GutHeart: Targeting Gut Microbiota to Treat Heart Failure

Sponsor

Oslo University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02637167

Collaborator

(none)

150

Enrollment

Location

Arms

45.7

Duration (Months)

3.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this trial is to study the effect of targeting the gut microbiota in patients with heart failure (HF). First, the investigators will characterize gut microbiota composition in patients with various degree of systolic HF as compared with healthy controls. Second, the potential impact of targeting gut microbiota to improve HF will be investigated through an open label randomized controlled trial (RCT) of probiotics, antibiotics and controls. The hypothesis being tested is that the gut microbiota is altered in HF; that gut microbiota of HF patients, through interaction with the intestinal and systemic innate immune system, contribute to a low-grade systemic inflammation as well as metabolic disturbances in these patients; and that an intervention with probiotics and the non-absorbable antibiotic Rifaximin attenuates these inflammatory and metabolic disturbances and improves heart function through modulation of the gut microbiota.

Condition or Disease	Intervention/Treatment	Phase
Systolic Heart Failure	Drug: Rifaximin Drug: Saccharomyces boulardii	Phase 2

Detailed Description

While most studies on inflammation in heart failure (HF) have focused on down-stream mediators of inflammation and tissue damage, the present study will focus on alterations of the gut microbiota as a potential upstream arm in the activation of inflammatory responses. The gut microbiota may play a central role not only in the inflammatory arm of the pathogenesis of HF, but could also be involved in the induction of metabolic disturbances that contribute to the progression of this disorder. Decompensated HF is characterized by decreased cardiac output and congestion, contributing to edema and ischemia of the gut wall. Consequently, structural and functional changes occur, causing increased gut permeability.

Several studies have shown that low grade leakage of microbial products such as lipopolysaccharides (LPS), occurs across the gut wall, potentially causing systemic inflammation by activation of Toll like receptors (TLRs). Very small amounts of LPS have been shown to effectively induce release of TNFα 6, which acts as a cardiosuppressor via several pathways, including reduced mitochondrial activity, altered calcium homeostasis and impaired β-adrenergic signaling in cardiomyocytes. Furthermore, the investigators have recently shown that the microbiota-dependent marker TMAO is associated with clinical outcome in chronic HF. Interestingly, gut decontamination with antibiotics have been shown to reduce intestinal LPS-levels, monocyte expression of the LPS-receptor CD14 and production of TNFα. In addition, selective gut decontamination has improved postoperative outcome in cardiac surgery patients. However, at present there are no studies that have fully characterized the gut microbiota in HF patients and our knowledge of the interaction between gut microbiota, systemic inflammatory, metabolic disturbances and myocardial dysfunction in these patients are scarce.

This project will focus on the gut microbiota as a potential therapeutic target in HF, through an open label randomized controlled trial (RCT) of probiotics, antibiotics and controls, with improved heart function as primary end point.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

GutHeart: Targeting Gut Microbiota to Treat Heart Failure

Study Start Date :

Mar 11, 2016

Anticipated Primary Completion Date :

Jun 20, 2019

Anticipated Study Completion Date :

Dec 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rifaximin Rifaximin: one tablet (550 mg) morning and evening for three months	Drug: Rifaximin Rifaximin has negligible intestinal absorption after oral administration, giving it a good safety profile. Unlike systemically available antibiotics, this antimicrobial allows localized enteric targeting of bacteria and is associated with a minimal risk of systemic toxicity or side effects. Other Names: Xifaxan
Active Comparator: Saccharomyces boulardii S. boulardii: two capsules (500 mg) morning and evening for three months	Drug: Saccharomyces boulardii The same advantage described above to Rifaximin applies to S. Boulardii, which might be therapeutically sufficient with the advantage of being less disruptive to the instestinal microbiota than broad-spectrum antibiotics. Other Names: Precosa
No Intervention: Control group The third group receives no intervention

Arm

Intervention/Treatment

Active Comparator: Rifaximin

Rifaximin: one tablet (550 mg) morning and evening for three months

Drug: Rifaximin

Rifaximin has negligible intestinal absorption after oral administration, giving it a good safety profile. Unlike systemically available antibiotics, this antimicrobial allows localized enteric targeting of bacteria and is associated with a minimal risk of systemic toxicity or side effects.

