Telmisartan to Reduce AIDS-Related Fibrotic and Inflammatory Contributors (TRAFIC Study)

Study Overview
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Brief Summary
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The main goal of this study was to see if a drug called telmisartan would decrease fibrosis (scarring) and inflammation (irritation) in people who are infected with HIV and doing well on their HIV medications. The study was also done to see what effects telmisartan has on other signs of disease and inflammation in the body, and to see whether people who have HIV can take telmisartan safely and without side effects that make them want to stop the drug. Telmisartan is FDA-approved for treating high blood pressure and decreasing the chance of heart attacks and strokes in people over the age of 55 years of age who are at high risk for these events.

Detailed Description
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This was a multicenter, randomized, open label, phase IIb, two-arm study to evaluate the effects of telmisartan on fibrotic and inflammatory contributors to end-organ disease in HIV-infected subjects well controlled on antiretroviral therapy (ART). Participants were randomized 2:1 to the telmisartan and control arms. The participants on telmisartan took 40 mg telmisartan daily during weeks 0-4 followed by telmisartan 80 mg daily during weeks 5-48. The participants in the control arm did not take any study medication, but did undergo all evaluations. All participants were followed for 48 weeks after randomization. The study clinic visits included Step 1 entry, Step 2 entry, and weeks 4, 12, 24, 36, 48. Biopsies for the primary outcomes were collected at Step 1 entry and Week 48. The evaluations of safety (clinical assessment for signs and symptoms, diagnoses, laboratory tests) were done at Step 2 entry and weeks 4, 12, 24, 36, 48. The co-primary objectives assessed the effects of telmisartan for 48weeks on lymph node and adipose tissue collagen I deposition. Currently, the results are entered for the primary outcome measures only. The results on the secondary outcomes will be posted when they become available.

Official Title
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Effects of Telmisartan on Fibrotic and Inflammatory Contributors to End-Organ Disease in HIV-Infected Patients Well Controlled on Antiretroviral Therapy

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Telmisartan


Participation Criteria
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Eligibility Criteria
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Step 1 Inclusion Criteria: HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to Step 1 entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load >2000 copies/mL on two occasions. On antiretroviral therapy (ART) continuously for ≥48 weeks prior to Step 1 entry. Documentation of HIV-1 RNA <50 copies/mL at screening, performed by any US laboratory that has a CLIA certification or its equivalent. At least one HIV-1 RNA level <200 copies/mL in the 48 weeks prior to Step 1 entry (not including the screening). No change in ART regimen in the 12 weeks prior to Step 1 entry (except as noted below). NOTE: Modifications of ART dosing during the 12 weeks prior to Step 1 entry are permitted. In addition, the change in formulation (eg, from standard formulation to fixed dose combination or single tablet regimen) is allowed within 12 weeks of Step 1 entry. A within-class single drug substitution (eg, switch from nevirapine to efavirenz or from atazanavir to darunavir) is allowed within 12 weeks of Step 1 entry, with the exception of a switch from any other NRTI to abacavir. No other changes in ART in the 12 weeks prior to Step 1 entry are permitted. No active plan to change ART for the 48-week study duration. Body mass index (BMI) 20-35 kg/m^2. For females of reproductive potential, negative serum or urine pregnancy test within 3 days prior to Step 1 entry. Ability and willingness of subject or legal guardian/representative to provide informed consent. Willingness to undergo the Step 1 entry and week 48 lymphoid and adipose tissue biopsies. Step 2 Inclusion Criteria: Entry lymphoid tissue and adipose tissue specimen for assay of the primary endpoint has been obtained. (Prior to Letter of Amendment #2, 11/19/14) (Letter of Amendment #2, 11/19/14) Entry lymphoid tissue and adipose tissue specimens for assay of the primary endpoint have been obtained, entered into the ACTG's Laboratory Data Management System (LDMS), and confirmed by the protocol team as adequate for endpoint determination. NOTE: If the lymph node specimen is determined by the protocol team to be inadequate for endpoint determination despite the interventions summarized in LOA #2, the participant will be permitted to enroll if adequate adipose tissue is obtained. However, as change in lymph node fibrosis remains one of the primary endpoints of this study, it is critical that every effort be made to obtain an adequate sample while still trying to minimize complication rates. Willingness to undergo the week 48 lymphoid and adipose tissue biopsies. (Prior to Letter of Amendment #2, 11/19/14) (Letter of Amendment #2, 11/19/14) Willingness to undergo the week 48 lymphoid and adipose tissue biopsies. NOTE: A week 48 lymph node biopsy is not required if the Step 1 lymph node specimen was deemed inadequate as noted in 4.3.1. Week 48 adipose tissue biopsies will still be required for these participants. Step 1 Exclusion Criteria: More than one HIV-1 RNA >200 copies/mL in the 48 weeks prior to Step 1 entry. One HIV-1 RNA 200-500 copies/mL in the 24 weeks prior to Step 1 entry that is not immediately preceded and followed by HIV-1 RNA <50 copies/mL. NOTE: The preceding viral load <50 copies/mL may be >24 weeks prior to Step 1 entry. Confirmed systolic blood pressure >160 mmHg or <100 mmHg or diastolic blood pressure >100 mmHg. Known untreated renal artery stenosis. Known cirrhosis or severe liver disease (eg, ascites, encephalopathy, history of variceal bleeding). NOTE: Potential subjects with chronic hepatitis B or C virus infection with no known cirrhosis or severe liver disease may participate in the study, provided there are no plans to start therapy for hepatitis C infection during the 48-week study duration. Unstable coronary artery disease/angina or decompensated congestive heart failure. Either breastfeeding or pregnant within 24 weeks prior to Step 1 entry. Use of thiazolidinediones or any angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEi) in the 24 weeks prior to Step 1 entry. If the subject took either of these classes of medications for less than 2 weeks in the 24 weeks prior to Step 1 entry, the subject may enroll if 30 days have passed since the last dose. If the subject is diabetic and/or has a calculated glomerular filtration rate (GFR) <60mL/min, aliskiren-containing medications are also prohibited. History of intolerance, other than cough, to any ARB or ACEi. Use of anticoagulants other than aspirin 81 mg or 325 mg daily. NOTE: If the subject is on aspirin 81 mg or 325 mg daily and is willing/able to stop therapy for 7 days prior to the biopsy procedures, the subject may enroll. Any known bleeding disorder or coagulopathy. Projected need for daily potassium supplementation for ≥2 weeks during the study period. The following laboratory values obtained within 30 days prior to Step 1 entry by any US laboratory that has a CLIA certification or its equivalent: Absolute neutrophil count (ANC) ≤750 cells/mm^3 Hemoglobin ≤10 g/dL Platelet count ≤75,000/mm^3 Calculated creatinine clearance (CrCl) <50 mL/min, as estimated by the Cockcroft-Gault equation Aspartate aminotransferase (AST) (SGOT) >/=3x ULN (upper limit of normal) Alanine aminotransferase (ALT) (SGPT) >/=3x ULN Partial thromboplastin time (PTT) >1.2x ULN Prothrombin time (PT) >1.2x ULN Heritable connective tissue disorders (eg Ehlers-Danlos syndrome, osteogenesis imperfecta, Stickler syndrome, Marfan's syndrome). NOTE: Subjects with acquired/autoimmune chronic inflammatory diseases/connective tissue disorders who are clinically stable (in the opinion of the site investigator) and not on a prohibited medication may enroll with approval of the A5317 study chairs. Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to Step 1 entry. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Any condition that, in the opinion of the site investigator, would compromise the subject's ability to participate in the study. Step 2 Exclusion Criteria: - Any AE associated with the Step 1 entry biopsy that would exclude the subject from undergoing follow-up biopsy at week 48.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Telmisartan<br> | Drug: Telmisartan<br>* Participants received Telmisartan 40 mg daily during weeks 0-4 followed by telmisartan 80 mg daily during weeks 5-48.<br>|
| No Intervention: Arm B: No Study Drug<br>Participants received no study drug and followed the week 0-48 evaluation schedule. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Collagen I Deposition on Lymph Node Pathology From Baseline to Week 48 | Percent collagen I deposition is defined as the average % collagen stained in multiple uniform sized high magnification images in each sample. Change was absolute change defined as the Week 48 value minus the baseline value. | baseline and week 48 | 
