Clinical Evaluation of Adjusted Doses of Darunavir/Ritonavir With Rifampicin in HIV-infected Volunteers (Darifi)

April 1, 2019 updated by: Helen Margaret McIlleron, University of Cape Town

The DaRifi study aims:

  1. Develop adjusted doses of darunavir/ritonavir for use in HIV-infected patients requiring co-treatment of TB with a rifampicin-based regimen.
  2. Compare the steady state pharmacokinetics of doubled doses of DRV/r with rifampicin (in once daily and 12-hourly approaches) to standard daily doses without rifampicin.
  3. Twenty-eight volunteers will be enrolled for a target of 24 participants completing the study.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

A significant barrier to the use of better tolerated antiretrovirals in many low-to-middle income countries (LMIC), where tuberculosis (TB) is endemic, is a lack of evidence to support their use in patients with TB. Access to optimal protease inhibitor (PI)-based regimens for patients with and without TB is urgent. Switching rifampicin to rifabutin, a weak inducer that does not significantly reduce PI concentrations, is recommended in high income countries for patients on boosted PIs who develop TB. However, rifabutin is not available in most LMIC where TB is typically treated with fixed dose combination tablets.

We will enrol virologically suppressed participants on a second-line DRV/r regimen without TB. Based on data from a Physiologically-Based PK model, we selected two adjusted doses of DRV/r (1600/200 mg daily and 800/100 mg 12 hourly) with RIF for comparison to plasma exposures with DRV/r 800/100 mg daily without RIF, in a cross-over design.

Baseline DRV steady state PK will be determined and RIF added for 7 days, then the dose of ritonavir will be increased to 200 mg; 7 days later the dose of DRV will be increased; after another 7 days participants will be crossed over to the alternative adjusted DRV dose.

DRV will be measured in plasma samples after observed doses at baseline and after each dose adjustment. Non-compartmental analysis will be used to estimate the PK measures. Clinical adverse events, ALT, and bilirubin will be monitored every 2 to 3 days during treatment with RIF.

Study Type

Interventional

Enrollment (Actual)

17

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • South Africa
    • Western Cape
      • Cape Town, Western Cape, South Africa, 7725
        • Clinical Research Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

  • Male or female
  • Aged 18 to 60 years, inclusive
  • Weighing > 38 kg
  • BMI > 18.5 kg/m2
  • HIV-1 infected
  • HIV-1 RNA <50 copies/mL
  • CD4+ lymphocyte count > 200 cells/L
  • C-reactive protein <10 mg/L
  • Established on current ART regimen of boosted protease inhibitor plus 2 NRTIs for at least 3 months.
  • Women must be postmenopausal, surgically sterile or practicing an effective birth control method (established before and maintained throughout the trial). Women who are not sexually active must agree to use an effective birth control method if they become heterosexually active during the trial.
  • Understand the purpose of and procedures required for the study and having confirmed they are willing to participate in the study by signing the informed consent document.

Exclusion criteria (volunteers meeting any of the criteria will be excluded)

  • TB (confirmed or suspected)
  • Any symptoms of TB - as assessed by the WHO symptom-screening algorithm: self-reported or documented weight loss, cough, night sweats or fever.
  • Clinical or laboratory evidence of significantly impaired hepatic function, or documented hepatic cirrhosis
  • Clinical or laboratory evidence of acute viral hepatitis
  • Co-infected with HBV or HCV.
  • ALT grade 2 or higher (as defined by DAIDS grading table (ALT >2.5 x ULN)
  • DAIDS grade 3 or 4 laboratory abnormality
  • Active (not clinically stabilized >4 weeks) AIDS defining illness (Category C conditions according to the Center for Disease Control Classification System for HIV infection) with the following exceptions:
  • Stable cutaneous Kaposi's Sarcoma (no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study.
  • Estimated creatinine clearance <50 mL/min.
  • Active clinically significant renal or gastro-intestinal disease.
  • Any active clinically significant or life-threatening disease, medical or psychiatric condition, or findings during screening, that in the investigator's opinion would compromise the safety of the participant or the study outcome, or their ability to comply with the study procedures.
  • Chronic medical requirement for any drugs that are known to affect the PK of the study drugs.
  • Active drug/alcohol abuser.
  • Pregnant or breastfeeding.
  • Increased risks of drug side effects/hypersensitivity reactions e.g. haemophilia or history of sulfonamide allergy.
  • Currently enrolled in an investigational drug study or has participated in an investigational drug study within the 4 weeks before screening.
  • Unable to comply with peri-study restrictions

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Standard dose DRV/r
Standard dose DRV/r 800/100mg without Rifampicin
Drug: Darunavir/ritonavir 800/100 mg tablet
Standard dose DRV/r administered
EXPERIMENTAL: Standard DRV/r with Rifampicin
Rifampicin 600mg QD will be added and darunavir/ritonavir steady state pharmacokinetic analysis will be performed.
Drug: Darunavir/ritonavir 800/100 mg tablet
Standard dose DRV/r administered
Drug: Rifampicin 600mg QD tablet and DTG 50mg BD
Rifampicin and DTG added
EXPERIMENTAL: Boosed ritonavir 200mg
Rifampicin 600mg QD continued with ritonavir 200mg dose doubled QD and darunavir remains 800mg QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.
Drug: Darunavir/ritonavir 800/100 mg tablet
Standard dose DRV/r administered
Drug: Rifampicin 600mg QD tablet and DTG 50mg BD
Rifampicin and DTG added
EXPERIMENTAL: Double dose DRV/r 1600/200mg QD
Rifampicin 600mg QD and DTG QD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.
Drug: Darunavir/ritonavir 800/100 mg tablet
Standard dose DRV/r administered
Drug: Rifampicin 600mg QD tablet and DTG 50mg BD
Rifampicin and DTG added
EXPERIMENTAL: Double dose DRV/r 800/100mg BD
Rifampicin 600mg QD and DTG BD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.
Drug: Darunavir/ritonavir 800/100 mg tablet
Standard dose DRV/r administered
Drug: Rifampicin 600mg QD tablet and DTG 50mg BD
Rifampicin and DTG added

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Darunavir plasma concentrations nanogram per milliliter (ng/ml)
Time Frame: 1 year
Darunavir plasma concentrations will be compared with rifampicin and without rifampicin.
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Alanine Transaminase (ALT) blood level (iu/L)
Time Frame: 1 Year
Clinical safety will be monitored, ALT liver enzyme tests will be evaluated every 3 days.
1 Year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Cape Town

Collaborators

Desmond Tutu HIV Centre
Wits Reproductive Health and HIV Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

April 12, 2018

Primary Completion (ACTUAL)

November 22, 2018

Study Completion (ACTUAL)

November 22, 2018

Study Registration Dates

First Submitted

April 23, 2018

First Submitted That Met QC Criteria

March 25, 2019

First Posted (ACTUAL)

March 27, 2019

Study Record Updates

Last Update Posted (ACTUAL)

April 3, 2019

Last Update Submitted That Met QC Criteria

April 1, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Darifi

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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