Rifaximin for Chronic Immune Activation in People With HIV

NCT01866826 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 13006213-I-0062
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 3

Brief Summary

Background:

• Human immunodeficiency virus (HIV) treatment can control the amount of virus in the blood, but it does not provide a cure. The reasons why HIV treatment does not cure the infection are not well understood. HIV persists in blood cells for years, even if people receive treatment for it. In addition, HIV infection leads to an activated immune system, which can cause other problems.
• One theory for why HIV infection causes immune activation involves the intestinal tract. HIV infects immune cells the intestine soon after infection and damages their immune barrier. This damage lets bacteria cross into the bloodstream, leading to ongoing inflammation. Even when a person with HIV feels well, this chronic inflammation may affect the immune system. Researchers want to see if the antibiotic Rifaximin can reduce this inflammation. Rifaximin is designed to stay inside the digestive system, so it affects only bacteria in the intestines. Objectives: \- To see if Rifaximin can reduce bacteria-related inflammation in people with HIV. Eligibility: \- Individuals at least 18 years of age who have HIV infection and are taking medications to treat it. Design:
• Participants will be screened with a physical exam, blood test, and medical history.
• Participants will take either Rifaximin or a placebo for 4 weeks. They will have no medication for 4 to 6 weeks, and then take the other drug for 4 more weeks.
• During the study, participants will have frequent blood and urine tests. They will also provide stool samples. Liver and kidney function tests will be performed. HIV viral load (the amount of virus in the blood) will also be studied.
• Participants will have a final follow-up visit after an additional 4 weeks.
• Two additional tests are optional for study participants:
• Two blood draws: one on the third day after starting Rifaximin, and one on the third day after starting the placebo.
• Up to three colonoscopies of the lower intestine and biopsies of the intestine. These studies will collect samples of the intestinal tract to look at the effects of Rifaximin in the study.

Conditions

HIV

Keywords

HIV; Eradication Strategies; Immune Activation

Outcome Measures

Primary Outcomes (1)

• Changes in Soluble Cluster of Differentiation 14 (sCD14) Levels Between the Placebo and Rifaximin Phases of the Study

  One sample Wilcoxon statistic was applied to evaluate the difference on treatment phases between the placebo and Rifaximin.

  Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2

Secondary Outcomes (4)

• Number of Participants With Viral (HIV-1)-Ribonucleic Acid (RNA) Elevated by Greater Than 50 Copies/ml Plasma at the End of the Rifaximin or Placebo Phase

  Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2

• Changes in Soluble Markers of Inflammation Between the Placebo and Rifaximin Phases of the Study

  Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2

• Changes in Cellular Markers of Immune Activation Between the Placebo and Rifaximin Phases of the Study

  Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2

• Number of Participants With Serious and Non-Serious Adverse Events

  From baseline until up to approximately 14 weeks

Study Arms (2)

HIV Infected Subjects

EXPERIMENTAL

Human immunodeficiency virus (HIV) infected subjects with viral suppression on antiretroviral (ART). Double-blinded/placebo controlled trial with cross-over design. Rifaximin

Drug: Rifaximin

HIV Infected Subjects Placebo

PLACEBO COMPARATOR

HIV infected subjects with viral suppression on ART. Double-blinded/placebo controlled trial with cross-over design. Placebo

Other: Placebo

Interventions

Rifaximin DRUG

subject will receive three capsules of rifaximin (183.3 mg each) by mouth twice daily (total 1100 mg Daily)

Also known as: Xifaxan

HIV Infected Subjects

Placebo OTHER

subject will receive three capsules of placebo by mouth twice daily.

