Clinical trial NCT03008941: Microbiota Restoration Therapy in HIV With Repeated Low-Dose Interventions
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infection
Keywords: HIV
microbiota
inflammation
fecal microbiota restoration
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
First posted: 2017-01-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: From baseline through week 48
Secondary outcomes:
measure: Changes in CD4+ T cell counts
timeFrame: From baseline through week 48
measure: Changes in CD8+ T cell counts
timeFrame: From baseline through week 48
measure: Changes in CD4/CD8 ratio
timeFrame: From baseline through week 48
measure: Changes in microbiota alpha diversity metrics
timeFrame: From baseline through week 48
measure: Changes in microbiota Unifrac distances
timeFrame: From baseline through week 48
measure: Changes in microbiota Canberra distances
timeFrame: From baseline through week 48
measure: Changes in plasma Interleukin-6 levels
timeFrame: From baseline through week 48
measure: Changes in plasma hs-CRP levels
timeFrame: From baseline through week 48
measure: Changes in plasma lipoteichoic acid levels
timeFrame: From baseline through week 48
measure: Changes in plasma LBP levels
timeFrame: From baseline through week 48
measure: Changes in plasma kynurenine/tryptophan ratio
timeFrame: From baseline through week 48
measure: Percentage of HLA-DR+/CD38+ T cells in blood
timeFrame: From baseline through week 48
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
Study officials:
References:
citation: 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.