Other Names:

Xifaxan

Active Comparator: Saccharomyces boulardii

S. boulardii: two capsules (500 mg) morning and evening for three months

Drug: Saccharomyces boulardii

The same advantage described above to Rifaximin applies to S. Boulardii, which might be therapeutically sufficient with the advantage of being less disruptive to the instestinal microbiota than broad-spectrum antibiotics.

Other Names:

Precosa

No Intervention: Control group

The third group receives no intervention

Outcome Measures

Primary Outcome Measures

baseline-adjusted LVEF as measured by echocardiography [after 3 months of intervention]
A General Electrics Healthcare Vivid E9 Doppler ultrasound scanner or a similar, top specified cardiac ultrasound device will be used for echocardiographic imaging. Patients are examined in the lateral recumbent position after > 5 minutes of rest at baseline, prior to the start of study drug treatment, and at follow-up after 3 months, prior to study drug discontinuation. The heart is visualized by the standard ultrasonic techniques and imaging planes as recommended by the European society of echocardiography20,21 providing a comprehensive hemodynamic and valvular assessment.

Secondary Outcome Measures

Chao1 (index) [at baseline]
It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)
Chao1 (index) [after 3 months]
It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)
Chao1 (index) [after 6 months]
It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)
TMAO [at baseline]
TMAO [after 3 months]
Left ventricular end diastolic volume [at baseline]
Left ventricular end diastolic volume [after 3 months]
CRP [at baseline]
CRP [after 3 months]
Health-related quality of life score [at baseline and after 3 months]
measured by the Minnesota Living with Heart Failure Questionnaire
Functional capacity [at baseline and after 3 months]
6 minutes walk test
Number of patients with adverse events (any event) [at baseline, after 1 month, after 3 month and after 6 months]
Number of adverse events (any event) [at baseline, after 1 month, after 3 month and after 6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 74 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must be at least 18 years of age, and less than 75.
Have heart failure in New York Heart Association class II or III
Echocardiographically verified LVEF < 40 %.
On optimal treatment for at least 3 months
Must have lab values as the following:

Hemoglobin above 10 g/l; eGFR above 30 ml/min; ALT < 150 units/l

Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.

Exclusion Criteria:

Treatment with antibiotics or probiotics within the last 12 weeks
History of hypersensitivity to Rifaximin or other Rifamycin derived antimicrobial agents, or any of the components of Xifaxan
History of hypersensitivity to S. boulardii, yeast, or any of the components of Precosa
Polypharmacia with increased risk for interactions. i.e. patient with an extensive medication lists (e.g. 10 drugs or more) which may influence with the patient safety or compromise the study results
Malignancy of any cause, excluding basal cell carcinoma of the skin
Acute coronary syndrome over the last 12 weeks
Severely impaired kidney function (i.e., estimated glomerular filtration rate < 30 ml/minute/1.73 m2)
Impaired liver function (Alanine aminotransferase > 150 U/l) or decompensated liver cirrhosis classified as Child-Pugh B or C.
On-going infection, including GI infection
Inflammatory bowel disease
Bowel obstruction
Active myocarditis, including Chagas disease
Severe primary valvular heart disease
Atrial fibrillation with ventricular frequency > 100/min
Any other, severe co morbid disease that must be expected to severely reduce the efficacy of the interventional products, survival or compliance
Treatment with immunosuppressive drugs
Treatment with rifamycins other than Rifaximin
Central venous catheter
Pregnancy or planned pregnancy
Nursing
Poor compliance
Any reason why, in the opinion of the investigator, the patient should not participate