Nitrates In Combination With Hydralazine in cardiorEnal Syndrome (NICHE) Study

NCT ID: NCT02343393

Last Updated: 2015-01-22

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2016-06-30

Brief Summary

This is a single-blind, randomised, clinical trial assessing the efficacy of Hydralazine and Isosorbidedinitrate combination (oral agents) in HF patients with renal dysfunction.

Detailed Description

Cardiorenal syndrome (CRS), where renal failure and heart failure (HF) co-exist in a vicious cycle, is a very common problem of great morbidity and mortality. The management of CRS is challenging as therapeutic options are mutually contradictory and largely empirical.

Endothelial dysfunction from oxidative injury has recently emerged as a common link between the failing heart and kidneys in CRS. The endothelium plays an obligatory role in cardiovascular homeostasis, and impaired endothelium-mediated nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction. There is a high prevalence of endothelial dysfunction in our Asian HF patients, with a greater degree of dysfunction seen in those with CRS. We hypothesise that targeting endothelial dysfunction may improve clinical status among Asian patients with CRS.

Isosorbide dinitrate (ISDN) increases NO bioavailability. Concomitant hydralazine (H) therapy prevents nitrate tolerance and protects NO from oxidative stress-induced degradation. The synergistic combination of H-ISDN is thought to exert beneficial effects on the endothelium.

We aim to perform a prospective randomised controlled trial to assess the effect of H-ISDN therapy for 6 months on exercise capacity, endothelial function, renal function, clinical outcomes and quality of life (QOL) in Asian patients with CRS. Specifically, we hypothesise that H-ISDN therapy will lead to improvement in exercise capacity (6 minute walk test (6MWT)), endothelial dysfunction (assessed by non-invasive peripheral arterial tonometry(PAT)), renal function, cardiac structure and function, clinical outcomes (all-cause mortality, HF hospitalisations) and QOL in Asian patients with CRS.

Conditions

Cardio-Renal Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

H-ISDN

Eligible patients randomised to treatment arm will be initiated on a starting dose of hydralazine 60mg and ISDN 30mg daily (20/10mg three times daily). After 7 days following the first dose, if the starting medication is well-tolerated, the patient is instructed to double the dose of study medication to the target maintenance dose of hydralazine 120mg and ISDN 60mg daily for 24 weeks

Group Type: EXPERIMENTAL

Hydralazine

Intervention Type: DRUG

Isosorbide Dinitrate

Intervention Type: DRUG

Standard Medical Therapy

Current standard HF therapy include the use of beta-blockers, ACE inhibitors/ARBs and diuretics.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Hydralazine

Intervention Type: DRUG

Isosorbide Dinitrate

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. At least 21 years of age

2. Asian patients with symptomatic HF (regardless of EF) and renal impairment (eGFR<60ml/min/1.73m2)

3. At least one hospitalisation for HF during the preceeding year

4. On stable (at least 1 month) optimal medical therapy (maximum tolerated doses of ACE inhibitors or ARBs, beta blockers and aldosterone antagonists for HFREF, and optimally managed cardiovascular risk factors for HFPEF)

5. Able to complete 6 minute walk test (6MWT)

6. Able to maintain a systolic blood pressure ≥100mmHg

7. Able to provide written informed consent

Exclusion Criteria

1. On chronic therapy with hydralazine and/or nitrates.

2. Known hypersensitivity to hydralazine and/or nitrates

3. Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors

4. Females who are pregnant, nursing, or of childbearing potential and not practising effective contraception

5. Have had acute myocardial infarction, unstable or stable angina pectoris, or a cerebrovascular accident within the last 3 months

6. Have had cardiac revascularisation within the last 3 months or are likely to require coronary revascularisation within the study period

7. Have had cardiac arrest or life-threatening ventricular arrhythmia requiring intervention within 3 months

8. Rapidly deteriorating HF (2 admissions for acute decompensated HF, not due to non-compliance, within 6 months)

9. eGFR< 15ml/min/1.73m2, or on regular dialysis, or planned dialysis within the study period

10. Serious medical condition, emergency condition, uncontrolled systemic disease or any other medical condition that, in the judgement of the investigator, prohibits the patient from entering or potentially completing the study

11. Planned participation in any other interventional study or having received trial medication in the last 4 weeks within a clinical trial

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Singapore Clinical Research Institute

OTHER

Sponsor Role: collaborator

Changi General Hospital

OTHER

Sponsor Role: collaborator

National Heart Centre Singapore

OTHER

Sponsor Role: collaborator

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Su Ping Carolyn Lam, MBBS, MRCP, MS

Role: STUDY_CHAIR

National University Hospital, Singapore

Locations

National University Hospital, Singapore

Singapore, , Singapore

Site Status: RECRUITING

National Heart Centre Singapore

Singapore, , Singapore

Site Status: NOT_YET_RECRUITING

Changi General Hospital

Singapore, , Singapore

Site Status: NOT_YET_RECRUITING

Countries

Singapore

Central Contacts

Su Ping Carolyn Lam, MBBS, MRCP, MS

Role: CONTACT

carolyn_lam@nuhs.edu.sg

Facility Contacts

Shir Lynn Lim, MBBS, MRCP, MMed

Role: primary

shir_lynn_lim@nuhs.edu.sg

Kheng Leng David Sim, MBBS, MRCP, MS

Role: primary

david_sim@nhcs.com.sg

Kui Toh Gerard Leong, MBBS, MRCP, MS

Role: primary

gerard_leong@cgh.com.sg

Other Identifiers

NICHE

Identifier Type: -

Identifier Source: org_study_id