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

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ClinicalTrials.gov Identifier: NCT03008941
Recruitment Status : Active, not recruiting
First Posted : January 4, 2017
Last Update Posted : February 7, 2018
Sponsor:
Information provided by (Responsible Party):
Sergio Serrano-Villar, Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Study Description
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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.

Condition or disease Intervention/treatment Phase
HIV Infection Biological: FMT Other: Placebo Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : January 2017
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : December 2018

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Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: From baseline through week 48 ]

Secondary Outcome Measures :
  1. Changes in CD4+ T cell counts [ Time Frame: From baseline through week 48 ]
  2. Changes in CD8+ T cell counts [ Time Frame: From baseline through week 48 ]
    1. Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.
    2. Monocyte/macrophage activation: sCD14, SCD163,
    3. Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).
    4. Bacterial translocation: lipoteichoic acid (LTA)
    5. Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio
    6. Coagulation: D-dimers

  3. Changes in CD4/CD8 ratio [ Time Frame: From baseline through week 48 ]
    1. Inflammation: interleukin (IL)-6, high sensitivity C reactive protein (hs-CRP), interferon gamma-induced protein (IP)-10.
    2. Monocyte/macrophage activation: sCD14, SCD163,
    3. Gut epithelial integrity: zonulin-1, intestinal fatty acid binding protein (IFABP).
    4. Bacterial translocation: lipoteichoic acid (LTA)
    5. Indolamine deoxygenase-1 induction: kynurenine/tryptophan ratio
    6. Coagulation: D-dimers

  4. Changes in microbiota alpha diversity metrics [ Time Frame: From baseline through week 48 ]
  5. Changes in microbiota Unifrac distances [ Time Frame: From baseline through week 48 ]
  6. Changes in microbiota Canberra distances [ Time Frame: From baseline through week 48 ]
  7. Changes in plasma Interleukin-6 levels [ Time Frame: From baseline through week 48 ]
  8. Changes in plasma hs-CRP levels [ Time Frame: From baseline through week 48 ]
  9. Changes in plasma lipoteichoic acid levels [ Time Frame: From baseline through week 48 ]
  10. Changes in plasma LBP levels [ Time Frame: From baseline through week 48 ]
  11. Changes in plasma kynurenine/tryptophan ratio [ Time Frame: From baseline through week 48 ]
  12. Percentage of HLA-DR+/CD38+ T cells in blood [ Time Frame: From baseline through week 48 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03008941


Locations
Spain
Hospital Ramón y Cajal
Madrid, Spain, 28034
Sponsors and Collaborators
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
More Information
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Responsible Party: Sergio Serrano-Villar, MD, PhD, Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
ClinicalTrials.gov Identifier: NCT03008941     History of Changes
Other Study ID Numbers: 165-16
GESIDA 9116 ( Other Identifier: GESIDA Study group )
First Posted: January 4, 2017    Key Record Dates
Last Update Posted: February 7, 2018
Last Verified: February 2018

Keywords provided by Sergio Serrano-Villar, Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal:
HIV
microbiota
inflammation
fecal microbiota restoration

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
 Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases