Saint Louis, Missouri 63110

  • 1 Infection

Purpose:

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.


Study summary:

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).


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.


Study is Available At:


Original ID:

ACTG A5346


NCT ID:

NCT02513771


Secondary ID:

UM1AI068636


Study Acronym:


Brief Title:

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)


Overall Status:

Completed


Study Phase:

Phase 2


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

AIDS Clinical Trials Group


Oversight Authority:

United States: Federal Government


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

90


Enrollment Type:

Actual


Overall Contact Information

Official Name:Michael Dube, MD
Study Chair
University of Southern California

Study Dates

Start Date:September 2015
Completion Date:January 10, 2017
Completion Type:Actual
Primary Completion Date:December 13, 2016
Primary Completion Type:Actual
Verification Date:May 2018
Last Changed Date:May 18, 2018
First Received Date:July 13, 2015
First Results Date:November 6, 2017

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Number of Participants With Grade ≥2 Adverse Events Related to Study Drug
Time Frame:From study entry to end of study (Week 20)
Safety Issues:False
Description:The DAIDS Adverse Event Grading Table, Version 2.0, was used for grading of AEs
Outcome Type:Secondary Outcome
Measure:Change in %CD14dim/CD16++ (Non-classical Monocytes)
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:%CD14dim/CD16++ is the percentage of cells that expressed low levels of CD14dim and high levels of CD16++ in total monocytes (also known as non-classical monocytes). This endpoint is measuring the change from week 0 to week 15 (week 15 - week 0) and chan
Outcome Type:Secondary Outcome
Measure:Change in %CD14+/CD16+ (Intermediate Monocytes)
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:%CD14+/CD16+ is the percentage of cells that expressed both CD14 and CD16 in total monocytes (also known as intermediate monocytes). This endpoint is measuring the change from week 0 to week 15 (week 15 - week 0) and change from week 15 to week 20 (week
Outcome Type:Secondary Outcome
Measure:Change in %CD14+/CD16- (Classical Monocytes)
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:CD14+/CD16- is the percentage of cells that expressed CD14 and low CD16 in total monocytes (also known as classical monocytes). This endpoint is measuring the change from week 0 to week 15 (week 15 - week 0) and change from week 15 to week 20 (week 20 -
Outcome Type:Secondary Outcome
Measure:Change in CD8+ T-cell Activation
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38+ and Human leukocyte antigen (HLA)-DR+. The endpoint is measuring the change from week 0 to week 15 (week 15 - week 0) and
Outcome Type:Secondary Outcome
Measure:Change in CD4+ T-cell Activation
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:Level of CD4+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38+ and Human leukocyte antigen (HLA)-DR+. The endpoint is measuring the change from week 0 to week 15 (week 15 - week 0) and
Outcome Type:Secondary Outcome
Measure:Change in CD4+/CD8+ T-cell Ratio
Time Frame:Week 0 and week 15
Safety Issues:False
Description:CD4+/CD8+ T-cell ratio change from week 0 to week 15 (week 15 - week 0). Note that CD4 and CD8 were not evaluated at week 20 in this study.
Outcome Type:Secondary Outcome
Measure:Change in IP-10
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:IP-10 (also known as CXCL10) is a biomarker implicated in cardiovascular disease. Change in log10 transformed IP-10 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in sTNF-r2
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:sTNF-r2 (soluble tumour necrosis alpha receptor 2) is a biomarker of inflammation. Change in log10 transformed sTNF-r2 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in sTNF-r1
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:sTNF-r1 (soluble tumour necrosis alpha receptor 1) is a biomarker of inflammation. Change in log10 transformed sTNF-r1 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in hsCRP
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:hsCRP (high-sensitivity C-reactive protein) is a biomarker of inflammation. Change in log10 transformed hsCRP from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in IL-6
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:IL-6 (Interleukin-6) is a biomarker of systemic inflammation. Change in log10 transformed IL-6 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in sCD26
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:sCD26 (soluble cluster of differentiation 26) is an enzyme that metabolizes DPP-4 (dipeptidyl peptidase-4), an enzyme that is inhibited by sitagliptin. Change in log10 transformed sCD26 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week
Outcome Type:Secondary Outcome
Measure:Change in sCD163
Time Frame:Week 0, week 15, week 20
Safety Issues:False
Description:sCD163 (soluble CD 163) is a marker of macrophage activation and arterial inflammation. Change in log10 transformed sCD163 from Week 0 to week 15 (week 15 - week 0), and from week 15 to week 20 (week 20 - week 15).
Outcome Type:Secondary Outcome
Measure:Change in sCD14 From Week 15/16 to Week 20
Time Frame:Week 15, week 16, week 20
Safety Issues:False
Description:sCD14 (soluble cluster of differentiation 14) is a biomarker of gut microbial translocation and monocyte/macrophage activation. The outcome measures are changes in log10 transformed sCD14 from week 15/16 to week 20 (week 20 - week 15/16). Levels measure
Outcome Type:Primary Outcome
Measure:Change in sCD14 From Baseline to Week 15/16
Time Frame:Pre-entry, Week 0, Week 15, Week 16
Safety Issues:False
Description:sCD14 (soluble cluster of differentiation 14) is a biomarker of gut microbial translocation and monocyte/macrophage activation. The outcome measures are changes in log10 transformed sCD14 from baseline to week 15/16 (week 15/16 - baseline) Levels measure

Study Interventions

Intervention Type:Drug
Name:Sitagliptin
Description:100 mg one tablet taken orally daily for 16 weeks, followed by a 4-week post-treatment follow-up
Arm Name:Sitagliptin Arm
Other Name:Januvia
Intervention Type:Drug
Name:Placebo for sitagliptin
Description:One tablet taken orally daily for 16 weeks, followed by a 4-week post-treatment follow-up.
Arm Name:Placebo Arm
Other Name:Placebo

Study Arms

Study Arm Type:Placebo Comparator
Arm Name:Placebo Arm
Description:Placebo for sitagliptin one tablet daily p.o.for 16 weeks, followed by a 4-week post-treatment follow-up.
Study Arm Type:Active Comparator
Arm Name:Sitagliptin Arm
Description:Sitagliptin (Januvia) 100 mg one tablet daily p.o. for 16 weeks, followed by a 4-week post-treatment follow-up.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:AIDS Clinical Trials Group
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Institute of Allergy and Infectious Diseases (NIAID)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: March 30, 2020

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