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Rifaximin for Chronic Immune Activation in People With HIV

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ClinicalTrials.gov Identifier: NCT01866826
Recruitment Status : Completed
First Posted : June 3, 2013
Results First Posted : February 24, 2020
Last Update Posted : February 26, 2020
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
University of Pittsburgh
Walter Reed National Military Medical Center
Information provided by (Responsible Party):
Frank Maldarelli, M.D., National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
HIV Drug: Rifaximin Other: Placebo Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Double Blind Randomized Placebo Controlled Study Examining the Effects of a Non-Absorbable (Rifaximin) Antibiotic on the Chronic Immune Activation Observed In HIV-infected Subjects
Actual Study Start Date : January 18, 2013
Actual Primary Completion Date : June 30, 2016
Actual Study Completion Date : February 28, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Rifaximin

Arm Intervention/treatment
Experimental: HIV Infected Subjects
Human immunodeficiency virus (HIV) infected subjects with viral suppression on antiretroviral (ART). Double-blinded/placebo controlled trial with cross-over design. Rifaximin
Drug: Rifaximin
subject will receive three capsules of rifaximin (183.3 mg each) by mouth twice daily (total 1100 mg Daily)
Other Name: Xifaxan

Placebo Comparator: HIV Infected Subjects Placebo
HIV infected subjects with viral suppression on ART. Double-blinded/placebo controlled trial with cross-over design. Placebo
Other: Placebo
subject will receive three capsules of placebo by mouth twice daily.




Primary Outcome Measures :
  1. Changes in Soluble Cluster of Differentiation 14 (sCD14) Levels Between the Placebo and Rifaximin Phases of the Study [ Time Frame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 ]
    One sample Wilcoxon statistic was applied to evaluate the difference on treatment phases between the placebo and Rifaximin.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 ]
    HIV-1-RNA levels were assessed by using the single copy assay or the traditional HIV Branched Deoxyribonucleic Acid bDNA assay to determine elevations in HIV-1 RNA >50 copies/ml plasma at the end of the Rifaximin or placebo phase. Differences were tested by using both the Wilcoxon and the t-test.

  2. Changes in Soluble Markers of Inflammation Between the Placebo and Rifaximin Phases of the Study [ Time Frame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 ]
    Changes in soluble marker of inflammation Interleukin 6 (IL6) between the placebo and rifaximin phases of the study. Differences will be tested by using both the Wilcoxon and the t-test.

  3. Changes in Cellular Markers of Immune Activation Between the Placebo and Rifaximin Phases of the Study [ Time Frame: Between Day 28 of Treatment Phase 1 and Day 28 of Treatment Phase 2 ]
    Changes in cellular markers of immune activation (IA) is defined as changes in the percentage of cluster of differentiation 4 (CD4) + or cluster of differentiation 8 (CD8)+ T cells that express human leukocyte antigen - antigen D Related (HLA-DR) and cluster of differentiation 38 (CD38). Differences will be tested by using both the Wilcoxon and the t-test.

  4. Number of Participants With Serious and Non-Serious Adverse Events [ Time Frame: From baseline until up to approximately 14 weeks ]
    The number of participants with serious and non-serious adverse events that were possibly related to Rifaximin or Placebo as assessed by the Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0 A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • PARTICIPANT INCLUSION CRITERIA:

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.

  1. Subjects must be 18 years of age or older.
  2. Able and willing to provide written informed consent
  3. Must have a history of documented HIV infection.
  4. 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.
  5. 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.
  6. Viral RNA level < 50 c/ml at Screen 1.
  7. 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.
  8. Stable dose of statin therapy for 6 months if receiving statin therapy.
  9. No known allergy or contraindication to the use of rifamycin compounds such as rifampin, rifabutin or rifaximin. .
  10. 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.

  1. Absolute Neutrophil count (ANC) greater than or equal to 750/mm(3)
  2. Hemoglobin greater than or equal to 10.0 g/dL for women and Hemoglobin 11.0 g/dl for men
  3. Platelet count greater than or equal to 75,000/mm(3)
  4. Estimated Glomerular Filtration Rate (eGFR) >60 mL/min, eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
  5. Confirmed serum glutamate pyruvate transaminase (SGPT)/serum glutamate oxaloacetate transferase (SGOT) less than or equal to 3 times the upper limit of normal (ULN)
  6. International Normalized Ratio (INR) less than or equal to the upper limit of normal (ULN) for the assay
  7. Negative urine pregnancy test of child bearing potential at randomization
  8. No evidence of active hepatitis B or hepatitis C (active hepatitis B will be defined as a positive hepatitis B surface antigen present on a single determination, whereas a positive result on hepatitis C RNA will be considered as evidence of active hepatitis C)

All routine laboratory testing used to determine safety will be completed within the 70 days prior to randomization.

EXCLUSION CRITERIA:

  1. Known bleeding diathesis (for example a diagnosis of hemophilia or Von Willebrand disease)
  2. 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
  3. Serious illness requiring systemic treatment and/or hospitalization within 30 days of screening into the study
  4. Evidence of active opportunistic infections or neoplasms (excluding cutaneous basal cell carcinoma and squamous cell carcinoma) in the 6 months prior to randomization
  5. History of inflammatory bowel disease (Crohn's Disease, ulcerative colitis)
  6. Positive urine pregnancy test at screening (of child bearing potential).
  7. Breastfeeding
  8. Current imprisonment
  9. Concurrent immunomodulatory agents, including systemic corticosteroids in the 12 weeks prior to randomization. Topical, nasal or inhaled corticosteroid use is allowed
  10. Concomitant use of probiotics except yogurt
  11. Chronic antibiotic use such as tetracyclines for acne
  12. Vaccinations within 6 weeks of randomization
  13. Concomitant use of anticoagulants (other than aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS)) is an exclusion criterion for subjects opting in for the colonoscopy. Aspirin and NSAIDs will be discontinued per each institutions requirement before the procedure.
  14. Child-Pugh Class C disease
  15. A prior history of Clostridium difficile colitis
  16. 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.

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): NCT01866826


Locations
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United States, Maryland
Walter Reed National Medical Center
Bethesda, Maryland, United States, 20301
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
National Cancer Institute (NCI)
National Institute of Allergy and Infectious Diseases (NIAID)
University of Pittsburgh
Walter Reed National Military Medical Center
Investigators
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Principal Investigator: Frank Maldarelli, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by Frank Maldarelli, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] July 20, 2015

Additional Information:
Publications:
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Responsible Party: Frank Maldarelli, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01866826    
Other Study ID Numbers: 130062
13-I-0062 ( Other Identifier: NIAID )
First Posted: June 3, 2013    Key Record Dates
Results First Posted: February 24, 2020
Last Update Posted: February 26, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Frank Maldarelli, M.D., National Cancer Institute (NCI):
HIV
Eradication Strategies
Immune Activation
Additional relevant MeSH terms:
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Rifaximin
Anti-Bacterial Agents
Anti-Infective Agents
Gastrointestinal Agents