Effect of Intensive FMT on Primary Hypertension

Effect and Safety of Intensive Fecal Microbiota Transplantation on Primary Hypertension: a Randomized Clinical Trial.

Mounting preclinical and clinical evidences have proved the causal role of gut microbiota on the pathogenesis of primary hypertension. Restoration of gut microbiota ameliorated high BP in rodents and/or human cases.A hypothesis is thus raised that gut microbiome restoration can be a potential approach to ameliorate hypertension. This study will perform intense fecal microbiota transplantation (FMT) intervention via oral capsules, in comparison with placebo capsules, to investigate the effect, safety and underlying mechanisms of gut microbiome intervention on primary hypertension.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypertension
• Intervention / Treatment: Biological: FMT capsules; Other: Placebo capsules

Detailed Description

Primary hypertension is a most prevalent cardiovascular diseases, and becomes a severe global public health issue because of the high morbidity and potential risk to other cardiovascular diseases. Several animal studies and diverse patient cohorts reported that the disorder of gut microbiome correlated with hypertension. Based on the investigators' previous work findings, a casual role of gut microbiome disorder was observed in primary hypertension (Microbiome. 2017;5(1):14.), and trend of ameliorating SBP was observed after short-course FMT intervention but recovery after intervention termination(Trials. 2022;23(1):178, unpublished results). The investigators therefore developed a consecutive study of intensive FMT intervention on primary hypertension.

Objective: To explore the effect, safety and underlying mechanisms of intensive FMT on primary hypertension.

Study Design: A multi-center, randomized, blinded, placebo-controlled pilot study.

Data quality control and statistical analysis: The investigators have invited professional statistic analysts to assist analyzing data and a third party to supervise data quality.

• Study Type: Interventional
• Enrollment (Anticipated): 72
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jun Jun, MD,PhD; Phone Number: 86-010-88392165; Email: caijun7879@126.com
• Study Contact Backup: Name: Jun Jun, MD,PhD; Phone Number: 86-010-60866432; Email: caijun7879@126.com

Study Locations

• China
  • Guangdong
    • Shantou, Guangdong, China
      • The Second Affiliated Hospital of Shantou University
  • Shanxi
    • Taiyuan, Shanxi, China
      • Shanxi Bethune Hospital
  • Tianjin
    • Tianjin, Tianjin, China
      • The People's Hospital of Ji Xian District

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18~65 years.
2. Established Diagnosis of Grade 1 Hypertension (initial diagnosis or free from antihypertensive drugs within a month): 140mmHg≤ Office SBP<160mmHg and/or 90mmHg≤ Office DBP<100mmHg for three measurements at different days without any antihypertensive medications, according to the"2010 Chinese Guidelines for Prevention and Treatment of Hypertension".
3. Patients with informed consent after thorough explanation.

Exclusion Criteria:

1. Antibiotics or probiotics usage within last 4 weeks
2. Participants of other clinical trials related to hypertension currently or within last 3 months
3. Antihypertensive medications usage currently or within last month
4. Diagnosed secondary hypertension
5. Severe hepatic or renal diseases ((ALT >3 times the upper limit of normal value, or end stage renal disease on dialysis or eGFR <30 mL/min/1.73 m2, or serum creatinine >2.5 mg/dl [>221 μmol/L])
6. History of large atherosclerotic cerebral infarction or hemorrhagic stroke(not including lacunar infarction and transient ischemic attack [TIA])
7. Hospitalization for myocardial infarction within last 6 months; Coronary revascularization (PCI or CABG) within last 12 months; Planned for PCI or CABG in the next 12 months.
8. Sustained atrial fibrillation or arrhythmias at recruitment disturbing the electronic BP measurement.
9. NYHA class III-IV heart failure; Hospitalization for chronic heart failure exacerbation within last 6 months.
10. Severe valvular diseases; Potential for surgery or percutaneous valve replacement within the study period.
11. Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Rheumatic heart disease; Congenital heart disease.
12. Other severe diseases influencing the entry or survival of participants, such as malignant tumor or acquired immune deficiency syndrome.
13. Cognitive impairment or severe neuropsychiatric comorbidities who are incapable of providing their own informed consent.
14. Participants preparing for or under pregnancy and/or lactation.
15. Other conditions inappropriate for recruitment according to the investigators.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: FMT capsules; FMT capsules containing extensively screened donor stool. FMT capsules will be orally taken on Day 0 (randomization), Day 1, Day 2, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49.	Biological: FMT capsules; FMT capsules containing extensively screened donor stool.
Placebo Comparator: Placebo capsules; Placebo capsules that do not contain donor stool or any active drug. Placebo capsules will be orally taken on Day 0 (randomization), Day 1, Day 2, Day 7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49.	Other: Placebo capsules; Placebo capsules that do not contain donor stool or any active drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Office Systolic Blood Pressure (SBP)	Change in Office Systolic Blood Pressure (SBP)	From baseline to Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Office Systolic Blood Pressure (SBP)	Change in Office Systolic Blood Pressure (SBP)	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 12
Change in Office Diastolic Blood Pressure (DBP)	Change in Office Diastolic Blood Pressure (DBP)	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12
Change in Home Systolic Blood Pressure (SBP)	Change in Home Systolic Blood Pressure (SBP)	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12
Change in Home Diastolic Blood Pressure (DBP)	Change in Home Diastolic Blood Pressure (DBP), compared with baseline	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 12
Change in average SBP via 24-hour Ambulatory BP Monitoring	Change in average SBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Change in average DBP via 24-hour Ambulatory BP Monitoring	Change in average DBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Change in daytime SBP via 24-hour Ambulatory BP Monitoring	Change in daytime SBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Change in daytime DBP via 24-hour Ambulatory BP Monitoring	Change in daytime DBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Change in nighttime SBP via 24-hour Ambulatory BP Monitoring	Change in nighttime SBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Change in nighttime DBP via 24-hour Ambulatory BP Monitoring	Change in nighttime DBP via 24-hour Ambulatory BP Monitoring	Baseline, Week 4, Week 8, Week 12
Number of Participants with Adverse Events (AEs) as a Measure of Safety	Number of Participants with Adverse Events (AEs) as a Measure of Safety	All AEs over 12 weeks
Changes in Intestinal Microbiota Composition Pre- and Post-intervention via Metagenomic Analysis	Changes in Intestinal Microbiota Composition Pre- and Post-intervention (FMT or Placebo) via Metagenomic Analysis, stratified by: Randomisation; Change in Office SBP	Baseline, Week 4, Week 8, Week 12
Changes in Intestinal Microbiota function revealed by KEGG pathways and KEGG Orthology (KO) Pre- and Post-intervention via Metagenomic Analysis	Changes in Intestinal Microbiota function revealed by KEGG pathways and KEGG Orthology (KO) Pre- and Post-intervention via Metagenomic Analysis, stratified by: Randomisation; Change in Office SBP	Baseline, Week 4, Week 8, Week 12
Durability of Engraftment of Donor Microbiome Following FMT	Durability of engraftment of donor microbiome following FMT, measured by similarity comparison of intestinal microbiota composition between donor and recipient	Baseline, Week 4, Week 8, Week 12
Changes in Plasma Metabolite Composition Pre- and Post-intervention via Metabolomic Analysis	Changes in Plasma Metabolite Composition Pre- and Post-intervention (FMT or Placebo) via Metabolomic Analysis, stratified by: Randomisation; Change in Office SBP	Baseline, Week 4, Week 8, Week 12
Change in Fasting Blood Glucose Level	Change in Fasting Blood Glucose Level	Baseline, Week 4, Week 8, Week 12
Change in blood HbA1c level	Change in blood glycosylated hemoglobin, type A1C (HbA1c) level	Baseline, Week 4, Week 8, Week 12
Change in blood lipid level	Change in Blood Lipid Level (Total Cholesterol, Total Triglyceride, Low Density Lipoprotein Cholesterol, High Density Lipoprotein Cholesterol)	Baseline, Week 4, Week 8, Week 12
Change in Body Mass Index	Change in Body Mass Index	Baseline, Week 4, Week 8, Week 12

Collaborators and Investigators

• Sponsor: Chinese Academy of Medical Sciences, Fuwai Hospital
• Investigators: Principal Investigator: Jun Cai, MD,PhD, Fuwai Hospital, CAMS&PUMC

Publications and helpful links

General Publications

• Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, Satokari R, Sokol H, Arkkila P, Pintus C, Hart A, Segal J, Aloi M, Masucci L, Molinaro A, Scaldaferri F, Gasbarrini G, Lopez-Sanroman A, Link A, de Groot P, de Vos WM, Hogenauer C, Malfertheiner P, Mattila E, Milosavljevic T, Nieuwdorp M, Sanguinetti M, Simren M, Gasbarrini A; European FMT Working Group. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017 Apr;66(4):569-580. doi: 10.1136/gutjnl-2016-313017. Epub 2017 Jan 13.
• Li J, Zhao F, Wang Y, Chen J, Tao J, Tian G, Wu S, Liu W, Cui Q, Geng B, Zhang W, Weldon R, Auguste K, Yang L, Liu X, Chen L, Yang X, Zhu B, Cai J. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017 Feb 1;5(1):14. doi: 10.1186/s40168-016-0222-x.
• Fan L, Ren J, Chen Y, Wang Y, Guo Z, Bu P, Yang J, Ma W, Zhu B, Zhao Y, Cai J. Effect of fecal microbiota transplantation on primary hypertension and the underlying mechanism of gut microbiome restoration: protocol of a randomized, blinded, placebo-controlled study. Trials. 2022 Feb 24;23(1):178. doi: 10.1186/s13063-022-06086-2.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): September 30, 2023

Study Registration Dates

• First Submitted: November 1, 2022
• First Submitted That Met QC Criteria: November 1, 2022
• First Posted (Actual): November 8, 2022

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: treatment; hypertension; fecal microbiota transplantation; microbiome
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension
• Other Study ID Numbers: 2017-GZ10 (Part III)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The collected data, study protocol, and SAP are planned to be shared after the study ends 2 years later (anticipated)
• IPD Sharing Time Frame: after the study ends 2 years later (anticipated)
• IPD Sharing Access Criteria: Access to these de-identified data will be required for written permission from the responsible investigation center and only for qualified researchers.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No