Clinical trial NCT02513771: Sitagliptin for Reducing Inflammation and Immune Activation
Official title: A Randomized, Double-Blinded, Placebo-Controlled Trial of a Dipeptidyl Peptidase-4 Inhibitor (Sitagliptin, Januvia) for Reducing Inflammation and Immune Activation in HIV-Infected Men and Women: A Multicenter Trial of the AIDS Clinical Trials Group (ACTG)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Keywords: Sitagliptin
Inflammation
Immune activation
Viral suppression
HIV-1
Immunology biomarkers
sCD14
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)
First posted: 2015-08-03
Enrollment: 90
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 is to evaluate whether sitagliptin (Januvia is the brand name for sitagliptin) reduces inflammation and immune activation markers in HIV-infected men and women when compared to a placebo (inactive medication like a dummy pill). The study evaluated whether taking 100 mg of sitagliptin by mouth daily for 16 weeks is safe and effective for HIV-infected persons on antiretroviral therapy (ART) who do not have diabetes. Sitagliptin is a medication that is used to treat people with diabetes (high blood sugar) but also may reduce inflammation in the body.

Detailed description: ACTG A5346 is a phase II, randomized, double-blinded, placebo-controlled, trial of sitagliptin 100 mg vs. placebo for 16 weeks followed by a 4-week post-intervention follow-up. A5346 studied whether sitagliptin reduced plasma concentrations of sCD14 in HIV-infected men and women ≥18 years of age who were on suppressive ART with HIV-1 RNA below the limit of quantification at screening and for at least the prior 48 weeks. Participants were randomized 1:1 to Sitagliptin arm vs. Placebo arm, and were stratified by screening CD4 count (100-350 vs. \>350 cells/mm\^3) and statin use (on statins vs. not on statins).

Eligibility criteria: Inclusion Criteria:

* Documented HIV-1 infection.
* Currently on an antiretroviral regimen consisting of at least 2 NRTIs and either a protease inhibitor boosted with low dose ritonavir, an integrase inhibitor, or an NNRTI. (Other ART regimens may be acceptable. Sites must consult the protocol team for approval)
* Currently on continuous ART for ≥48 weeks prior to study entry with no interruption longer than 7 consecutive days during that period.
* Plasma HIV-1 RNA levels below 75 copies/mL for at least 48 weeks prior to study entry. The participant must have a minimum of two values in the last 48 weeks obtained \>30 days apart, with the most recent value obtained within 90 days prior to entry. (Single determinations that are between the assay quantification limit and 500 copies/mL (i.e., "blips") are allowed as long as the preceding and subsequent determinations are below the level of quantification).
* CD4+ cell count ≥100 cells/mm\^3 obtained within 90 days prior to study entry.
* The following laboratory values obtained within 90 days prior to entry.

  * Absolute neutrophil count (ANC) ≥750/mm\^3
  * Hemoglobin ≥8.0 g/dL
  * Platelet count ≥50,000/mm\^3
  * Calculated creatinine clearance (CrCl) ≥60 mL/min as estimated by the Cockroft-Gault formula NOTE: Calculation for the Cockcroft-Gault equation is available at https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.cfm
  * Aspartate aminotransferase (AST) (SGOT) ≤5 x upper limit of normal (ULN).
  * alanine aminotransferase (ALT) (SGPT) ≤5 x ULN.
  * alkaline phosphatase ≤5 x ULN.
  * Total bilirubin ≤2.5 x ULN (if the participant is receiving atazanavir, a total bilirubin of ≤5 x ULN is acceptable).
  * Hemoglobin A1C ≤6.5%
* For females of reproductive potential, adequate contraception.
* Karnofsky performance score ≥70 within 90 days prior to entry.
* Ability and willingness of participant or legal guardian/representative to provide informed consent.
* Participants on statin therapy must be stable on the same dose for at least the prior 12 weeks with no anticipated change in statin or dose during the intervention.

Exclusion Criteria:

* Change in the ART regimen within the 12 weeks prior to study entry, or anticipated/intended modification of ART during the study period.
* Two or more HIV-1 RNA determinations \>200 copies/mL within the 48 week period prior to study entry.
* History of clinical pancreatitis or diabetes mellitus diagnosed by a medical provider.
* Acute or chronic liver disease with evidence of cirrhosis or portal hypertension.
* Chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable).
* History of chronic hepatitis B (defined as surface antibody negative, surface antigen positive, and/or HBV DNA detectable).
* Use of any immunomodulator, HIV vaccine, investigational therapy, or anti-TNF therapies within 90 days prior to study entry.
* Active malignancy with expected need for systemic chemotherapy or radiation therapy during the study period.
* Use of human growth hormone, tesamorelin, testosterone or anabolic steroids within 90 days prior to study entry (except chronic, stable, replacement dosages in men with diagnosed hypogonadism is allowed).
* Pregnant or breastfeeding.
* Use of any anti-diabetic medication or GLP-1 analogues within the 12 weeks prior to study entry.
* Current diagnosis of congestive heart failure.
* Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation.
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to entry.

Primary outcomes:
measure: Change in sCD14 From Baseline to Week 15/16
timeFrame: Pre-entry, Week 0, Week 15, Week 16
Secondary outcomes:
measure: Change in sCD14 From Week 15/16 to Week 20
timeFrame: Week 15, week 16, week 20
measure: Change in sCD163
timeFrame: Week 0, week 15, week 20
measure: Change in sCD26
timeFrame: Week 0, week 15, week 20
measure: Change in IL-6
timeFrame: Week 0, week 15, week 20
measure: Change in hsCRP
timeFrame: Week 0, week 15, week 20
measure: Change in sTNF-r1
timeFrame: Week 0, week 15, week 20
measure: Change in sTNF-r2
timeFrame: Week 0, week 15, week 20
measure: Change in IP-10
timeFrame: Week 0, week 15, week 20
measure: Change in CD4+/CD8+ T-cell Ratio
timeFrame: Week 0 and week 15
measure: Change in CD4+ T-cell Activation
timeFrame: Week 0, week 15, week 20
measure: Change in CD8+ T-cell Activation
timeFrame: Week 0, week 15, week 20
measure: Change in %CD14+/CD16- (Classical Monocytes)
timeFrame: Week 0, week 15, week 20
measure: Change in %CD14+/CD16+ (Intermediate Monocytes)
timeFrame: Week 0, week 15, week 20
measure: Change in %CD14dim/CD16++ (Non-classical Monocytes)
timeFrame: Week 0, week 15, week 20
measure: Number of Participants With Grade ≥2 Adverse Events Related to Study Drug
timeFrame: From study entry to end of study (Week 20)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California (1201)
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS (603)
state: California
city: Washington
country: United States
facility: Whitman Walker Health CRS (31791)
state: District of Columbia
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: Columbia Physicians and Surgeons CRS (30329)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
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: Univ. 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 Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pittsburgh CRS (1001)
state: Pennsylvania
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
Study officials:
affiliation: University of Southern California
name: Michael Dube, MD
role: STUDY_CHAIR
affiliation: Washington University School of Medicine
name: Kevin Yarasheski, PhD
role: STUDY_CHAIR
References: