort.

Detailed Description
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The study will enroll 200 women newly diagnosed with peripartum cardiomyopathy within 5 months postpartum in a randomized trial of bromocriptine therapy to evaluate its impact on myocardial recovery. All women will have an assessment of LVEF demonstrating an LVEF < or = 0.35 within 4 weeks prior to consent. At entry they will then have an assessment of LVEF by echocardiogram which will be repeated at 6- and 12-months post study entry. Subjects in the randomized trial will be randomized to standard medical therapy for heart failure plus placebo or standard therapy plus 8 weeks of bromocriptine (2.5 mg twice daily for 2 weeks then once 2.5 mg daily for 6 weeks). Women receiving bromocriptine not currently on anticoagulation will also receive prophylactic anticoagulation with rivaroxaban 10 mg once daily for 8 weeks. Primary analysis will compare LVEF at 6 months post entry in the women receiving standard therapy plus bromocriptine to those on standard therapy plus placebo (controlling for initial baseline LVEF). Secondary endpoints will analyze the LVEF in both treatment groups at 12 months post randomization. In addition, subjects will be followed for up to 3 years post randomization and survival free from a major event (cardiac transplantation or durable LVAD implantation) and survival free from heart failure hospitalization will be compared by treatment group. The benefits of bromocriptine are theoretically related to suppression of prolactin secretion. Breastfeeding increases prolactin levels, and whether continued breastfeeding will impact myocardial recovery in women with peripartum cardiomyopathy remains unknown. As bromocriptine prevents breastfeeding, women who want to continue breastfeeding are excluded from the randomized trial. Up to 50 women meeting all other criteria but excluded from REBIRTH due to an intent to continue to breastfeed will be enrolled in an observational cohort. They will receive standard therapy with no additional intervention and will have the same follow up and assessment of myocardial recovery by echocardiogram at 6- and 12-months post entry as women in the randomized trial. Blood will be obtained at entry for DNA banking, and analysis of serum, and whole blood RNA . Additional serum and whole blood RNA will be banked at 1-, 3-, and 6-months post randomization. This investigation will evaluate the impact of bromocriptine therapy on the levels of intact 23 kilodalton (kDa) prolactin and the 16 kDa prolactin fragment, as well as microRNA (miR) 146a. The biomarker analysis will also be performed in the observational cohort of women excluded due to continued breast feeding. The impact of these biomarkers on outcomes in both the treatment and control groups as well as the observational cohort excluded due to breastfeeding will be examined. A core laboratory will analyze all echocardiograms. In addition to quantifying the LVEF at entry, 6 months and 12 months post entry, the core will evaluate global longitudinal strain (LGS) and remodeling (LV volumes) at entry as predictors of outcome and drug response. They will also evaluate the impact of therapy on LGS and LV volumes at 6- and 12-months post randomization.

Official Title
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Randomized Evaluation of Bromocriptine In Myocardial Recovery THerapy for Peripartum Cardiomyopathy (REBIRTH)

Conditions
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Peripartum Cardiomyopathy, Postpartum

