Microbiota Restoration Therapy in HIV With Repeated Low-Dose Interventions

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
HIV Infection

Intervention / Treatment
-----------------
* Biological: FMT
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 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 hs-CRP levels |  | From baseline through week 48 | 
| Changes in plasma lipoteichoic acid levels |  | From baseline through week 48 | 
| Changes in plasma LBP levels |  | From baseline through week 48 | 
| Changes in plasma kynurenine/tryptophan ratio |  | From baseline through week 48 | 
| Percentage of HLA-DR+/CD38+ T cells in blood |  | From baseline through week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, microbiota, inflammation, fecal microbiota restoration