| Change in Percent Collagen I Deposition on Subcutaneous Abdominal Adipose Tissue Pathology From Baseline to Week 48 | Percent collagen I deposition defined as percentage of fibrotic/collagen area to total area. Change was absolute change defined as the Week 48 value minus the baseline value. | baseline and week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Fibronectin Deposition on Lymph Node Pathology From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Percent Fibronectin Deposition on Subcutaneous Abdominal Adipose Tissue Pathology From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Percent Collagen VI Deposition on Subcutaneous Abdominal Adipose Tissue Pathology From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Highest Grade Non-biopsy-related Adverse Event | Safety was summarized as the highest grade non-biopsy-related sign/symptom, laboratory event, or diagnosis per participant. Grading (Grade 0: normal, Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening) was done by site clinicians using DAIDS AE Grading table. NOTE: As adipose tissue and lymph node biopsies are generally considered to be minimal risk procedures, biopsy safety profile were not formally be evaluated as an endpoint in this protocol. | after baseline to week 48 | 
| Change in IL-6 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in IL-6 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in IL-6 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in IL-7 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in IL-7 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in IL-7 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Adiponectin From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in Adiponectin From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Adiponectin From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Collagen I C-terminal Pro-peptide (CICP) From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in Collagen I C-terminal Pro-peptide (CICP) From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Collagen I C-terminal Pro-peptide (CICP) From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Hyaluronic Acid From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in Hyaluronic Acid From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Hyaluronic Acid From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in sCD14 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in sCD14 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in sCD14 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in sCD163 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in sCD163 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in sCD163 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in TGF-β1 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in TGF-β1 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in TGF-β1 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in TGF-β2 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in TGF-β2 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in TGF-β2 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in TGF-β3 From Baseline to Week 4 | Absolute change was calculated as the value at week 4 minus the value at baseline. | baseline and week 4 | 
| Change in TGF-β3 From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in TGF-β3 From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Circulating CD4+ T Cell Count From Baseline to Week 12 | Absolute change was calculated as the value at week 12 minus the value at baseline. | baseline and week 12 | 
| Change in Circulating CD4+ T Cell Count From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Circulating CD4+ T Cell Count From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Circulating CD8+ T Cell Count From Baseline to Week 12 | Absolute change was calculated as the value at week 12 minus the value at baseline. | baseline and week 12 | 
| Change in Circulating CD8+ T Cell Count From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Circulating CD8+ T Cell Count From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting Glucose From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting HDL Cholesterol From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting Insulin From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting LDL Cholesterol From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting Total Cholesterol From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Fasting Triglycerides From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in HOMA-IR From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Prevalence of Metabolic Syndrome at Week 24. | Components of the metabolic syndrome will be defined according to the 2004 updated National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] criteria) as the presence of any 3 of the following: Waist: >40 (101.6 cm) in men, >35 (88.9 cm) in women with the exception of Asian-Americans: >35 (88.9 cm) in men, 31 (78.7 cm) in women; Fasting HDL-C <40 mg/dL in men, <50 mg/dL in women; Fasting TG ≥150 mg/dL; Diastolic blood pressure ≥85 mmHg or systolic blood pressure ≥130 mmHg; Fasting plasma glucose ≥100 mg/dL. NOTE: This definition of metabolic syndrome may be subject to change in accordance with current guidelines at the time of the final analysis. It will be defined in the Final Statistical Analysis Plan prior to data review for final analysis. | Week 24 | 
| Presence of Metabolic Syndrome at Week 48. | Components of the metabolic syndrome were defined according to the 2004 updated National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] criteria) as the presence of any 3 of the following: Waist: >40 (101.6 cm) in men, >35 (88.9 cm) in women with the exception of Asian-Americans: >35 (88.9 cm) in men, 31 (78.7 cm) in women; Fasting HDL-C <40 mg/dL in men, <50 mg/dL in women; Fasting TG ≥150 mg/dL; Diastolic blood pressure ≥85 mmHg or systolic blood pressure ≥130 mmHg; Fasting plasma glucose ≥100 mg/dL. | Week 48 | 
| Change in Waist Circumference From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Waist Circumference From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Waist-to-hip Ratio From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | baseline and week 24 | 
| Change in Waist-to-hip Ratio From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | baseline and week 48 | 
| Change in Expression of CD38+HLA-DR+ on CD4+ From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | 24 weeks | 
| Change in Expression of CD38+HLA-DR+ on CD8+ From Baseline to Week 24 | Absolute change was calculated as the value at week 24 minus the value at baseline. | 24 weeks | 
| Change in Expression of CD38+HLA-DR+ on CD4+ From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD38+HLA-DR+ on CD8+ From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD163+ in Adipose Tissue From Baseline to Week 48 | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD4+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD8+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD163+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD68+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD38+HLA-DR+ on CD4+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks | 
| Change in Expression of CD38+HLA-DR+ on CD8+ in Lymphoid Tissue From Baseline to Week 48. | Absolute change was calculated as the value at week 48 minus the value at baseline. | 48 weeks |