Dose Escalation Study to Determine the Pharmacokinetics of Atazanavir Administered With RIfampicin to HIV Positive Adults on sEcond-line ART Regimen With Suppressed HIV-1 Viral Load

NCT04121195 | Completed Phase 2 DMC

• 1 other identifier: DERIVE
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

The standard treatment for TB consists of rifampicin (RIF) as part of the regimen. However, due to drug-drug interactions (DDI), the bioavailability of PIs is greatly reduced when co-administered with RIF necessitating use of higher doses of the PI to overcome this effect. However, the potential effect of this increased dose on the DDI with bPIs is uncertain. Though some data has been collected that shows safe use of higher doses of LPV to overcome the DDI with standard doses of RIF in HIV-infected individuals, no substantive data has been collected on ATV to correctly adjust its dose when co-administered with RIF-based TB treatment. Physiologically-based pharmacokinetic (PBPK) modelling was developed to understand ATV and RIF DDIs, and identified potential dosing strategies to overcome this challenge in adults and special populations under workpackage 1 of the VirTUAL consortium. From this work, it is anticipated that the dose of ATV/r should be increased from 300/100 once daily to 300/100mg twice daily in order to overcome the interaction with rifampicin and attain therapeutic plasma concentrations. This dose escalation trial aims to:

1. 1.Evaluate the steady state plasma and intracellular PK of ATV/r, when administered in adjusted (PBPK model-predicted) doses concurrently with RIF
2. 2.Evaluate the safety and tolerability / acceptability of the adjusted dose of ATV/r that provides the therapeutic concentration when co-administered with RIF.
3. 3.Evaluate the concentration of dolutegravir (DTG) and RIF when co-administered and explore the potential DDI with ATV/r

Conditions

HIV/AIDS; Tuberculosis

Outcome Measures

Primary Outcomes (4)

• Plasma Cmax of ritonavir-boosted Atazanavir

  The steady state plasma Cmax of ATV/r when administered in adjusted (PBPK model-predicted) doses (300/100mg twice daily) concurrently with standard dose of RIF (600mg) in HIV infected individuals.

  18 months

• Plasma AUC of ritonavir-boosted Atazanavir

  The steady state plasma AUC of ATV/r when administered in adjusted (PBPK model-predicted) doses (300/100mg twice daily) concurrently with standard dose of RIF (600mg) in HIV infected individuals.

  18 months

• Plasma Clearance of ritonavir-boosted Atazanavir

  The steady state plasma CL of ATV/r when administered in adjusted (PBPK model-predicted) doses (300/100mg twice daily) concurrently with standard dose of RIF (600mg) in HIV infected individuals.

  18 months

• Intracellular clearance of ritonavir-boosted Atazanavir

  The steady state intracellular CL of ATV/r when administered in adjusted (PBPK model-predicted) doses (300/100mg twice daily) concurrently with standard dose of RIF (600mg) in HIV infected individuals.

  18 months

Secondary Outcomes (7)

• Plasma Cmax of ritonavir-boosted Atazanavir when given with 1200mg rifampicin

  18 months

• Plasma AUC of ritonavir-boosted Atazanavir when given with 1200mg rifampicin

  18 months

• Plasma Clearance of ritonavir-boosted Atazanavir when given with 1200mg rifampicin

  18 months

• Intracellular concentration of ritonavir-boosted atazanavir

  18 months

• Intracellular concentration of DTG

  18 months

Study Arms (1)

Dose escalation sequence (all participants)

OTHER

The trial will enrol virologically suppressed HIV infected volunteers who are stable on ATV/r and 2 NRTI containing ART following stringent screening to rule out evidence of renal, hepatic or gastrointestinal dysfunction which may affect the PK evaluation. A steady-state PK (PK1) sample collection shall be done on day 7 (+/-3) after enrolment. RIF will be added at standard dose (600 mg once daily) with a further PK evaluation 14 days later (PK2); due to the potential risk of sub therapeutic PI concentrations and emergence of HIV drug resistant strains, these individuals will be given DTG 50 mg twice daily for the duration of the dose-escalation study. ATV/r dose will be increased in a single step to the total modelled dose (PK3), given as twice daily doses. Once at maximum ATV/r dose, RIF will be increased to 1200 mg once a day for a further seven days (PK4). RIF will then be stopped, ATV/r stepped down to 300/100mg once a day and DTG continued for a further one week.

