Clinical trial NCT02706717: Effects of the Probiotic Visbiome Extra Strength on Gut Microbiome & Immune Activation Markers
Official title: Safety, Tolerability, and Effects of the Probiotic Visbiome Extra Strength on Gut Microbiome and Immune Activation Markers in HIV-Infected Participants on Suppressive Antiretroviral Therapy: A Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Exegi Pharma, LLC
First posted: 2016-03-11
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study was to evaluate whether the probiotic Visbiome Extra Strength reduces inflammation in HIV-infected men and women when compared to a placebo (inactive medication like a dummy pill). The study evaluated whether taking Visbiome Extra Strength by mouth for 24 weeks was safe and well-tolerated for HIV-infected persons on antiretroviral therapy (ART). Probiotics are germs such as yeast or bacteria that are found in food and supplements that are used to improve the health of the digestive system. Many people refer to probiotics as "helpful bacteria." These bacteria live in the body and help the body work normally. In some medical conditions, including HIV infection, helpful bacteria are replaced with bacteria that can change the normal intestinal function and increase inflammation. The investigators tested whether giving a probiotic restored normal intestinal function and decreased inflammation.

Detailed description: This was a phase II, randomized, double-blind, two-arm study to evaluate whether there is a significant change in sCD14 after 24 weeks of probiotic Visbiome Extra Strength (ES) therapy, and to determine the safety and tolerability of this agent in HIV-infected participants on stable antiretroviral therapy (ART). Participants were randomized 1:1 to Visbiome ES and placebo arms. Both arms initiated study treatment at Week 2 and took 1 sachet per day for the first 2 weeks and then 1 sachet twice daily for the next 22 weeks. All participants were followed for an additional 12 weeks off study product.

The study clinic visits included Entry (Week 0), and Weeks 2, 6, 14, 25, 26, and 38. Plasma for the primary outcome was collected at Weeks 0, 2, 25, and 26. The evaluations of safety (clinical assessment for signs and symptoms, diagnoses, and laboratory tests) were done at Weeks 2, 6, 14, 26, and 38.

Currently, the results are entered for the primary outcome measure and select secondary outcomes only. The results on the remaining secondary outcomes will be posted when they become available.

Eligibility criteria: Inclusion Criteria:

- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" refers to a US FDA-approved kit.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

- Currently on continuous antiretroviral therapy (ART) for ≥48 weeks prior to study entry with no change in the ART regimen within the 24 weeks prior to study entry except as noted below.

NOTE A: Continuous ART is defined as continuous ART for the 48-week period prior to study entry with no ART interruption longer than 7 consecutive days.

NOTE B: Modifications of ART during the 24 weeks prior to study entry are permitted in certain circumstances. For example, the change in formulation (eg, from standard formulation to fixed-dose combination including ART modifications switching from ritonavir- to cobicistat-boosted protease inhibitors or from tenofovir disoproxil fumarate to tenofovir alafenamide) is allowed within 24 weeks prior to study entry. A within-class, single-drug substitution (eg, switch from nevirapine to efavirenz or from atazanavir to darunavir) is allowed within 24 weeks prior to study entry, with the exception of a switch between any other NRTI to/from abacavir. No other changes in ART within the 24 weeks prior to study entry are permitted.

* No plan to change ART regimen for the study duration.
* Screening CD4+ cell count \>200 cells/mm3 obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent.
* Screening HIV-1 RNA levels \<50 copies/mL using a FDA-approved assay performed by any laboratory that has a CLIA certification or its equivalent within 45 days prior to study entry.
* HIV-1 RNA levels below the limit of quantification using a FDA-approved assay with a quantification limit of 50 copies/mL or lower for at least 48 weeks prior to study entry performed by any laboratory that has a CLIA certification or its equivalent.

NOTE: Single determinations that are between the assay quantification limit and 500 copies/mL (ie, "blips") are allowed as long as the preceding and subsequent determinations are below the level of quantification. The screening value may serve as the subsequent undetectable value following a blip.

* The following laboratory values obtained within 45 days prior to entry by any US laboratory that has a CLIA certification or its equivalent:

  * Absolute neutrophil count (ANC) ≥1000/mm3
  * Hemoglobin ≥10.0 g/dL for men and 9.0 g/dL for women
  * Platelet count ≥50,000/mm3
  * Aspartate aminotransferase (AST) (SGOT) ≤5 x upper limit normal (ULN)
  * Alanine aminotransferase (ALT) (SGPT) ≤5 x ULN
  * Alkaline phosphatase ≤5 x upper limit normal ULN
  * Total bilirubin ≤2.5 x ULN (if on atazanavir ≤5 x ULN)
  * Calculated creatinine clearance (CrCl) \>60 mL/min, as estimated by the Cockcroft-Gault equation.
* For females of reproductive potential, negative serum or urine pregnancy test within 45 days prior to entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point-of-care (POC)/ CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.
* If participating in sexual activity that could lead to pregnancy, the female study participant must be willing to use a contraceptive while receiving protocol-specified medication. At least one of the following methods MUST be used:

  * Condoms (male or female), with or without a spermicidal agent
  * Diaphragm or cervical cap with spermicide
  * Intrauterine device (IUD)
  * Hormone-based contraceptive
* Ability and willingness of participant or legal guardian/representative to provide informed consent.

Exclusion Criteria:

- Initiation of ART during acute HIV infection.

