Microbiota Restoration Therapy in HIV With Repeated Low-Dose Interventions (REFRESH)

A Phase I/II Randomized, Double-Blind, Placebo Controlled Study of Repeated Low-Dose Fecal Microbiota Restoration in HIV-Infected Subjects. The REFRESH Study

Altered interplay between gut mucosa and dysbiotic bacteria during HIV infection seems to contribute to chronic immune dysfunction. Manipulation of the intestinal microbiota with nutritional interventions exert limited immunologic effects, but a deep understanding of how these interventions could ameliorate gut dysbiosis and influence health among HIV-infected individuals remain unexplored. In this Phase I clinical trial, 30 HIV-infected subjects on effective ART with evidence of persistent immune dysfunction, indicated by a CD4/CD8 ratio<1 will be included and randomized to either repeated low-dose oral fecal microbiota transplantation or placebo during 8 weeks. The primary outcome will be safety. Secondary outcomes will include changes in CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio, inflammatory markers, T cell activation and markers of enterocyte barrier function through week 48. Engraftment on host microbiota will be examined using Illumina sequencing of the V3-V4 16S RNA, and changes in bacterial metabolism and in the plasma metabolite fingerprint will be studied by combination of untargeted mass spectrometry and two different and complementary separation techniques in bacterial and plasma samples.

Study Overview

• Status: Completed
• Conditions: HIV Infection
• Intervention / Treatment: Other: Placebo; Biological: FMT

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• On stable antiretroviral therapy with plasma HIV RNA <20 copies/mL during at least 48 weeks.
• CD4/CD8 ratio <1

Exclusion Criteria:

• Pregnancy
• Gastrointestinal diseases, including cirrhosis
• Active infections, including HCV
• EBV and/or CMV negative patients (donors are not screened for EBV/CMV).
• Planned used of chemotherapy or antibiotics
• Allergy to sodium chloride or glycerol (the former components are capsule ingredients Generally Recognized As Safe (GRAS)
• Current or planned use of antimicrobial agents (including prophylactic treatments against P. jiroveci) other than ART.
• Neutropenia <500 cells/uL or CD4 counts <350 cells/uL
• Patients unable to give informed consent
• Patients unable to comply with the protocol requirements
• Predicted death within time period of follow-up
• Any other condition for which the treating physician thinks the treatment may pose a health risk
• Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple sclerosis, ALS)
• History of aspiration
• History of gastroparesis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FMT; Fecal microbiota capsules (provided by Openbiome). Dosage: Induction: 10 capsules (single dose); Maintenance: 5 capsules, weekly, during 7 weeks.	Biological: FMT; Capsules with fecal microbiota from healthy donors
Placebo Comparator: Placebo; Placebo capsules (provided by Openbiome). Dosage: Induction: 10 capsules (single dose); Maintenance: 5 capsules, weekly, during 7 weeks.	Other: Placebo; Placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	From baseline through week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in plasma hs-CRP levels		From baseline through week 48
Changes in plasma lipoteichoic acid levels		From baseline through week 48
Changes in plasma kynurenine/tryptophan ratio		From baseline through week 48
Changes in CD4+ T cell counts		From baseline through week 48
Changes in CD8+ T cell counts	Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.; Monocyte/macrophage activation: sCD14, SCD163,; Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).; Bacterial translocation: lipoteichoic acid (LTA); Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio; Coagulation: D-dimers	From baseline through week 48
Changes in CD4/CD8 ratio	Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.; Monocyte/macrophage activation: sCD14, SCD163,; Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).; Bacterial translocation: lipoteichoic acid (LTA); Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio; Coagulation: D-dimers	From baseline through week 48
Changes in microbiota alpha diversity metrics		From baseline through week 48
Changes in microbiota Unifrac distances		From baseline through week 48
Changes in microbiota Canberra distances		From baseline through week 48
Changes in plasma Interleukin-6 levels		From baseline through week 48
Changes in plasma LBP levels		From baseline through week 48
Percentage of HLA-DR+/CD38+ T cells in blood		From baseline through week 48

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Publications and helpful links

General Publications

• Serrano-Villar S, Talavera-Rodriguez A, Gosalbes MJ, Madrid N, Perez-Molina JA, Elliott RJ, Navia B, Lanza VF, Vallejo A, Osman M, Dronda F, Budree S, Zamora J, Gutierrez C, Manzano M, Vivancos MJ, Ron R, Martinez-Sanz J, Herrera S, Ansa U, Moya A, Moreno S. Fecal microbiota transplantation in HIV: A pilot placebo-controlled study. Nat Commun. 2021 Feb 18;12(1):1139. doi: 10.1038/s41467-021-21472-1.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: December 28, 2016
• First Submitted That Met QC Criteria: December 30, 2016
• First Posted (Estimate): January 4, 2017

Study Record Updates

• Last Update Posted (Actual): October 30, 2018
• Last Update Submitted That Met QC Criteria: October 27, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: HIV; inflammation; microbiota; fecal microbiota restoration
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 165-16; GESIDA 9116 (Other Identifier: GESIDA Study group)