Drug: Dose escalation

Interventions

Dose escalation DRUG

The trial will enrol virologically suppressed HIV infected volunteers who are stable on ATV/r and 2 NRTI containing ART following stringent screening to rule out evidence of renal, hepatic or gastrointestinal dysfunction which may affect the PK evaluation. A steady-state PK (PK1) sample collection shall be done on day 7 (+/-3) after enrolment. RIF will be added at standard dose (600 mg once daily) with a further PK evaluation 14 days later (PK2); due to the potential risk of sub therapeutic PI concentrations and emergence of HIV drug resistant strains, these individuals will be given DTG 50 mg twice daily for the duration of the dose-escalation study. ATV/r dose will be increased in a single step to the total modelled dose (PK3), given as twice daily doses. Once at maximum ATV/r dose, RIF will be increased to 1200 mg once a day for a further seven days (PK4). RIF will then be stopped, ATV/r stepped down to 300/100mg once a day and DTG continued for a further one week.

Dose escalation sequence (all participants)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide a signed and dated informed consent
• HIV positive male or female ≥ 18 years of age
• kg of weight
• On ATV/rand 2 nucleos(t)ide reverse transcriptase inhibitor containing ART regimen for at least 6 months
• Undetectable HIV viral load (\<50 copies/ml) at screening PLUS an undetectable VL during the most recent test done between 6 and 12 months prior to screening.
• A negative pregnancy test for females of child-bearing potential. Should also not be breast feeding.
• On or willing to use effective contraception for at least 4 weeks prior to enrolment, throughout the study period and at least 4 weeks after end of the study(please see section 10.3 for a detailed definition of effective contraception for this study).
• Clinically stable with no AIDS defining illness within the past 6 months.
• A normal chest x-ray
• Ability and willingness to understand and adhere to the study procedures for the entire study duration.
• Able to attend for regular study follow-up visits

You may not qualify if:

• Any clinical contraindications to the use of ATV/r, DTG or RIF.
• Currently receiving treatment for tuberculosis
• Hepatitis B surface antigen positive or Hepatitis C Antibody positive.
• Requirement for concomitant medication with known major interactions with study drugs
• Current participation in another clinical trial or research protocol
• Symptoms of TB
• weight loss \> 2.5% in 4 weeks;
• cough \> 2 weeks;
• night sweats\> 2 weeks;
• fever \> 2 weeks;
• Clinical or laboratory evidence of any of the following:
• AST/ALT \> 1.5 x the upper limit of normal range (ULN)
• AST/ALT \> 1.0 x ULN
• \> 125 mg/dl fasting serum glucose;
• Serum creatinine ≥ 1.5 X ULN in the absence of dehydration. Or estimated glomerular filtration rate \<60mL/min according to Cockcroft-Gault formula for creatinine clearance.

Sponsors & Collaborators

• University of Liverpool: lead
• European and Developing Countries Clinical Trials Partnership (Funder): collaborator
• Joint Clinical Research Centre, Kampala, Uganda: collaborator
• University of Cape Town, Cape Town, South Africa: collaborator
• Makerere University: collaborator
• University of Turin, Turin, Italy: collaborator

Study Sites (1)

Joint Clinical Research Centre

Kampala, PO Box 10005, Uganda

Location

Related Publications (2)

• Gausi K, Mugerwa H, Siccardi M, Montanha MC, Lamorde M, Wiesner L, D'Avolio A, McIlleron H, Wilkins E, De Nicolo A, Maartens G, Khoo S, Kityo C, Denti P, Waitt C. Pharmacokinetics and Safety of Twice-daily Ritonavir-boosted Atazanavir With Rifampicin. Clin Infect Dis. 2024 May 15;78(5):1246-1255. doi: 10.1093/cid/ciad700.

  PMID: 37982585 DERIVED

• Urbaniak A, Thummel KE, Alade AN, Rettie AE, Prasad B, De Nicolo A, Martin JH, Sheppard DN, Jarvis MF. Experimental pharmacology in precision medicine. Pharmacol Res Perspect. 2023 Dec;11(6):e01147. doi: 10.1002/prp2.1147. No abstract available.

  PMID: 37885364 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome; Tuberculosis

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Investigator

Model Details: This is a dose-escalation study where pharmacokinetic assessments will be undertaken after dose-adjustments. In this type of study, each participant will serve as their own control, allowing the changes brought about by each dose change to be understood.

Study Record Dates

• First Submitted: October 2, 2019
• First Posted: October 9, 2019
• Study Start: October 30, 2020
• Primary Completion: May 20, 2022
• Study Completion: May 20, 2023
• Last Updated: July 12, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Will become available after publication of primary endpoint
• Access Criteria: To be determined. Website for the consortium is via the URL, with data sharing section not yet developed.

Locations

UG (1)