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

Primary Purpose

Cardio-Renal Syndrome

Status

Unknown status

Phase

Phase 3

Locations

Singapore

Study Type

Interventional

Intervention

Hydralazine

Isosorbide Dinitrate

About this trial

This is an interventional treatment trial for Cardio-Renal Syndrome focused on measuring Endothelial Dysfunction, Biomarkers, Hydralazine-Isosorbide Dinitrate

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

At least 21 years of age
Asian patients with symptomatic HF (regardless of EF) and renal impairment (eGFR<60ml/min/1.73m2)
At least one hospitalisation for HF during the preceeding year
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)
Able to complete 6 minute walk test (6MWT)
Able to maintain a systolic blood pressure ≥100mmHg
Able to provide written informed consent

Exclusion Criteria:

On chronic therapy with hydralazine and/or nitrates.
Known hypersensitivity to hydralazine and/or nitrates
Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors
Females who are pregnant, nursing, or of childbearing potential and not practising effective contraception
Have had acute myocardial infarction, unstable or stable angina pectoris, or a cerebrovascular accident within the last 3 months
Have had cardiac revascularisation within the last 3 months or are likely to require coronary revascularisation within the study period
Have had cardiac arrest or life-threatening ventricular arrhythmia requiring intervention within 3 months
Rapidly deteriorating HF (2 admissions for acute decompensated HF, not due to non-compliance, within 6 months)
eGFR< 15ml/min/1.73m2, or on regular dialysis, or planned dialysis within the study period
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
Planned participation in any other interventional study or having received trial medication in the last 4 weeks within a clinical trial

Sites / Locations

National University Hospital, SingaporeRecruiting
National Heart Centre Singapore
Changi General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

H-ISDN

Standard Medical Therapy

Arm Description

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

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

Outcomes

Primary Outcome Measures

Effort tolerance by assessing 6 Minute Walk Test (6MWT)

Secondary Outcome Measures

Endothelial function as measured via a reactive hyperaemic index (RHI) by Peripheral Arterial Tonometry (PAT)

Renal function (eGFR, Cystatin C, markers of kidney injury (proteinuria as quantified by urine protein-creatinine ratio (uPCR), NGAL))

Cardiac structure and function by 2D and Doppler echocardiography

Quality of Life by self-reported 36-item Short Form Health Survey (SF-36)

Clinical outcomes by recording deaths and HF hospitalisations

Full Information

NCT ID

NCT02343393

First Posted

January 15, 2015

Last Updated

January 15, 2015

Sponsor

National University Hospital, Singapore

Collaborators

Singapore Clinical Research Institute, Changi General Hospital, National Heart Centre Singapore

1. Study Identification

Unique Protocol Identification Number

NCT02343393

Brief Title

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

Acronym

NICHE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2015

Overall Recruitment Status

Unknown status

Study Start Date

January 2015 (undefined)

Primary Completion Date

December 2015 (Anticipated)

Study Completion Date

June 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National University Hospital, Singapore

Collaborators

Singapore Clinical Research Institute, Changi General Hospital, National Heart Centre Singapore

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardio-Renal Syndrome

Keywords

Endothelial Dysfunction, Biomarkers, Hydralazine-Isosorbide Dinitrate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

H-ISDN

Arm Type

Experimental

Arm Description

Arm Title

Standard Medical Therapy

Arm Type

No Intervention

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Hydralazine

Intervention Type

Drug

Intervention Name(s)

Isosorbide Dinitrate

Primary Outcome Measure Information:

Title

Effort tolerance by assessing 6 Minute Walk Test (6MWT)

Time Frame

24 weeks

Secondary Outcome Measure Information:

Title

Endothelial function as measured via a reactive hyperaemic index (RHI) by Peripheral Arterial Tonometry (PAT)

Time Frame

24 weeks

Title

Renal function (eGFR, Cystatin C, markers of kidney injury (proteinuria as quantified by urine protein-creatinine ratio (uPCR), NGAL))

Time Frame

24 weeks

Title

Cardiac structure and function by 2D and Doppler echocardiography

Time Frame

24 weeks

Title

Quality of Life by self-reported 36-item Short Form Health Survey (SF-36)

Time Frame

24 weeks

Title

Clinical outcomes by recording deaths and HF hospitalisations

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: At least 21 years of age Asian patients with symptomatic HF (regardless of EF) and renal impairment (eGFR<60ml/min/1.73m2) At least one hospitalisation for HF during the preceeding year 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) Able to complete 6 minute walk test (6MWT) Able to maintain a systolic blood pressure ≥100mmHg Able to provide written informed consent Exclusion Criteria: On chronic therapy with hydralazine and/or nitrates. Known hypersensitivity to hydralazine and/or nitrates Concurrent use of phosphodiesterase type 5 (PDE5) inhibitors Females who are pregnant, nursing, or of childbearing potential and not practising effective contraception Have had acute myocardial infarction, unstable or stable angina pectoris, or a cerebrovascular accident within the last 3 months Have had cardiac revascularisation within the last 3 months or are likely to require coronary revascularisation within the study period Have had cardiac arrest or life-threatening ventricular arrhythmia requiring intervention within 3 months Rapidly deteriorating HF (2 admissions for acute decompensated HF, not due to non-compliance, within 6 months) eGFR< 15ml/min/1.73m2, or on regular dialysis, or planned dialysis within the study period 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 Planned participation in any other interventional study or having received trial medication in the last 4 weeks within a clinical trial

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Su Ping Carolyn Lam, MBBS, MRCP, MS

carolyn_lam@nuhs.edu.sg

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Su Ping Carolyn Lam, MBBS, MRCP, MS

Organizational Affiliation

National University Hospital, Singapore

Official's Role

Study Chair

Facility Information:

Facility Name

National University Hospital, Singapore

City

Singapore

ZIP/Postal Code

119228

Country

Singapore

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Shir Lynn Lim, MBBS, MRCP, MMed

shir_lynn_lim@nuhs.edu.sg

First Name & Middle Initial & Last Name & Degree

Shir Lynn Lim, MBBS, MRCP, MMed

Facility Name

National Heart Centre Singapore

City

Singapore

ZIP/Postal Code

169609

Country

Singapore

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kheng Leng David Sim, MBBS, MRCP, MS

david_sim@nhcs.com.sg

First Name & Middle Initial & Last Name & Degree

Kheng Leng David Sim, MBBS, MRCP, MS

Facility Name

Changi General Hospital

City

Singapore

ZIP/Postal Code

529889

Country

Singapore

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Kui Toh Gerard Leong, MBBS, MRCP, MS

gerard_leong@cgh.com.sg

First Name & Middle Initial & Last Name & Degree

Kui Toh Gerard Leong, MBBS, MRCP, MS

12. IPD Sharing Statement

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

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