E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Adult patients with systolic heart failure who fulfill the inclusion and
exclusion criteria will be invited to participate in the study |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the study is to investigate the gut microbiota as a
potential therapeutic target in HF:
• By characterizing the composition of gut microbiota in HF patients
compared to healthy controls.
• By characterizing the effect of antibiotics and probiotics on the gut
microbiota and systemic inflammatory and metabolic markers in HF
patients.
• By characterizing the effect of antibiotics and probiotics on cardiac
function in HF patients. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 18 ≥ and <75 years of age
• Clinical or symptomatic evidence of HF, in NYHA class II-III and LVEF
< 40%
• 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
• Patients should be stabilized on state-of-art HF medication for more
than 3 months prior to inclusion
• Acceptable acoustic windows for echocardiographic assessment
All of the following conditions must apply to the prospective patient at
screening prior to receiving study agent (e.g.):
• 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. |
|
E.4 | Principal 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
(http://www.legemiddelverket.no/_layouts/Preparatomtaler/Spc/11-
8645.pdf?id=05122013165930).
• History of hypersensitivity to S. boulardii, yeast, or any of the
components of Precosa
(http://www.legemiddelverket.no/_layouts/Preparatomtaler/Spc/1994
-02012.pdf?id=03042014142345).
• 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
• Severly impaired kidney function (i.e., estimated glomerulus 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 comorbid 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point of this study is baseline-adjusted LVEF as
measured by echocardiography after 3 months of intervention.The trial
is powered to show a 5 per cent point increase in either intervention arm
compared to the control group (the statistical null-hypothesis being that
there is no difference between any of the two intervention arms and the
control arm). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and after 3 months intervention |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints will assess differences between either of the
treatment arms an the control group at the end-of study, as well as at
the pre-defined follow-up time points, regarding (i) the gut microbiota
composition, (ii) microbiota-related metabolites, (iii) extended
parameters on cardiac function in addition to LVEF, (iv) inflammatory
and anti-inflammatory mediators in plasma, serum, peripheral blood
mononuclear cells (PBMC) and whole blood, (v) health-related quality of
life, (vi) functional capacity and (vii) safety |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline and after 3 months intervention |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Blinded end point analysis |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |