- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03092206
Changes in Insulin Sensitivity in Healthy Volunteers Taking Tenofovir Alafenamide (TAF)-Containing Antiretroviral Medication (TAF-IR)
Changes in Insulin Sensitivity in Healthy Volunteers Taking Tenofovir Alafenamide (TAF)-Containing Antiretroviral Medication: The TAF-IR Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Nearly immediately following the characterization of HIV, the metabolic disturbances in HIV-positive patients, particularly changes in insulin sensitivity, were reported. The chronic inflammation due to metabolic changes caused by HIV-Infection on one hand and the antiretroviral therapy (ART) itself on the other hand were considered major contributors to pathological changes in insulin sensitivity in HIV-positive patients. There were two possible mechanisms discussed in the literature: Direct effects on insulin-associated cellular glucose uptake and indirect effects of changes in lipid metabolism, i.e. the lipotoxicity. Particularly, thymidine analogues, such as nucleoside reverse transcriptase inhibitors (NRTI) were strongly linked to lipotoxicity and depletion of mitochondric DNA, causing insulin resistance (IR) in HIV-positive patients and healthy volunteers, ultimately resulting in overt diabetes mellitus. Furthermore, protease inhibitors (PI) showed lipotoxicity, further increasing insulin resistance.
The incidence of insulin resistance and, ultimately, diabetes mellitus in patients receiving ART increases over time, significantly contributing to cardiovascular morbidity and mortality in HIV-positive patients. Due to significant increases both in life expectation and duration of ART in HIV-patients, the early recognition of unfavorable metabolic changes (i. e. insulin resistance) gains in importance. Particularly, the considerations of long-term toxicity and safety of ART are receiving more and more attention. Unfortunately, the appropriate strategies for screening, surveillance and therapeutic consequences are not well established in HIV-positive patients.
While the very well established HIV nucleoside reverse transcriptase inhibitor Tenofovir disaproxil fumarate (TDF) was associated with a favorable influence on lipids and with no known negative effects on insulin sensitivity, the new drug Tenofovir alafenamide (TAF) has not been analyzed in concern of changes in insulin sensitivity yet. As TAF has been recently submitted for approval by FDA and EMEA for treatment of HIV-positive patients, widespread use and potential replacement of TDF can be expected soon. Fixed dose combinations with Emtricitabine (F/TAF) or cobicistat-boosted elvitegravir (E/C/F/TAF) or rilpivirine (R/F/TAF) have been developed and will take part in ART settings. Unfortunately, only limited data exists on metabolic effects of TAF or TAF-containing fixed dose combination drugs, particularly concerning changes in lipid metabolism and insulin sensitivity in HIV-positive patients or healthy volunteers. For providing more safety data concerning changes in insulin sensitivity and associated effects on lipids more data should be provided.
We intend to investigate the possible changes in insulin sensitivity, measured as described below by "hyperinsulinemic eugylcemic clamp" in healthy volunteers taking TAF/FTC (group 1) as compared to E/C/F/TAF (group 2) as compared to R/F/TAF (group 3). To our best of knowledge, there are currently no data available investigating changes in insulin sensitivity of TAF-containing ART-regiments.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Munich, Germany, 81675
- Klinikum rechts der Isar (IZAR)
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male, healthy volunteers, age range ≥18-40 years
- Written informed consent and willingness to attend study visits
- Willingness for taking study medication during study period
- Birth control during study period
Exclusion Criteria:
- Participation in other interventional clinical trials and/or participation in another clinical trial with medicinal products within the last 4 weeks
- Known allergies or contraindications against study medication
- Known metabolic dysfunction, e.g. Hypertriglyceridemia or Diabetes mellitus
- Smoking or alcohol abuse (> 15g/day alcohol consumption)
- Documented HIV-infection
- BMI <18 >25
- Recurrent medication or any antiretroviral medication within the last 30 days
ALT, AST, Bilirubin, Creatinine, TSH, blood pressure, heart rate, QTc are out of normal range
o Normal ranges for clinical chemistry are defined by local laboratory. For blood pressure normal range is defined as 100/60-140/90; for heart rate 60-100
- Known liver, kidney, heart, pulmonary, gastrointestinal, endocrinological, rheumathoid, neurological, psychiatric or metabolic diseases
- Any situation of which the sponsors sees relevant contraindication against study participation
- Imprisoned or situated people
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Group 1
F/TAF ; oral; Dose: 25/200 mg; Frequency: QD
|
antiretroviral therapy
Other Names:
|
Experimental: Group 2
Group 2: E/C/F/TAF; oral; Dose: 150/150/200/10 mg; Frequency: QD
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antiretroviral therapy
Other Names:
|
Experimental: Group 3
Group 3: R/F/TAF; oral; Dose: 25/200/25 mg; Frequency: QD
|
antiretroviral therapy
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Changes in insulin sensitivity
Time Frame: 14±2 days
|
To assess changes in insulin sensitivity (mean glucose disposal rate normalized to body weight (MBW [mg glucose/min*kg]) in HIV-negative, healthy, non-obese (BMI 18-25) male volunteers following 14±2 days of treatment with group 1 or group 2 or group 3, as measured by HEGC.
|
14±2 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
changes in insulin sensitivity
Time Frame: 14 +/-2 days
|
To asses changes in insulin sensitivity as measured by mean glucose disposal rate normalized to body weight and steady-state insulin concentration (MBW/L [mg glucose/min kg UIU]) and normalized to body weight and steady-state glucose concentration (MCR [dL/min kg]), HOMA-IR, HOMA-, QUICKI and 1/QUICKI indices in HIV-negative, healthy, non-obese male volunteers following 14 +/-2 days of administration of IMP in group 1, 2 or 3.
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14 +/-2 days
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lipid metabolism
Time Frame: 14±2 days
|
Changes in lipid metabolism in HIV-negative, healthy, non-obese male volunteers following 14±2 days of administration of IMP in group 1, 2 or 3.
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14±2 days
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Hyperinsulinism
- Insulin Resistance
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- Emtricitabine tenofovir alafenamide
- Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Other Study ID Numbers
- TAF-1688-0030-I
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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