Sitagliptin for Reducing Inflammation and Immune Activation

Study Overview
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Brief Summary
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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
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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).

Official Title
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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)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo for sitagliptin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sitagliptin Arm<br>Sitagliptin (Januvia) 100 mg one tablet daily p.o. for 16 weeks, followed by a 4-week post-treatment follow-up. | Drug: Sitagliptin<br>* 100 mg one tablet taken orally daily for 16 weeks, followed by a 4-week post-treatment follow-up<br>* Other names: Januvia;|
| Placebo Comparator: Placebo Arm<br>Placebo for sitagliptin one tablet daily p.o.for 16 weeks, followed by a 4-week post-treatment follow-up. | Drug: Placebo for sitagliptin<br>* One tablet taken orally daily for 16 weeks, followed by a 4-week post-treatment follow-up.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sCD14 From Baseline to Week 15/16 | 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 measured at pre-entry and entry were averaged for baseline, levels measured at week 15 and week 16 were averaged for week 15/16. | Pre-entry, Week 0, Week 15, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sCD14 From Week 15/16 to Week 20 | 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 measured at week 15 and week 16 were averaged for week 15/16. | Week 15, week 16, week 20 | 
| Change in sCD163 | 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). | Week 0, week 15, week 20 | 
| Change in sCD26 | 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 20 (week 20 - week 15). | Week 0, week 15, week 20 | 
| Change in IL-6 | 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). | Week 0, week 15, week 20 | 
| Change in hsCRP | 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). | Week 0, week 15, week 20 | 
| Change in sTNF-r1 | 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). | Week 0, week 15, week 20 | 
| Change in sTNF-r2 | 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). | Week 0, week 15, week 20 | 
| Change in IP-10 | 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). | Week 0, week 15, week 20 | 
| Change in CD4+/CD8+ T-cell Ratio | 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. | Week 0 and week 15 | 
| Change in CD4+ T-cell Activation | 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 change from week 15 to week 20 (week 20 - week 15). Data for cellular markers are not available as of December 2017. These data are based on immunology assays which were tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 1 month after the primary complete date. Please note that these secondary outcomes were not included in the primary analyses. There are many outcomes in this study and the immunology lab had to give priority to the assays planned to be included in the primary manuscript. Results will be entered once the data is complete and analyzed. | Week 0, week 15, week 20 | 
| Change in CD8+ T-cell Activation | 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 change from week 15 to week 20 (week 20 - week 15). Data for cellular markers are not available as of December 2017. These data are based on immunology assays which were tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 1 month after the primary complete date. Please note that these secondary outcomes were not included in the primary analyses. There are many outcomes in this study and the immunology lab had to give priority to the assays planned to be included in the primary manuscript. Results will be entered once the data is complete and analyzed. | Week 0, week 15, week 20 | 
| Change in %CD14+/CD16- (Classical Monocytes) | 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 - week 15). Data for cellular markers are not available as of November 2017. The study team prioritized completion of the soluble markers (including the primary outcome measure), which are reported herein, over the completion of the cellular markers. Results will be entered once the data is complete and analyzed. | Week 0, week 15, week 20 | 
| Change in %CD14+/CD16+ (Intermediate Monocytes) | %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 20 - week 15). Data for cellular markers are not available as of December 2017. These data are based on immunology assays which were tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 1 month after the primary complete date. Please note that these secondary outcomes were not included in the primary analyses. There are many outcomes in this study and the immunology lab had to give priority to the assays planned to be included in the primary manuscript. Results will be entered once the data is complete and analyzed. | Week 0, week 15, week 20 | 
| Change in %CD14dim/CD16++ (Non-classical Monocytes) | %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 change from week 15 to week 20 (week 20 - week 15). Data for cellular markers are not available as of December 2017. These data are based on immunology assays which were tested in batch to minimize variability. Due to batch testing, shipment of samples for testing could not begin until after the study follow-up completion, which was 1 month after the primary complete date. Please note that these secondary outcomes were not included in the primary analyses. There are many outcomes in this study and the immunology lab had to give priority to the assays planned to be included in the primary manuscript. Results will be entered once the data is complete and analyzed. | Week 0, week 15, week 20 | 
| Number of Participants With Grade ≥2 Adverse Events Related to Study Drug | The DAIDS Adverse Event Grading Table, Version 2.0, was used for grading of AEs | From study entry to end of study (Week 20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sitagliptin, Inflammation, Immune activation, Viral suppression, HIV-1, Immunology biomarkers, sCD14