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Healthy VolunteersPhase 1NCT03510468

Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)

A Phase 1 study testing Tenofovir alafenamide, Rifapentine and Isoniazid (INH) in people with Healthy Volunteers, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Background: Human immunodeficiency virus (HIV) is treated with antiretroviral drugs. Many people with HIV also have the lung infection tuberculosis (TB). Most TB treatments are complicated. A simpler treatment of two TB drugs can be taken once a week. Read more about this study

Who is it for?
Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for
Healthy Volunteers
What is being tested?
Tenofovir alafenamide, Rifapentine and Isoniazid (INH)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
51 participants
Where
1 siteUnited States
Study dates
12 Jun 2018to 21 Dec 2022
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult
  • PARTICIPANT INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

  1. Ages 18-65 years.
  2. Weight greater than or equal to 45 kg and less than or equal to 120 kg OR body mass index greater than or equal to 18.0 and < 30.
  3. Judged to be healthy based on medical history, physical examination, vital signs, and clinical laboratory tests: liver function tests (AST, alanine transaminase( ALT), Tbili) less than or equal to upper limit of normal [ULN], serum creatinine (SCr) less than or equal to ULN, platelets (PLT) > 150,000/microL, hemoglobin (Hgb) > 13 g/dL (males); greater than or equal to 12g/dL (females), C-reactive protein (CRP) less than or equal to ULN, creatine kinase (CK) less than or equal to 2x ULN, fasting total cholesterol < 240 mg/dL, or fasting triglycerides < 240 mg/dL, urine glucose < grade 2 (per Division of Acquired Immunodeficiency Syndrome (DAIDS) adverse event (AE) table), urine protein < grade 2 (per DAIDS AE table).
  4. Negative QuantiFERON-TB Gold test at screening.
  5. HIV-negative, as determined by standard serologic assays for HIV infection.
  6. No laboratory evidence of active or chronic hepatitis A, B, or C infection.
  7. Willing to abstain from alcohol consumption throughout the study period.
  8. Agrees to genetic testing and storage of specimens for future research.
  9. Able to provide informed consent.
  10. Negative serum or urine pregnancy test for females of child-bearing potential.
  11. Participants must agree not to become pregnant or impregnate a partner for the duration of the study. The use of hormonal contraceptives will not be permitted. Study participants must use one of the following methods of birth control when engaging in sexual activities that can result in pregnancy, beginning at screening until the final study visit.
  12. Male or female condom.
  13. Diaphragm or cervical cap with a spermicide.
  14. Intrauterine device without hormones.

PARTICIPANT EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

  1. Known hypersensitivity to TAF, tenofovir disoproxil fumarate (TDF), INH, RPT, and other rifamycin analogues.
  2. History or presence of any of the following:
  3. Latent or active TB infection.
  4. Gastrointestinal (GI) disease that is uncontrolled, requires daily treatment with medication, or would interfere with a participant s ability to absorb drugs (eg, diarrhea, pancreatitis, or peptic ulcer disease).
  5. Renal impairment (chronic renal insufficiency of any chronic kidney disease stage, or acute renal failure not induced by drug therapy defined as estimated glomerular filtration rate (eGFR) < 90 mL/min or SCr > ULN).
  6. Respiratory disease that is uncontrolled or requires daily treatment with medication (eg, asthma or chronic obstructive pulmonary disease).
  7. Cardiovascular disease (eg, hypertension [systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg], heart failure, or arrhythmia).
  8. Metabolic disorders (eg, diabetes mellitus).
  9. Hematologic or bleeding disorders (eg, anemia, hemophilia, serious/major bleeding events, menorrhagia [female participants]).
  10. Immunologic disorders.
  11. Hormonal or endocrine disorders.
  12. Psychiatric illness that would interfere with their ability to comply with study procedures or that requires daily treatment with medication.
  13. Seizure disorder, with the exception of childhood febrile seizures.
  14. Any current or history of malignancy, with the exception of cutaneous basal cell carcinoma,non-invasive squamous cell carcinoma, or any other malignancies not requiring systemic therapy.
  15. Current or history of osteopenia and osteoporosis.
  16. Current participation in an ongoing investigational drug protocol or use of any investigational drug within 30 days (based on last dose received) prior to receipt of any study drugs.
  17. Therapy with any prescription, over-the-counter (OTC), herbal, or holistic medications, including hormonal contraceptives by any route, within 5 half-lives of the agent prior to receipt of any study medications will not be permitted with the following exception: Intermittent or short-course therapy (<14 days) with prescription or OTC medications, herbals, or holistic medications within the screening period prior to starting study drugs may be permitted, and will be reviewed by investigators on a case-by-case basis for potential drug interactions. Receipt of influenza vaccination will be allowed prior to, during, and/or after the study.
  18. Inability to obtain venous access for sample collection.
  19. Inability to swallow whole capsules and/or tablets.
  20. Pregnant or breastfeeding.
  21. Drug use that may impair safety or adherence.
  22. Use of nicotine-containing products, including cigarettes and chewing tobacco, nicotine patches, gum, electronic cigarettes, etc.
  23. Organ or stem cell transplant recipient.
  24. Uncorrected and persistent electrolyte abnormalities (eg, potassium, magnesium, and calcium).
  25. Current alcohol use disorders (DSM-5 criteria).
  26. Fasting total cholesterol > 240 mg/dL or fasting triglycerides > 240 mg/dL at screening.
  27. Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers

Background:

Human immunodeficiency virus (HIV) is treated with antiretroviral drugs. Many people with HIV also have the lung infection tuberculosis (TB). Most TB treatments are complicated. A simpler treatment of two TB drugs can be taken once a week. Researchers want to study how the HIV and TB drugs affect each other so people who take both can be treated safely.

Read more

Objective:

To study if rifapentine and isoniazid affect blood levels of the common antiretroviral TAF.

Eligibility:

Healthy adults ages 18-65 without HIV, TB, or hepatitis

Design:

Participants will fast before the screening visit. They will have a medical history, physical exam, and blood tests. Women may have a pregnancy test.

During the study, participants must:

Use effective birth control

Not take most medicine

Not drink alcohol

At the baseline visit, participants will repeat screening tests and get TAF tablets.

Participants will take TAF once a day for 31 days. They will keep track of doses and side effects.

Over 32 days, participants will have 4 long visits and 4 short.

At all visits, participants will:

Fast the night before

Get food

Take that day's TAF

Review their TAF supply

Have pregnancy and blood tests

Report side effects

At 3 visits, participants will also take the 2 TB drugs and vitamin B6.

At 3 long visits, participants will also have blood collected 8 times over 8 hours by plastic tube in an arm vein.

Around Day 46, participants will fast and have blood and pregnancy tests. Two weeks later, they will get a call to see how they are feeling.

Read the detailed description

Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this regimen offers several potential benefits, the use of weekly RPT plus INH is limited in adults infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) due to lack of drug interaction data with antiretrovirals (ARVs). Tenofovir alafenamide (TAF) is a preferred backbone agent by the current Department of Health and Human Services ARV guidelines and is a part of multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular TFV diphosphate (dp).

This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of TAF, TFV, and TFV-dp with coadministration of once-weekly RPT + INH administered at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily alone (days 1-14) and (2) TAF once daily + weight-based RPT + INH once weekly (days 15-31). Participants will undergo periodic serial ARV PK blood draws over 24 hours on days 14-15, 22-23, and 31-32.

TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.

Being tested
Tenofovir alafenamide, Rifapentine, Isoniazid (INH), Pyridoxine
Keywords
Antiretroviral Therapy, Human Immunodeficiency Virus, Latent Tuberculosis, Drug-Drug Interactions, Rifamycin
Medical subject headings
Acquired Immunodeficiency Syndrome, Latent Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tenofovir alafenamideDrug

    Also called Vemlidy

    Each tablet contains 25 mg of tenofovir alafenamide.

  • RifapentineDrug

    Also called Priftin

    Each tablet contains 150 mg of rifapentine. Participants who weigh 45 to < 50 kg will take 750 mg (5 tablets), and participants who weigh (Bullet) 50 kg will take 900 mg (6 tablets).

  • Isoniazid (INH)Drug

    Each tablet is formulated as 100 or 300 mg of isoniazid.

