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

Primary Purpose

HIV Infections

Status

Terminated

Phase

Phase 1

Locations

South Africa

Study Type

Interventional

Intervention

Darunavir/ritonavir 800/100 mg tablet

Rifampicin 600mg QD tablet and DTG 50mg BD

About this trial

This is an interventional treatment trial for HIV Infections

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Clinical Research Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Standard dose DRV/r

Standard DRV/r with Rifampicin

Boosed ritonavir 200mg

Double dose DRV/r 1600/200mg QD

Double dose DRV/r 800/100mg BD

Arm Description

Standard dose DRV/r 800/100mg without Rifampicin

Rifampicin 600mg QD will be added and darunavir/ritonavir steady state pharmacokinetic analysis will be performed.

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.

Rifampicin 600mg QD and DTG QD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Rifampicin 600mg QD and DTG BD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Outcomes

Primary Outcome Measures

Darunavir plasma concentrations nanogram per milliliter (ng/ml)

Darunavir plasma concentrations will be compared with rifampicin and without rifampicin.

Secondary Outcome Measures

Alanine Transaminase (ALT) blood level (iu/L)

Clinical safety will be monitored, ALT liver enzyme tests will be evaluated every 3 days.

Full Information

NCT ID

NCT03892161

First Posted

April 23, 2018

Last Updated

April 1, 2019

Sponsor

University of Cape Town

Collaborators

Wits Reproductive Health and HIV Institute, Desmond Tutu HIV Centre

1. Study Identification

Unique Protocol Identification Number

NCT03892161

Brief Title

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

Acronym

Darifi

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Terminated

Why Stopped

Risks to participation

Study Start Date

April 12, 2018 (Actual)

Primary Completion Date

November 22, 2018 (Actual)

Study Completion Date

November 22, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Cape Town

Collaborators

Wits Reproductive Health and HIV Institute, Desmond Tutu HIV Centre

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The DaRifi study aims: Develop adjusted doses of darunavir/ritonavir for use in HIV-infected patients requiring co-treatment of TB with a rifampicin-based regimen. 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infections

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

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).

Masking

ParticipantCare ProviderInvestigator

Masking Description

Eligible volunteers will be switched from their standard of care PI to DRV/r 800/100 mg daily, and intensive sampling for measurement of drug concentrations will be performed at steady state. Rifampicin (600-750 mg daily depending on body weight) will then be started and subsequently the protease inhibitor doses escalated to DRV/r 1600/200 mg daily (participants randomized to arm A), OR 800/100 mg 12-hourly (arm B) for 7 days, after which patients will be switched from the daily to the 12-hourly dosing schedule (arm A) or vice versa (arm B) for a further 7 days. Rifampicin will then be stopped but the increased doses of DRV/r will be continued for a further week, before participants are switched back to their standard-of-care ART regimen. Dolutegravir (DTG) 50 mg twice daily (the dose which overcomes any interaction with rifampicin (Dooley 2013) will be added to minimize the risk of viral rebound due to possible suboptimal protease inhibitor exposures during the study.

Allocation

Randomized

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard dose DRV/r

Arm Type

Experimental

Arm Description

Standard dose DRV/r 800/100mg without Rifampicin

Arm Title

Standard DRV/r with Rifampicin

Arm Type

Experimental

Arm Description

Rifampicin 600mg QD will be added and darunavir/ritonavir steady state pharmacokinetic analysis will be performed.

Arm Title

Boosed ritonavir 200mg

Arm Type

Experimental

Arm Description

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.

Arm Title

Double dose DRV/r 1600/200mg QD

Arm Type

Experimental

Arm Description

Rifampicin 600mg QD and DTG QD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Arm Title

Double dose DRV/r 800/100mg BD

Arm Type

Experimental

Arm Description

Rifampicin 600mg QD and DTG BD continued. Double dose DRV/r QD. The darunavir/ritonavir steady state pharmacokinetic analysis will be performed and compared.

Intervention Type

Drug

Intervention Name(s)

Darunavir/ritonavir 800/100 mg tablet

Intervention Description

Standard dose DRV/r administered

Intervention Type

Drug

Intervention Name(s)

Rifampicin 600mg QD tablet and DTG 50mg BD

Intervention Description

Rifampicin and DTG added

Primary Outcome Measure Information:

Title

Darunavir plasma concentrations nanogram per milliliter (ng/ml)

Description

Darunavir plasma concentrations will be compared with rifampicin and without rifampicin.

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Alanine Transaminase (ALT) blood level (iu/L)

Description

Clinical safety will be monitored, ALT liver enzyme tests will be evaluated every 3 days.

Time Frame

1 Year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Helen McIlleron, PhD

Organizational Affiliation

University of Cape Town

Official's Role

Principal Investigator

Facility Information:

Facility Name

Clinical Research Centre

City

Cape Town

State/Province

Western Cape

ZIP/Postal Code

7725

Country

South Africa

12. IPD Sharing Statement

Plan to Share IPD

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

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