Investigation of the Gut Microbiome and Statin Response

Healthy Volunteers Clinical Trial

— INGEST  

Official title:

INvestigation of the Gut microbiomE and STatin Response (INGEST)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04098003
• Other study ID #: 832874
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: February 6, 2020
• Est. completion date: June 1, 2024

Study information

• Verified date: July 2023
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There is evidence that the bacteria that naturally reside in the gut can influence how well we respond to medications. Therefore this study will look at how rosuvastatin, a medication used to lower cholesterol levels, may change the bacteria in the gut. Investigators will also examine how the gut bacteria will affect the ability of rosuvastatin to lower cholesterol levels. There will be 4 study visits over the course of about 16 weeks.The expected duration of the study is 2 years. Investigators plan to enroll 100 healthy volunteers during that time.

Description:

The gut microbiome plays an important role in the metabolism of xenobiotics and contributes to the variation in drug response. Atorvastatin, simvastatin and rosuvastatin, three of the most commonly prescribed statin medications, also display evidence for modulation by the gut microbiome.The objective of this study is to understand the interaction between the gut microbiome and host drug response to statin therapy using 16S rRNA sequencing, metagenomics sequencing and bile acid metabolomics. Aim 1: To compare changes in the gut microbiome in healthy volunteers randomized to an 8-week intervention with rosuvastatin 10mg daily or placebo. Aim 2: To determine the relationship with gut microbiome, fecal bile acid composition, serum FGF19 levels and the change in plasma LDL-C with rosuvastatin. This is a randomized, placebo controlled trial to investigate the effects of rosuvastatin on the gut microbiome, fecal bile acids and FGF19 levels. Healthy volunteers will be randomized to rosuvastatin 20 mg daily or placebo for eight weeks in a 2:1 ratio. Participants will be blinded to treatment assignment. Stool and blood will be collected at baseline, 8 weeks, and 12 weeks for 16S sequencing, plasma lipid assays, bile acid metabolites and FGF19 assays. A subgroup of participants at the tails of LDL-C response will undergo metagenomics sequencing.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 62
• Est. completion date: June 1, 2024
• Est. primary completion date: June 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Participant is capable of giving informed consent

2. Participant is aged 18 to 65 years. The gut microbiome has been shown to change gradually with time, although there is no cut-off in age when this occurs.

Exclusion Criteria:

1. Participants with cardiovascular disease such as a history of heart failure (New York Heart Association class II-IV), myocardial infarction, stroke, coronary artery bypass graft, hypertension, and hyperlipidemia as these conditions are associated with altered gut microbiome composition.74 Hypertension is defined as blood pressure greater than 160/110 or on any anti-hypertensive medications. LDL-C >190 mg/dl or <100 mg/dl and triglycerides > 400 mg/dl.

2. Participants with a history of cancer.

3. Kidney disease (serum creatinine >1.5 mg/dl).

4. Liver dysfunction (alanine aminotransferase > 2 times the upper limit of normal).

5. Diabetes mellitus (DM) - Diabetes itself may affect the gut microbiome although this has not been extensively studied. In addition to a prior diagnosis of diabetes mellitus other than that related to pregnancy, a fasting glucose level of greater than 125mg/dL will be used to exclude participation.

6. Clinical diagnosis of hypothyroidism

7. History of inflammatory disorders of the intestinal tract (i.e. IBD, celiac sprue).

8. Use of antibiotics in the prior 6 months.

9. Use of pre-, pro-, or synbiotics.

10. Chronic medication use (including over the counter medications and herbal supplements) with the exception of oral contraceptives. Since we are evaluating the impact of rosuvastatin on the gut microbiome we would like to exclude the potential impact of confounding medications.

11. Current smoker. The effect of smoking on the microbiome of the gut is unknown.

12. Known history of alcohol or substance abuse.

13. Body Mass Index (BMI) <18.5 or >30 kg/m2. Volunteers with BMI below normal will be excluded to prevent inclusion of subjects with a subclinical systemic disease that may influence the gut microbiome. Volunteers with moderate or severe obesity will be excluded as obesity may be associated with altered gut microbiome composition.31

14. Unable to abstain from consumption of illicit drugs during the study period.

15. Prior bowel resection surgery other than appendectomy. It is unknown how prior bowel resection surgery may influence the microbiome composition; hence we will exclude these participants.

16. Baseline bowel frequency less than every 2 days or greater than 3 times daily. Normal bowel frequency is every 3rd day to 3 times per day. Although unknown, stool frequency could be related to the microbiome composition. To avoid the need for use of antidiarrheal medications or laxatives, which themselves could alter the microbiome composition, these patients will be excluded.

17. Participant has experienced diarrhea within the two weeks prior to entry. Diarrhea is defined as a change in bowel habits with an increased frequency or loose stools such that the stool could not be lifted with a fork.

18. Vegans and Vegetarians.

19. Known intolerance to statin medications.

20. Unwilling to obtain from grapefruit containing foods or drinks.

21. Pregnant women. To avoid any risk to an unborn fetus from study drug exposure.

22. Refusal to use two medically accepted method of birth control while participating in the study, such as a barrier method, hormonal contraceptives, implanted birth control devices, permanent methods (such as a vasectomy), and/or abstinence.

23. Nursing mothers

24. Any condition that the investigator feels may limit the volunteer's ability to complete the study protocol.

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• Rosuvastatin
rosuvastatin 20 mg daily or placebo for eight weeks
• Placebo
Matched placebo control

Locations

Country	Name	City	State
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Sony Tuteja

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in fecal bile acid concentrations	concentration of bile acids (nM)	8 weeks
Other	Change in serum FGF19 levels	Fibroblast growth factor 19 levels (pg/mL)	8 weeks
Primary	Change in bacterial abundance	as measured by operational taxonomic units (OTUs)	8 weeks
Secondary	Change in LDL-C	low density lipoprotein cholesterol levels (mg/dl)	8 weeks