  • PyridoxineDietary supplement

    Also called Vitamin B6

    Each tablet contains 50 mg of pyridoxine

Study groups in NCT03510468
Study groupRoleWhat they receive
Pharmacokinetic study in healthy volunteersExperimentalHealthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.
Receives: Drug: Tenofovir alafenamide; Drug: Rifapentine; Drug: Isoniazid (INH); Dietary Supplement: Pyridoxine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Plasma Area Under the Curve (AUC) for Tenofovir Alafenamide (TAF) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)

    Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of TAF was calculated using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®

    Measured: 0-24 hours post dosing on days 14, 22, and 31

  2. Plasma Area Under the Curve (AUC) for Tenofovir (TFV) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)

    Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of TFV was calculated using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®

    Measured: 0-24 hours post dosing on days 14, 22, and 31

  3. Maximum Total Plasma Concentration (Cmax) for Tenofovir Alafenamide (TAF)

    Maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Cmax for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

  4. Maximum Total Plasma Concentration (Cmax) for Tenofovir (TFV)

    Maximum total plasma concentration (Cmax) following a 25mg dose of tenofovir alafenamide (TAF) on day 14, 22, and 31. Cmax for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

  5. Time to Maximum Plasma Concentration (Tmax) for Tenofovir Alafenamide (TAF)

    Time to maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Tmax for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

  6. Time to Maximum Plasma Concentration (Tmax) for Tenofovir (TFV)

    Time to maximum total plasma concentration (Cmax) following a 25mg dose of TAF on day 14, 22, and 31. Tmax for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

  7. Terminal Half-life (t½) of Tenofovir (TFV)

    Half-life calculated as natural log of 2 [ln(2)]/lambda Z of TFV on day 14, 22, and 31.

    Measured: Days 14, 22, and 31

  8. Apparent Oral Clearance (CL/F) of Tenofovir Alafenamide (TAF)

    Apparent oral clearance of TAF was calculated as "dose/plasma area under the curve (AUC)" on day 14, 22, and 31.

    Measured: Days 14, 22, and 31

  9. Minimum Total Plasma Concentration (Cmin) for Tenofovir Alafenamide (TAF)

    Minimum total plasma concentration (Cmin) following a 25mg dose of TAF on day 14, 22, and 31. Cmin for TAF was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

  10. Minimum Total Plasma Concentration (Cmin) for Tenofovir (TFV)

    Minimum total plasma concentration (Cmin) following a 25mg dose of tenofovir alafenamide (TAF) on day 14, 22, and 31. Cmin for TFV was obtained directly by visual inspection of the plasma concentration versus time profiles over 24 hours postdose.

    Measured: Days 14, 22, and 31

Secondary outcomes (2)

  1. Plasma Area Under the Curve (AUC) for Intracellular Tenofovir Di-phosphate During the Dosing Interval of 0 to 24 Hours (AUC0-24hr)

    Plasma area under the curve (AUC) during the dosing interval of 0 to 24 hours (AUC0-24hr) on day 14, 22, and 31 of intracellular tenofovir di-phosphate using the linear-up/log-down trapezoidal rule using noncompartmental methods on Phoenix WinNonlin ®

    Measured: 0-24 hours post dosing on days 14, 22, and 31

  2. Terminal Half-life (t½) of Intracellular Tenofovir-diphosphate

    Half-life calculated as natural log of 2[ ln(2)]/lambda Z of TFV on day 14, 22, and 31.

    Measured: Days 14, 22, and 31

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Apr 2018
  2. Study start12 Jun 2018
  3. Primary completion15 Nov 2022
  4. Study completion21 Dec 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
51 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03510468
Sponsor's protocol ID
180087
Other IDs
18-CC-0087
Status last verified
21 Dec 2022
First submitted
26 Apr 2018
Last updated
13 Aug 2024
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: .Individual participant data will not reported or shared. The study team are the only individuals who have access to individual participant data. All data will be analyzed and reported in aggregate.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Tenofovir alafenamide, Rifapentine and Isoniazid (INH) in people with Healthy Volunteers, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma Area Under the Curve (AUC) for Tenofovir Alafenamide (TAF) During the Dosing Interval of 0 to 24 Hours (AUC0-24hr) (time frame: 0-24 hours post dosing on days 14, 22, and 31). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03510468.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2024.

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Clinical Trial NCT03510468 | AzTrials