NCT02637167

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
150

participants targeted

Target at P75+ for phase_2

Timeline
Completed

Started Mar 2016

Typical duration for phase_2

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

November 10, 2015

Completed
1 month until next milestone

First Posted

Study publicly available on registry

December 22, 2015

Completed
3 months until next milestone

Study Start

First participant enrolled

March 11, 2016

Completed
3.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 20, 2019

Completed
6 months until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2019

Completed
Last Updated

March 26, 2019

Status Verified

March 1, 2019

Enrollment Period

3.3 years

First QC Date

November 10, 2015

Last Update Submit

March 25, 2019

Conditions

Systolic Heart Failure

Keywords

Heart failureinflammationrifaximinSaccharomyces boulardiigut microbiota

Outcome Measures

Primary Outcomes (1)

  • 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.

    after 3 months of intervention

Secondary Outcomes (13)

  • Chao1 (index)

    at baseline

  • Chao1 (index)

    after 3 months

  • Chao1 (index)

    after 6 months

  • TMAO

    at baseline

  • TMAO

    after 3 months

  • +8 more secondary outcomes

Study Arms (3)

Rifaximin

ACTIVE COMPARATOR

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

Drug: Rifaximin

Saccharomyces boulardii

ACTIVE COMPARATOR

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

Drug: Saccharomyces boulardii

Control group

NO INTERVENTION

The third group receives no intervention

Interventions

RifaximinDRUG

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.

Also known as: Xifaxan
Rifaximin
Saccharomyces boulardiiDRUG

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.

Also known as: Precosa
Saccharomyces boulardii

Eligibility Criteria

Age18 Years - 74 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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.

You may not qualify if:

  • 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
  • +7 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Oslo University Hospital - Rikshospitalet

Oslo, 0372, Norway

RECRUITING

Related Publications (16)

  • Aukrust P, Yndestad A, Ueland T, Damas JK, Gullestad L. Anti-inflammatory trials in chronic heart failure. Heart Fail Monit. 2006;5(1):2-9.

    PMID: 16547529BACKGROUND

  • Backhed F. Meat-metabolizing bacteria in atherosclerosis. Nat Med. 2013 May;19(5):533-4. doi: 10.1038/nm.3178. No abstract available.

    PMID: 23652100BACKGROUND

  • Vinje S, Stroes E, Nieuwdorp M, Hazen SL. The gut microbiome as novel cardio-metabolic target: the time has come! Eur Heart J. 2014 Apr;35(14):883-7. doi: 10.1093/eurheartj/eht467. Epub 2013 Nov 11.

    PMID: 24216389BACKGROUND

  • Charalambous BM, Stephens RC, Feavers IM, Montgomery HE. Role of bacterial endotoxin in chronic heart failure: the gut of the matter. Shock. 2007 Jul;28(1):15-23. doi: 10.1097/shk.0b013e318033ebc5.

    PMID: 17510602BACKGROUND

  • Genth-Zotz S, von Haehling S, Bolger AP, Kalra PR, Wensel R, Coats AJ, Anker SD. Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure. Am J Cardiol. 2002 Dec 1;90(11):1226-30. doi: 10.1016/s0002-9149(02)02839-4.

    PMID: 12450603BACKGROUND

  • Sandek A, Anker SD, von Haehling S. The gut and intestinal bacteria in chronic heart failure. Curr Drug Metab. 2009 Jan;10(1):22-8. doi: 10.2174/138920009787048374.

    PMID: 19149510BACKGROUND

  • Troseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, Aakhus S, Gude E, Bjorndal B, Halvorsen B, Karlsen TH, Aukrust P, Gullestad L, Berge RK, Yndestad A. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med. 2015 Jun;277(6):717-26. doi: 10.1111/joim.12328. Epub 2014 Dec 1.

    PMID: 25382824BACKGROUND

  • Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, Ieven MM, Bosmans JM, Schuerwegh A, Bridts CH, Wuyts F, Stevens WJ, Anker SD, Rauchhaus M, Vrints CJ. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail. 2004 Jun;6(4):483-91. doi: 10.1016/j.ejheart.2003.12.004.

    PMID: 15182775BACKGROUND

  • Fox MA, Peterson S, Fabri BM, van Saene HK. Selective decontamination of the digestive tract in cardiac surgical patients. Crit Care Med. 1991 Dec;19(12):1486-90. doi: 10.1097/00003246-199112000-00008.

    PMID: 1959367BACKGROUND

  • Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400.

    PMID: 23614584BACKGROUND

  • Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, Rajapurohitam V, Sidaway JE, Martin G, Gloor GB, Swann JR, Reid G, Karmazyn M. Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ Heart Fail. 2014 May;7(3):491-9. doi: 10.1161/CIRCHEARTFAILURE.113.000978. Epub 2014 Mar 13.

    PMID: 24625365BACKGROUND

  • McFarland LV. Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World J Gastroenterol. 2010 May 14;16(18):2202-22. doi: 10.3748/wjg.v16.i18.2202.

    PMID: 20458757BACKGROUND

  • Costanza AC, Moscavitch SD, Faria Neto HC, Mesquita ET. Probiotic therapy with Saccharomyces boulardii for heart failure patients: a randomized, double-blind, placebo-controlled pilot trial. Int J Cardiol. 2015 Jan 20;179:348-50. doi: 10.1016/j.ijcard.2014.11.034. Epub 2014 Nov 11. No abstract available.

    PMID: 25464484BACKGROUND

  • ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available.

    PMID: 12091180BACKGROUND

  • Sugrue DD, Rodeheffer RJ, Codd MB, Ballard DJ, Fuster V, Gersh BJ. The clinical course of idiopathic dilated cardiomyopathy. A population-based study. Ann Intern Med. 1992 Jul 15;117(2):117-23. doi: 10.7326/0003-4819-117-2-117.

    PMID: 1605426BACKGROUND

  • Raju SC, Molinaro A, Awoyemi A, Jorgensen SF, Braadland PR, Nendl A, Seljeflot I, Ueland PM, McCann A, Aukrust P, Vestad B, Mayerhofer C, Broch K, Gullestad L, Lappegard KT, Halvorsen B, Kristiansen K, Hov JR, Troseid M. Microbial-derived imidazole propionate links the heart failure-associated microbiome alterations to disease severity. Genome Med. 2024 Feb 8;16(1):27. doi: 10.1186/s13073-024-01296-6.

    PMID: 38331891DERIVED

MeSH Terms

Conditions

Heart Failure, SystolicHeart FailureInflammation

Interventions

Rifaximin

Condition Hierarchy (Ancestors)

Heart DiseasesCardiovascular DiseasesPathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

RifamycinsHeterocyclic Compounds, 4 or More RingsHeterocyclic Compounds, Fused-RingHeterocyclic CompoundsLactams, MacrocyclicMacrocyclic CompoundsPolycyclic Compounds

Study Officials

  • Lars L Gullestad, MD, Prof

    Oslo University Hospital

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Lars L Gullestad, MD, Prof.

CONTACT

lars.gullestad@medisin.uio.no

Kaspar Broch, MD

CONTACT

sbbrok@ous-hf.no

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Professor

Study Record Dates

First Submitted

November 10, 2015

First Posted

December 22, 2015

Study Start

March 11, 2016

Primary Completion

June 20, 2019

Study Completion

December 31, 2019

Last Updated

March 26, 2019

Record last verified: 2019-03

Data Sharing

IPD Sharing
Will share

Locations

NO(1)