HIV Infected Subjects Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who have agreed in the course of other research studies to have their records reviewed will have the following elements evaluated from their existing records: age, history of human immunodeficiency virus (HIV) infection, antiretroviral therapy (ART) history and viral loads prior to informed consent, or else these elements will be assessed after informed consent. All blood draws to assess eligibility will be completed after obtaining informed consent. To participate in this study the criteria listed below will need to be met.
• Subjects must be 18 years of age or older.
• Able and willing to provide written informed consent
• Must have a history of documented HIV infection.
• HIV infection if not previously documented at host institutions will need to be documented by a plasma human immunodeficiency virus (HIV) ribonucleic acid (RNA) viral load, rapid HIV test or any other licensed enzyme-linked immunosorbent assay (ELISA) test and confirmed by another test using a different method such as a rapid HIV test, Western Blot, HIV culture, HIV antigen, HIV pro-viral deoxyribonucleic acid (DNA) at any time prior to study entry.
• ART- treated subjects who are virologically suppressed for greater than or equal to 3 years (1095 days). To meet this criteria all documented viral loads in the 3 years (1095 days) prior to the screening visit must be below the lower limit of detection \[LLD\] using Food and Drug Administration (FDA)-approved standard assays (i.e. \<50 copies/mL) with the following clarification: In each of the three prior years, subjects experiencing a single blip \[i.e. viral loads above the lower limit of detection, LLD\] may be included provided they satisfy the following criteria: the blips are below 200 copies/ml, and the blip is surrounded (i.e the preceding and succeeding viral loads) by undetectable HIV-1 RNA level measurements. That is all viral loads must be below LLD EXCEPT for up to one blip. In any 12 month period.
• Viral RNA level \< 50 c/ml at Screen 1.
• A minimum of 2 HIV-1 RNA levels that are below the lower limit of detection using standard assays will be required during the 12 month period prior to their screening visit. As assay characteristics across the sites can vary, LLD for the assay will be used to define whether or not a subject is suppressed.
• Stable dose of statin therapy for 6 months if receiving statin therapy.
• No known allergy or contraindication to the use of rifamycin compounds such as rifampin, rifabutin or rifaximin. .
• The effect of rifaximin on the developing human fetus are unknown, therefore subjects must be willing to use two methods of contraception (one of which must be a barrier method) during the study period. Adequate methods of birth control include: tubal ligation, hysterectomy, condoms (male or female) with or without a spermicide; diaphragm or cervical cap with spermicide; intrauterine device; any of the methods that require a prescription (such as contraceptive pills or patch, Norplant, Depo-Provera, and others) or a male partner who has previously undergone a vasectomy.
• The following elements will be assessed with a blood draw and after obtaining informed consent.
• Absolute Neutrophil count (ANC) greater than or equal to 750/mm(3)
• Hemoglobin greater than or equal to 10.0 g/dL for women and Hemoglobin 11.0 g/dl for men
• Platelet count greater than or equal to 75,000/mm(3)

You may not qualify if:

• Known bleeding diathesis (for example a diagnosis of hemophilia or Von Willebrand disease)
• Active drug use or alcohol abuse/dependence, which in the opinion of the investigators will interfere with the patients ability to participate in the study
• Serious illness requiring systemic treatment and/or hospitalization within 30 days of screening into the study
• Evidence of active opportunistic infections or neoplasms (excluding cutaneous basal cell carcinoma and squamous cell carcinoma) in the 6 months prior to randomization
• History of inflammatory bowel disease (Crohn's Disease, ulcerative colitis)
• Positive urine pregnancy test at screening (of child bearing potential).
• Breastfeeding
• Current imprisonment
• Concurrent immunomodulatory agents, including systemic corticosteroids in the 12 weeks prior to randomization. Topical, nasal or inhaled corticosteroid use is allowed
• Concomitant use of probiotics except yogurt
• Chronic antibiotic use such as tetracyclines for acne
• Vaccinations within 6 weeks of randomization
• Child-Pugh Class C disease
• A prior history of Clostridium difficile colitis
• Any condition that precludes the safe administration of conscious sedation for endoscopy (such as decompensated lung or heart disease) will not be able to participate in the colonoscopy aspect of the protocol.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• University of Pittsburgh: collaborator
• Walter Reed National Military Medical Center: collaborator

Study Sites (3)

Walter Reed National Medical Center

Bethesda, Maryland, 20301, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (3)

• Deeks SG. Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. Top HIV Med. 2009 Sep-Oct;17(4):118-23.

  PMID: 19890183 BACKGROUND

• Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Neuhaus J, Nixon D, Paton NI, Neaton JD; INSIGHT SMART Study Group. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 Oct 21;5(10):e203. doi: 10.1371/journal.pmed.0050203.

  PMID: 18942885 BACKGROUND

• Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, Deeks SG. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003 May 15;187(10):1534-43. doi: 10.1086/374786. Epub 2003 Apr 23.

  PMID: 12721933 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Rifaximin

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Frank Maldarelli, MD
• Organization: NCI

fmalli@mail.nih.gov

301-846-5611

Study Officials

• Frank Maldarelli, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 29, 2013
• First Posted: June 3, 2013
• Study Start: January 18, 2013
• Primary Completion: June 30, 2016
• Study Completion: February 28, 2018
• Last Updated: February 26, 2020
• Results First Posted: February 24, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)