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Dipeptidyl Peptidase-4 Inhibition and Immune Function in HIV (DPPIVinHIV)

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ClinicalTrials.gov Identifier: NCT01093651
Recruitment Status : Completed
First Posted : March 26, 2010
Results First Posted : January 23, 2014
Last Update Posted : February 17, 2014
Sponsor:
Collaborator:
The Campbell Foundation
Information provided by (Responsible Party):
Kevin Yarasheski, PhD, Washington University School of Medicine

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator)
Conditions Diabetes
Insulin Resistance
Interventions Drug: Sitagliptin
Drug: Placebo
Enrollment 20
Recruitment Details HIV-infected adults (18 – 65 years old) were recruited from the AIDS Clinical Trials Unit and the Infectious Diseases Clinic at Washington University School of Medicine. Thirty-one candidates were screened and 20 were enrolled; all participants were HIV positive but were otherwise healthy with stable immunologic and virologic status on HAART.
Pre-assignment Details Twenty participants were randomized to n=10 placebo or n=10 sitagliptin (Januvia(R)). Eleven volunteers were screened and found ineligible (see eligibility criteria), or did not choose to participate in the study.
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Period Title: Overall Study
Started 10 10
Completed 10 10
Not Completed 0 0
Arm/Group Title Placebo DPPIV Inhibition Total
Hide Arm/Group Description

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Total of all reporting groups
Overall Number of Baseline Participants 10 10 20
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
10
 100.0%
10
 100.0%
20
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 10 participants 10 participants 20 participants
40  (15) 36  (9) 38  (12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 10 participants 10 participants 20 participants
Female
2
  20.0%
1
  10.0%
3
  15.0%
Male
8
  80.0%
9
  90.0%
17
  85.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 10 participants 10 participants 20 participants
10 10 20
1.Primary Outcome
Title CD4+ T-cell Count
Hide Description [Not Specified]
Time Frame Monthly for 4 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
CD4+ T-cell count
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Mean (Standard Deviation)
Unit of Measure: cells/µL
Baseline 602  (91) 648  (185)
Week 4 689  (153) 750  (225)
Week 8 696  (194) 656  (207)
Week 12 686  (167) 706  (168)
Week 16 681  (151) 636  (173)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in CD4+ T-cell count between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for CD4+ T-cell count over time and between the 2 groups did not achieve p<0.05 (not statistically significant).
Method Mixed Models Analysis
Comments Study subject was included in these models as a random variable to account for within-participant correlation.
2.Primary Outcome
Title Plasma HIV Viremia (Viral Load)
Hide Description Percentage of participants with plasma HIV RNA copy number less than 48 copies/mL
Time Frame Monthly for 6 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Measure Type: Number
Unit of Measure: percentage of participants below 48 c/mL
Baseline 100 100
Week 4 100 100
Week 8 100 100
Week 12 100 100
Week 16 100 100
Week 24 100 100
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in plasma HIV RNA copy number/mL between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for plasma HIV RNA copy number/mL over time and between the 2 groups did not achieve p<0.05 (not statistically significant).
Method Mixed Models Analysis
Comments [Not Specified]
3.Secondary Outcome
Title Soluble TNFR2; Serum Biomarkers of Immune Activation
Hide Description serum soluble tumor necrosis factor receptor-2 concentration
Time Frame Baseline, week 8, week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
sTNFR2
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Mean (Standard Deviation)
Unit of Measure: pg/mL
Baseline 2220  (389) 2436  (431)
week 8 2218  (411) 2617  (638)
week 16 2279  (415) 2388  (449)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum TNFR2 levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for serum TNFR2 levels over time and between the 2 groups did not achieve p<0.05 (not statistically significant).
Method Mixed Models Analysis
Comments [Not Specified]
4.Secondary Outcome
Title SDF1α; Serum Biomarkers of Immune Activation
Hide Description serum stromal cell-derived factor-1α concentration
Time Frame Baseline, week 8, week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
SDF1α
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Mean (Standard Deviation)
Unit of Measure: pg/mL
Baseline 2327  (304) 2378  (441)
week 8 2313  (364) 1208  (605)
week 16 2309  (400) 1277  (490)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum SDF1α levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0002
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for SDF1-alpha levels over time and between the 2 groups achieved p<0.0002.
Method Mixed Models Analysis
Comments [Not Specified]
5.Secondary Outcome
Title RANTES; Serum Biomarkers of Immune Activation
Hide Description serum Regulated on Activation, Normal T cell Expressed and Secreted concentration
Time Frame Baseline, week 8, week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
RANTES
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Mean (Standard Deviation)
Unit of Measure: ng/mL
Baseline 80.8  (23.2) 64.4  (37.2)
week 8 85.3  (27.7) 68.5  (43.0)
week 16 74.9  (27.8) 62.8  (32.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in serum RANTES levels between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for serum RANTES levels over time and between the 2 groups did not achieve p<0.05 (not statistically significant).
Method Mixed Models Analysis
Comments [Not Specified]
6.Secondary Outcome
Title Oral Glucose Tolerance
Hide Description Area under the 75-gr oral glucose tolerance curve (AUCg) based on plasma glucose values measured at 0, 30, 60, 90, and 120 mins post-glucose challenge.
Time Frame Baseline, week 8, week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Mean (Standard Deviation)
Unit of Measure: mg*min/mL
Baseline AUCg 142.5  (26.6) 145.6  (32.5)
Week 8 AUCg 158.0  (26.7) 133.6  (24.6)
Week 16 AUCg 157.5  (23.2) 142.5  (21.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments The main effect analysis was applied to both rows (timepoint) and categories (groups). It used linear mixed models to simultaneously assess differences in area under the glucose tolerance curves between the DPP4 inhibitor and placebo groups (categories) over time (rows). Pairwise post-hoc contrasts were performed to assess the between and within group differences in outcome measures at each time point.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.04
Comments The a priori threshold for statistical significance was p<0.05. The main effect analysis for area under the glucose tolerance curve over time and between the 2 groups achieved p<0.04.
Method Mixed Models Analysis
Comments [Not Specified]
7.Secondary Outcome
Title Self-reported Symptoms
Hide Description Cumulative number of self-reported symptoms based on the Division of AIDS Grading Scale for the Severity of Adult Adverse Events (0-4 scale where 0 is no new symptoms, 4 is serious adverse event or toxicity)
Time Frame Monthly for 4 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Cumulative frequency over 16 weeks of any self-reported symptoms on the DAIDS scale
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description:

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

Overall Number of Participants Analyzed 10 10
Measure Type: Number
Unit of Measure: total number of self reported symptoms
Hypoglycemia symptoms 1 3
GI symptoms 8 3
Upper respiratory symptoms 10 5
Generalized fatigue 5 2
Headache 5 4
Other (e.g., rash, muscle pain, mood change) 6 5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, DPPIV Inhibition
Comments Kruskal-Wallis non-parametric test of cell frequencies
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The a priori threshold for statistical significance was p<0.05. The non-paramteric test for adverse event cummulative frequency between the 2 groups did not achieve p<0.05 (not statistically significant)
Method Kruskal-Wallis
Comments [Not Specified]
Time Frame 16 weeks
Adverse Event Reporting Description

SAE or AE Any self reported symptom that was graded greater than 2 on the DAIDS severity scale during the 16 week period. These were reported as a serious or adverse event or toxicity.

Other adverse event: Any self-reported symptom that was graded less than or equal to 2 (DAIDS scale) during the 16 week period;these are not serious adverse events.

 
Arm/Group Title Placebo DPPIV Inhibition
Hide Arm/Group Description

Four 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.

Placebo : Daily placebo for 4 months

Four 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.

Sitagliptin : 100 mg sitagliptin daily for 4 months

All-Cause Mortality
Placebo DPPIV Inhibition
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo DPPIV Inhibition
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/10 (0.00%)      0/10 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo DPPIV Inhibition
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/10 (70.00%)      6/10 (60.00%)    
Gastrointestinal disorders     
Gastrointestinal symptoms * [1]  5/10 (50.00%)  8 2/10 (20.00%)  3
General disorders     
Generalized fatigue * [1]  3/10 (30.00%)  5 1/10 (10.00%)  2
Headache * [1]  4/10 (40.00%)  5 2/10 (20.00%)  4
Metabolism and nutrition disorders     
Hypoglycemia symptoms * [1]  1/10 (10.00%)  1 2/10 (20.00%)  3
Musculoskeletal and connective tissue disorders     
Muscle pain * [1]  1/10 (10.00%)  1 1/10 (10.00%)  1
Psychiatric disorders     
Mood change * [1]  2/10 (20.00%)  3 2/10 (20.00%)  3
Respiratory, thoracic and mediastinal disorders     
Upper respiratory symptoms * [1]  6/10 (60.00%)  10 3/10 (30.00%)  5
Skin and subcutaneous tissue disorders     
Rash * [1]  1/10 (10.00%)  2 1/10 (10.00%)  1
*
Indicates events were collected by non-systematic assessment
[1]
Not SAE; severity graded less than 2 on DAIDS
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Kevin Yarasheski, PhD
Organization: Washington Univ Med Sch
Phone: 3143628173
EMail: key@wustl.edu
Publications of Results:
Goodwin SR, Reeds DN, Royal M, Struthers H, Laciny E, Yarasheski KE. Dipeptidyl Peptidase IV Inhibition Does Not Adversely Affect Immune and Virologic Status of HIV+ Men and Women. Diabetes. 2012;61(Suppl 1) A237 (abstract # 932-P).
Responsible Party: Kevin Yarasheski, PhD, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01093651     History of Changes
Other Study ID Numbers: KEY03222010
First Submitted: March 23, 2010
First Posted: March 26, 2010
Results First Submitted: May 13, 2013
Results First Posted: January 23, 2014
Last Update Posted: February 17, 2014