NOTE: Participants who initiate ART within 6 months of HIV seroconversion are considered to have been initiated during acute infection and are excluded.

- Receipt of antibiotic therapy within 60 days prior to study entry.

NOTE: Antibiotics for opportunistic infection prophylaxis are exclusionary.

* Known allergy/sensitivity or any hypersensitivity to components of Visbiome Extra Strength or its formulation.
* Use of investigational therapies or investigational vaccines within 90 days prior to study entry.
* Non-investigational vaccinations within 2 weeks prior to study entry.
* Active drug or alcohol use or dependence that in the opinion of the site investigator would interfere with adherence to study requirements.
* Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry.
* History of positive HCV antibody with detectable HCV RNA in plasma within 48 weeks prior to study entry.

NOTE: Persons with positive HCV Ab but negative plasma HCV RNA are allowed to participate. Sites must document negative HCV RNA within 24 weeks of study entry.

* History of positive HBsAg within 48 weeks prior to study entry.
* Liver cirrhosis, history of inflammatory bowel disease, total colectomy, colon or rectal anastomosis, bowel resection, or current colostomy.
* Current diagnosis of diabetes.
* Either breastfeeding or pregnant within 24 weeks prior to study entry.
* OIs within 45 days prior to study entry.
* Use of any of the following medications/products for more than 3 consecutive days within the 60 days prior to study entry:

  * Immunosuppressives (eg, azathioprine, corticosteroids greater than 20 mg per day \[physiologic replacement doses are allowed\], cyclosporine, mycophenolate, intravenous immunoglobulin (IVIG), interferon, sirolimus, sulfasalazine, tacrolimus).
  * Immune modulators (eg, cytokines \[eg, IL-2\], granulocyte colony stimulating factor, growth hormone, tumor necrosis factor antagonists, thalidomide).
  * Antineoplastic agents (except for topical agents for skin cancer).
  * Probiotics and prebiotics (supplements and products).

NOTE: Yogurt with live cultures is allowed.

* History of lactose intolerance or milk allergy.
* Any episode of acute or persistent diarrhea within 60 days prior to study entry.

NOTES:

1. Diarrhea is defined as three or more stools per day that are liquid/loose/watery and will take the shape of a container. If the duration of loose stools meeting this criterion definition is greater than 30 days, this is chronic diarrhea and is not exclusionary.
2. Acute diarrhea is defined as 3-14 day duration.
3. Persistent diarrhea is defined as 15-30 day duration.

   * Weight loss or gain of more than 25 pounds in the 24 weeks prior to study entry.

Primary outcomes:
measure: Change in sCD14 From Baseline to Week 25/26
timeFrame: Weeks 0, 2, 25, and 26
Secondary outcomes:
measure: Change in IL-6 From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in IP-10 From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in sCD163 From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in sTNF-RI From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in Oxidized LDL From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in Kynurenine to Tryptophan Ratio From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in D-dimer From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in LPS From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in LBP From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in CD4+ Cell Count From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in CD4+/CD8+ Ratio From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD14++CD16- From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD14++CD16+ From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in %CD14lowCD16hi From Week 2 to Week 26
timeFrame: Weeks 2 and 26
measure: Change in %CD4+CD38+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD4+HLA-DR+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD4+CD38+HLA-DR+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD8+CD38+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD8+HLA-DR+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD8+CD38+HLA-DR+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD4+CD28-CD57+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in %CD8+CD28-CD57+ From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in Chao1 Richness Index From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in Shannon Diversity Index From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Change in Chao1 Richness Index From Week 26 to Week 38.
timeFrame: Weeks 26 and 38
measure: Change in Shannon Diversity Index From Week 26 to Week 38.
timeFrame: Weeks 26 and 38
measure: Change in I-FABP From Week 2 to Week 26.
timeFrame: Weeks 2 and 26
measure: Safety
timeFrame: Treatment dispensation to Week 38
measure: Tolerability
timeFrame: Treatment dispensation to Week 38
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 31788 Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: San Diego
country: United States
facility: 701 University of California, San Diego AntiViral Research Center CRS
state: California
city: San Francisco
country: United States
facility: 801 University of California, San Francisco HIV/AIDS CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center (2702)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS (201)
state: Maryland
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: Newark
country: United States
facility: 31786 New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: New York
country: United States
facility: 7804 Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Columbia Physicians and Surgeons CRS (30329)
state: New York
city: New York
country: United States
facility: 7803 Weill Cornell Upton CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS (3203)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: 6201 Penn Therapeutics CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh CRS (1001)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS (31443)
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: Johns Hopkins University
name: Adriana Andrade, MD, MPH
role: STUDY_CHAIR
affiliation: University of Alabama at Birmingham
name: Edgar T Overton, MD
role: STUDY_CHAIR
References:
citation: Chao, Anne. Scandinavian Journal of Statistics, 1 January 1984, Vol.11(4), pp.265-270
citation: Lemos LN, Fulthorpe RR, Triplett EW, Roesch LF. Rethinking microbial diversity analysis in the high throughput sequencing era. J Microbiol Methods. 2011 Jul;86(1):42-51. doi: 10.1016/j.mimet.2011.03.014. Epub 2011 Mar 30.
citation: Magurran A. 2004. Measuring Biological Diversity. Blackwell Science Ltd, Oxford, United Kingdom