Early Metabolic Effects of Dolutegravir or Tenofovir Alefenamide in Healthy Volunteers

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05652478

Collaborator

(none)

120

Enrollment

Location

Arms

23.8

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

People with HIV take drugs to keep the amount of virus in their body low. One type of these drugs, called integrase strand transfer inhibitors (INSTIs), can cause weight gain over time. Weight gain can cause diabetes, heart disease, and other serious issues. Researchers want to understand how INSTIs cause weight changes.

Objective:

To see how a common INSTI, dolutegravir (DTG), affects how the body uses energy. DTG will be compared with a non-INSTI drug, tenofovir alafenamide (TAF).

Eligibility:

Healthy people aged 18 to 55.

Design:

Participants will be screened. They will have a physical exam and blood tests. They will have a nutritional assessment and tests of their heart function.

Participants will have 2 inpatient stays at the clinic. Each stay will be for 11 nights, with a 3-week break between.

Both DTG and TAF are gel caps swallowed once per day by mouth. Participants will take 1 drug for 8 days during each stay.

Participants will have tests to see how their body uses energy:

They will spend 23 continuous hours in a special room that measures how much oxygen they breathe in and how much carbon dioxide they breathe out. They will do this a total of 6 times.

They will have a DEXA (dual-energy X-ray absorptiometry). DEXA is a kind of X-ray that measures body fat and bone density.

They will lie on a table. Electrodes will be placed on their hands and feet to measure body fat and lean body mass.

They will stand still on a platform for about 30 seconds. High-resolution laser cameras will scan their bodies.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Effects Weight Gain HIV Integrase Strand Transfer Inhibitors	Drug: Tenofovir alafenamide Drug: Dolutegravir	Phase 2

Detailed Description

Study Description:

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral (ARV) drugs currently included in first-line therapy to treat HIV infection. Several observational trials have shown that one side effect of this class of ARVs is involuntary weight gain. How these drugs cause weight gain is unknown. In addition, these marketed drugs are formulated in combination with the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir alafenamide (TAF), which may also independently contribute to weight gain, as compared to the older formulation of tenofovir disoproxil fumarate (TDF). To better understand the effects of INSTIs and TAF on metabolism, participants will be randomized 1:1, in a double-blind manner, to either the INSTI dolutegravir (DTG) or TAF. Participants will be admitted to the Metabolic Unit of the NIH CC, undergo an initial baseline evaluation over 3 days, followed by an 8-day period during which they will take either drug (TAF or DTG) once daily. Following a 20-day washout period at home, participants will then be readmitted to the Metabolic Unit and assigned to the other drug, which they will follow for another 8 days. Throughout the study, participants will be assessed for metabolic processes, including 24-hour energy expenditure via metabolic chamber.

Primary Objective:

To determine if TAF or DTG induce changes in 24-hour energy expenditure and 24-hour respiratory quotient (RQ).

Secondary Objectives:

To determine if baseline demographic (eg, age, sex, or weight) or laboratory characteristics (eg, free thyroxine [T4], thyroid-stimulating hormone [TSH], cortisol, or other hormones) are associated with changes in 24-hour energy expenditure.
To determine if there is a correlation between steady-state pharmacokinetics of TAF or DTG and changes in 24-hour energy expenditure or caloric intake.

Primary Endpoint:

Change in 24-hour energy expenditure and 24-hour RQ from baseline to day 1 and day 8 of ARV therapy with each drug.

Secondary Endpoints:

Relationship between demographic data or baseline laboratory values and changes in energy expenditure or caloric intake.
Relationship between pharmacokinetic parameters for TAF and DTG and changes in energy expenditure or caloric intake.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

A Phase 2 Randomized, Double-Blinded Cross-Over Design Study of the Early Metabolic Effects of Dolutegravir or Tenofovir Alefenamide in Healthy Volunteers

Anticipated Study Start Date :

Feb 6, 2023

Anticipated Primary Completion Date :

Jan 31, 2025

Anticipated Study Completion Date :

Jan 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dolutegravir 50mg one tablet orally once daily for 8 days.	Drug: Dolutegravir 50mg dolutegravir (DTG) one tablet orally once daily for 8 days.
Active Comparator: Tenofovir alafenamide 25mg one tablet orally once a day for 8 days.	Drug: Tenofovir alafenamide 25mg tenofovir alafenamide (TAF) one tablet orally once a day for 8 days.

Arm

Intervention/Treatment

Active Comparator: Dolutegravir

50mg one tablet orally once daily for 8 days.

Drug: Dolutegravir

50mg dolutegravir (DTG) one tablet orally once daily for 8 days.

Active Comparator: Tenofovir alafenamide

25mg one tablet orally once a day for 8 days.

Drug: Tenofovir alafenamide

25mg tenofovir alafenamide (TAF) one tablet orally once a day for 8 days.

Outcome Measures

Primary Outcome Measures

Change in 24-hour energy expenditure and 24-hour RQ from baseline to day 1 and day 8 of ARV therapy with each drug [Baseline to day 1 and Day 8 of ARV therapy for drug regimen.]
To determine if TAF or DTG induce changes in 24-hour energy expenditure and 24-hour respiratory quotient (RQ)

Secondary Outcome Measures

Relationship between pharmacokinetic parameters for TAF and DTG and changes in energy expenditure or caloric intake. [Days 10 and 40]
To determine if there is a correlation between steady-state pharmacokinetics of TAF, or DTG and changes in 24-hour energy expenditure or caloric intake.
Relationship between demographic data or baseline laboratory values and changes in energy expenditure or caloric intake [Throughout study]
To determine if baseline demographic or laboratory characteristics are associated with changes in 24-hour energy expenditure.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Aged 18 to 55 years.
Able to provide informed consent.
Willing and able to stay in the whole-room indirect calorimetry suite on 6 occasions.
Willing to reside on the metabolic unit in the Clinical Center for 2 stays of 10 consecutive days over the course of 5 weeks.
Willing to allow samples and data to be stored and shared for future research.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

Current infection with HIV or hepatitis A, B, or C.
Body mass index (BMI) <18.5 kg/m^{2 or >30.0 kg/m}2.
Weight change >5% in the past 6 months or a trained athlete.
History of or current cardiovascular disease such as congestive heart failure, heart block, or clinically relevant abnormal ECG as determined by investigators.
History of or current liver disease or alanine transaminase serum level >2x upper limit of normal.
History of or current kidney disease or renal insufficiency, or estimated creatinine clearance <=50 mL/min (Modification of Diet in Renal Disease equation).
Current cancer or history of cancer within 5 years of screening, with the exception of squamous cell carcinoma or basal cell carcinoma that is localized and does not require systemic therapy.
History of bariatric surgery.
Diabetes mellitus.
Fasting serum glucose >126 mg/dL.
History of or current hypo- or hyper-thyroid or abnormal TSH, except minor deviations deemed to be of no clinical significance by the investigator.
History of or current asthma or chronic obstructive pulmonary disease.
History of or current glaucoma.
Psychological conditions by self-report, such as (but not limited to) claustrophobia, clinical depression, bipolar disorders, that would be incompatible with safe and successful participation in this study.
Pregnancy or within 1 year post-partum.
Experiences irregular menstrual cycles.
Breastfeeding.
Blood pressure >140/90 mm Hg or current antihypertensive therapy.
Anemia, defined as hemoglobin <13 g/dL (males) or <12 g/dL (females).
History of illicit drug, opioids, or alcohol abuse within the last 5 years; current use of illicit drugs or opioids (by history) or excessive alcohol (CAGE assessment score >=2).
Current use of medications/dietary supplements/alternative therapies known to alter energy metabolism.
Current use of prescription medications, including recent use (6 months) of Descovy or Truvada (eg, for purposes of PrEP).
Any history of exposure to cabotegravir (eg, as participant in research study for this drug).
Current use of nonprescriptive medications that may have interactions with study drugs as determined by the investigators.
History of adverse or allergic reactions to the study drugs.
Daily caffeine intake >500 mg (about 4 cups of coffee)
Current smoker or user of tobacco products.
Participants with dietary allergies, intolerances, or eating patterns that would preclude them from consuming controlled metabolic meals.
Any condition that, in the opinion of the investigator, contraindicates participation in this study.