Dipeptidyl Peptidase-4 Inhibition and Immune Function in HIV

NCT01093651 | Completed Phase 2 Results DMC

• 1 other identifier: KEY03222010
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

We will test the safety of a new class of anti-diabetes compounds (DPPIV-inhibitors) in people living with HIV. Future trials will examine efficacy for treating diabetes and reducing cardiovascular disease risk in people living with HIV.

Conditions

Diabetes; Insulin Resistance

Outcome Measures

Primary Outcomes (2)

• CD4+ T-cell Count

  Monthly for 4 months

• Plasma HIV Viremia (Viral Load)

  Percentage of participants with plasma HIV RNA copy number less than 48 copies/mL

  Monthly for 6 months

Secondary Outcomes (5)

• Soluble TNFR2; Serum Biomarkers of Immune Activation

  Baseline, week 8, week 16

• SDF1α; Serum Biomarkers of Immune Activation

  Baseline, week 8, week 16

• RANTES; Serum Biomarkers of Immune Activation

  Baseline, week 8, week 16

• Oral Glucose Tolerance

  Baseline, week 8, week 16

• Self-reported Symptoms

  Monthly for 4 months

Study Arms (2)

DPPIV inhibition

EXPERIMENTAL

Four to six months of sitagliptin administration (100mg/d) to people living with HIV-1 who have well-controlled immunologic (CD4+ T-cell count \>350 cells/µL) and virologic (plasma HIV RNA \<50 copies/mL) status.

Drug: Sitagliptin

Placebo

PLACEBO COMPARATOR

Four to six months of placebo to people living with HIV-1 who have well-controlled immunologic (CD4+ T-cell count \>350 cells/µL) and virologic (plasma HIV RNA \<50 copies/mL) status.

Drug: Placebo

Interventions

Sitagliptin DRUG

100 mg sitagliptin daily for 4-6 months

DPPIV inhibition

Placebo DRUG

Daily placebo for 4-6 months

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Thirty 18-65 yr old HIV-infected men and women (with source documentation of HIV status) who are stable on any antiretroviral therapy (cART) regimen
• Have stable (at least the past 12-months) immunologic (\>350 CD4+ T-cells/µL) and virologic (\<50 copies HIV RNA/mL) status.
• BMI 18-42kg/m2;
• Normal blood chemistry for at least 1 month prior to enrollment;
• Platelet count \> 30,000/mm3, absolute neutrophil count \>750/mm3, transaminases \< 2.5x the upper limit of normal (ULN).
• Long-term non-progressors (not on ART) are not eligible.

You may not qualify if:

• CD4+ T-cell count \<350 cells/µL or detectable plasma HIV RNA (\>50 copies HIV RNA/mL) within the past 12-months. During the study, if CD4+ T-cell count declines by \>100 cells/µL, or if plasma HIV RNA becomes detectable (\>50 copies HIV RNA/mL after repeat analysis 2wks apart), and the participant denies any lapse in their anti-HIV medication regimen, the study medication will be stopped and an adverse event documented. If at any time during the study, two participants experience a reduction in T-cell count \>100 cells/µL, or their plasma HIV RNA levels become detectable (\>50 copies HIV RNA/mL after repeat analysis 2wks apart), and they are confirmed (by unblinding) to have received sitagliptin, the study will be stopped for serious safety concerns.
• Systemic, secondary or opportunistic infection within past 12-months.
• Fasting glucose intolerance (FBG \>100mg/dL), fasting hyperinsulinemia (\>15µU/mL), or fasting insulin resistance (Homeostasis model for insulin resistance (HOMA) \>3.0). Any agents that might alter glucose metabolism (insulin, TZDs, metformin, glucocorticoids, sulfonylurea, corticosteroids, megace, rhGH, GH-secretagogue) during the 3 months prior to enrollment or at any time during enrollment. Volunteers with T2DM, IDDM or diabetic ketoacidosis will not be enrolled.
• History of serious CV disease or NYHA Functional Class III or IV, (e.g., recent MI, unstable angina, edema, CHF, CAD, CABG, valve disease (murmur), stroke, uncontrolled high blood pressure (resting \>160/95 mmHg), irregular heart rhythm, resting ST-segment depression \>1mm). Treatment with medications for a CV condition (cardiac glycosides α- or ß-blockers). Some antihypertensive medications (calcium-channel blocker, diuretic, angiotensin II receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE)) will be permitted.
• Moderate to severe renal insufficiency. Serum creatinine \>1.7 mg/dL (men) \>1.5 mg/dL (women).
• Known allergy or hypersensitivity to DPPIV-inhibitors.
• Plan to change anti-HIV medication regimen or prophylaxis for opportunistic infection within 6-months of starting study.Transitions among efavirenz-based regimens will be allowed (e.g., Efavirenz + lamivudine + zidovudine (combivir) to Efavirenz + emtricitabine + tenofovir (Atripla)).
• Lipid-lowering medications are permitted (fibrate or statin or niacin), but must be stable on that agent for at least 3 months prior to enrollment. Lipid-lowering agents cannot be started during the treatment period.
• Chronic hepatitis B infection (HB surface antigen positive). Active hepatitis C infection (detectable Hep C RNA). Those who have cleared hepatitis B or C infection are eligible.
• Hematocrit \<34% in men or \<25% in women with symptoms (fatigue, "tired-legs", shortness of breath). Hemoglobin \<10 gm/100ml with symptoms.
• Nausea, vomiting, diarrhea (\>4 loose stools/day) that are unresponsive to treatment. History of eating disorder or significant GI-disease.
• Pregnant or nursing mothers. Women must agree to use an acceptable form of birth control during the study. If birth control pills are used, the woman must be stable on these medications for at least 6 months prior to enrollment.
• Active malignancy or treatment with chemotherapeutic agents or radiation therapy (within past 12 months).
• \>10% unintentional body weight loss during the 12 months prior to enrollment.
• "Blinded" investigational drugs/medications during the 3 months prior to enrollment that will not be unblinded before enrollment. Open-label investigational drugs are permitted (within past 3 months, no plan to stop during enrollment and not known to affect glucose, lipid, adipose tissue or liver metabolism).

Sponsors & Collaborators

• Washington University School of Medicine: lead
• The Campbell Foundation: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (1)

• Goodwin SR, Reeds DN, Royal M, Struthers H, Laciny E, Yarasheski KE. Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study. J Clin Endocrinol Metab. 2013 Feb;98(2):743-51. doi: 10.1210/jc.2012-3532. Epub 2012 Dec 21.

  PMID: 23264399 RESULT

MeSH Terms

Conditions

Diabetes Mellitus; Insulin Resistance

Interventions

Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Limitations and Caveats

Potential for type 2 error given small sample size. But, study was powered to detect significant decline in CD4 count. Measures of monocyte and lymphocyte activation should be conducted.

Results Point of Contact

• Title: Kevin Yarasheski, PhD
• Organization: Washington Univ Med Sch

key@wustl.edu

3143628173

Study Officials

• Kevin E Yarasheski, PhD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: March 23, 2010
• First Posted: March 26, 2010
• Study Start: June 1, 2010
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2012
• Last Updated: February 17, 2014
• Results First Posted: January 23, 2014

Record last verified: 2014-01

Locations

US (1)