Clinical trial NCT03892161: Clinical Evaluation of Adjusted Doses of Darunavir/Ritonavir With Rifampicin in HIV-infected Volunteers
Official title: Clinical Evaluation of Adjusted Doses of Darunavir/Ritonavir With Rifampicin in HIV-infected Volunteers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: HIV Infections
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Wits Reproductive Health and HIV Institute
name: Desmond Tutu HIV Centre
First posted: 2019-03-27
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A phase I, open-label, cross-over, single center, PK drug-drug interaction study will be conducted in 24 medically stable HIV-1 infected adults with viral suppression (viral load \<50 copies/mL).
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Darunavir plasma concentrations nanogram per milliliter (ng/ml)
timeFrame: 1 year
Secondary outcomes:
measure: Alanine Transaminase (ALT) blood level (iu/L)
timeFrame: 1 Year
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Clinical Research Centre
state: Western Cape
Study officials:
affiliation: University of Cape Town
name: Helen McIlleron, PhD
role: PRINCIPAL_INVESTIGATOR
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