Intervention / Treatment
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* Drug: Bromocriptine
* Drug: Placebo
* Drug: Guideline Directed Medical Therapy for Heart Failure (GDMT)
* Drug: Rivaroxaban
* Drug: Second Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presentation with a new diagnosis of peripartum cardiomyopathy Post-delivery and within the first 5 months post-partum. Clinical assessment of an LVEF < or =0.35 within 4 weeks of randomization Age > or = 18. Exclusion Criteria: Previous diagnosis of cardiomyopathy, valvular disease or congenital heart disease (with the exception of women with a history of peripartum cardiomyopathy with complete recovery and a documented LVEF > 0.55 prior to or in early pregnancy) Refractory hypertension (Systolic >160 or Diastolic > 95) either at the time of enrollment or at the time of the qualifying LVEF. Postpartum women currently breastfeeding and planning to continue. Evidence of coronary artery disease (>50% stenosis of major epicardial vessel or positive non-invasive stress test) Previous cardiac transplant Current durable LVAD support Currently requiring support with extracorporeal membrane oxygenation (ECMO) Current history of alcohol or drug abuse Chemotherapy or chest radiation within 5 years of enrollment Evidence of ongoing bacterial septicemia Medical, social or psychiatric condition which limit the ability to comply with follow-up.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 200 women meeting all inclusion and exclusion criterial will be randomized in a placebo controlled double blind investigation evaluating the impact of bromocriptine on outcomes for women newly diagnosed with peripartum cardiomyopathy. An additional 50 women in excluded from the trial due to an intent to continue breastfeeding but meeting all other criteria will be enrolled in an observational cohort. All women with receive standard medical care for peripartum cardiomyopathy and will be followed for up to three years.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bromocriptine Treatment Arm<br>100 Women in the Treatment Arm will receive guideline directed medical therapy for heart failure plus 8 weeks of bromocriptine administered orally as 2.5 mg twice daily for 2 weeks then 2.5mg once daily for 6 weeks. Women not on clinical anticoagulation will also receive prophylactic anticoagulation with rivaroxaban 10 mg once daily for 8 weeks while on bromocriptine. | Drug: Bromocriptine<br>* Bromocriptine 2.5 mg one tablet by mouth twice daily for 2 weeks then once daily for 6 weeks. Subjects not on anticoagulation at the time of entry will also receive rivaroxaban 10 mg tablets once daily for 8 weeks while on bromocriptine.<br>* Other names: Cycloset;Drug: Guideline Directed Medical Therapy for Heart Failure (GDMT)<br>* GDMT will potentially include angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARB), angiotensin receptor blocker-neprilysin inhibitors (ARNI), beta adrenergic receptor antagonists (beta blockers) , Mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i),<br>Drug: Rivaroxaban<br>* Subjects not on anticoagulation clinically who are randomized to bromocriptine will receive rivaroxaban 10 mg tablets once tablet by mouth daily for 8 weeks while on bromocriptine.<br>* Other names: Xarelto;|
| Placebo Comparator: Placebo Arm<br>100 Women in the Placebo Arm will receive guideline directed medical therapy for heart failure plus 8 weeks of a placebo administered orally twice daily for 2 weeks then once daily for 6 weeks. Women not on clinical anticoagulation will not receive rivaroxaban but will instead receive a second placebo for 8 weeks. | Drug: Placebo<br>* Placebo one tablet by mouth twice daily for 2 weeks then once daily for 6 weeks. Subjects who are not on anticoagulation will not receive rivaroxaban but will receive a second placebo once daily for 8 weeks while on study drug.<br>Drug: Guideline Directed Medical Therapy for Heart Failure (GDMT)<br>* GDMT will potentially include angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARB), angiotensin receptor blocker-neprilysin inhibitors (ARNI), beta adrenergic receptor antagonists (beta blockers) , Mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i),<br>Drug: Second Placebo<br>* Subjects not on anticoagulation clinically who are randomized to placebo (rather than bromocriptine) will receive a second placebo one tablet by mouth daily for 8 weeks.<br>* Other names: Placebo;|
| Other: Breastfeeding Observational Cohort<br>Up to 50 women meeting all other criteria but excluded from REBIRTH due to an intent to continue to breastfeed will be enrolled in an observational cohort. They will receive guideline directed medical therapy with no additional interventions and will have the same follow up and assessment of myocardial recovery by echocardiogram at 6 and 12 months post entry as women in the randomized trial. | Drug: Guideline Directed Medical Therapy for Heart Failure (GDMT)<br>* GDMT will potentially include angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor antagonists (ARB), angiotensin receptor blocker-neprilysin inhibitors (ARNI), beta adrenergic receptor antagonists (beta blockers) , Mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i),<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) at 6 months post entry as determined by echocardiography |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) at 12 months post entry as determined by echocardiography |  | 12 months | 
| Survival free from cardiac transplantation or implantation of a durable left ventricular assist device (LVAD) |  | 3 years | 
| Survival free from heart failure hospitalization |  | 3 years |