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GutHeart: Targeting Gut Microbiota to Treat Heart Failure

Primary Purpose

Systolic Heart Failure

Status

Unknown status

Phase

Phase 2

Locations

Norway

Study Type

Interventional

Intervention

Rifaximin

Saccharomyces boulardii

About this trial

This is an interventional treatment trial for Systolic Heart Failure focused on measuring Heart failure, inflammation, rifaximin, Saccharomyces boulardii, gut microbiota

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Oslo University Hospital - RikshospitaletRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

No Intervention

Arm Label

Rifaximin

Saccharomyces boulardii

Control group

Arm Description

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

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

The third group receives no intervention

Outcomes

Primary Outcome Measures

baseline-adjusted LVEF as measured by echocardiography

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)

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

Chao1 (index)

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

Chao1 (index)

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

TMAO

Left ventricular end diastolic volume

CRP

Health-related quality of life score

measured by the Minnesota Living with Heart Failure Questionnaire

Functional capacity

6 minutes walk test

Number of patients with adverse events (any event)

Number of adverse events (any event)

Full Information

NCT ID

NCT02637167

First Posted

November 10, 2015

Last Updated

March 25, 2019

Sponsor

Oslo University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02637167

Brief Title

GutHeart: Targeting Gut Microbiota to Treat Heart Failure

Official Title

GutHeart: Targeting Gut Microbiota to Treat Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Unknown status

Study Start Date

March 11, 2016 (undefined)

Primary Completion Date

June 20, 2019 (Anticipated)

Study Completion Date

December 31, 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oslo University Hospital

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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.

6. Conditions and Keywords

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

Systolic Heart Failure

Keywords

Heart failure, inflammation, rifaximin, Saccharomyces boulardii, gut microbiota

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Rifaximin

Arm Type

Active Comparator

Arm Description

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

Arm Title

Saccharomyces boulardii

Arm Type

Active Comparator

Arm Description

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

Arm Title

Control group

Arm Type

No Intervention

Arm Description

The third group receives no intervention

Intervention Type

Drug

Intervention Name(s)

Rifaximin

Other Intervention Name(s)

Xifaxan

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Saccharomyces boulardii

Other Intervention Name(s)

Precosa

Intervention Description

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.

Primary Outcome Measure Information:

Title

baseline-adjusted LVEF as measured by echocardiography

Description

Time Frame

after 3 months of intervention

Secondary Outcome Measure Information:

Title

Chao1 (index)

Description

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

Time Frame

at baseline

Title

Chao1 (index)

Description

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

Time Frame

after 3 months

Title

Chao1 (index)

Description

It will be analyzed by sequencing of 16s ribosomal RNA gene (Illumina chemistry)

Time Frame

after 6 months

Title

TMAO

Time Frame

at baseline

Title

TMAO

Time Frame

after 3 months

Title

Left ventricular end diastolic volume

Time Frame

at baseline

Title

Left ventricular end diastolic volume

Time Frame

after 3 months

Title

CRP

Time Frame

at baseline

Title

CRP

Time Frame

after 3 months

Title

Health-related quality of life score

Description

measured by the Minnesota Living with Heart Failure Questionnaire

Time Frame

at baseline and after 3 months

Title

Functional capacity

Description

6 minutes walk test

Time Frame

at baseline and after 3 months

Title

Number of patients with adverse events (any event)

Time Frame

at baseline, after 1 month, after 3 month and after 6 months

Title

Number of adverse events (any event)

Time Frame

at baseline, after 1 month, after 3 month and after 6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

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

Lars L Gullestad, MD, Prof.

lars.gullestad@medisin.uio.no

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

Kaspar Broch, MD

sbbrok@ous-hf.no

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lars L Gullestad, MD, Prof

Organizational Affiliation

Oslo University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oslo University Hospital - Rikshospitalet

City

Oslo

ZIP/Postal Code

0372

Country

Norway

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Cristiane C Mayerhofer, MD

Phone

+47 97880206

cristiane.mayerhofer@gmail.com

12. IPD Sharing Statement

Plan to Share IPD

Yes

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16547529

Citation

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Citation

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GutHeart: Targeting Gut Microbiota to Treat Heart Failure

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