Pharmacokinetics of Efavirenz in the Presence of Rifampicin and Isoniazid

NCT02832778 | Unknown Phase 1 DMC

• 1 other identifier: SSAT062
• Study Type: interventional
• Target: 35
• Locations: 2 countries
• Sites: 2

Brief Summary

The purpose of the study is to measure the drug levels in the blood of HIV-infected individuals taking anti- HIV medication efavirenz 400 mg once daily in the presence of anti-TB medication rifampicin and isoniazid. The study is being run in two-stages - London (Stage 1) and Kampala (Stage 2). In London (Stage 1): HIV-1 infected patients (without tuberculosis infection) on established treatment with a combination based on 600 mg efavirenz dose will be recruited. In Kampala (Stage 2): Patients with both HIV-1 and tuberculosis infection being treated with 600 mg efavirenz combination for HIV AND undergoing TB treatment with a dual therapy regimen contaning rifampicin and isoniazid will be recruited. Efavirenz-containing regimens are recommended as first-line therapy for HIV-TB co-infected patients. It has been shown there is a lack of a significant difference between efavirenz 400 mg and efavirenz 600 mg, indicating that 400 mg efavirenz is non-inferior to the standard dose. The advantages of antiretroviral dose reductions may translate into greater benefits for more individuals infected by HIV globally, since they may allow access programs to reach higher numbers of infected patients and compensate for the finite global manufacturing capacity and increasing demand. For efavirenz, significant price reductions have been achieved through elimination of trade, logistics and manufacturing capacity barriers, and further price reductions could be achieved with a significant reduction in the cost of pharmaceutical ingredients. However, no data on the PK and effectiveness of efavirenz 400 mg once daily during TB treatment has been produced. Given that many patients on Efavirenz- based ART will need to be treated for TB during their lifetime and rifampicin is one of the most commonly used treatment for tuberculosis, it is important to study the reduced dose under carefully monitored conditions prior to roll out of a lower dose standard treatment. Therefore, we aim to investigate the PK of efavirenz 400 mg once daily in HIV-infected individuals in the presence of rifampicin and isoniazid in London, UK and in HIV/TB-co-infected individuals on dual anti-TB treatment in Kampala, Uganda

Conditions

HIV

Outcome Measures

Primary Outcomes (1)

• Steady- state plasma concentrations of efavirenz (Sustiva/Stocrin) when administered at 400 mg once daily in the presence of rifampicin and isoniazid (Rifinah or local generics).

  The primary endpoint will be the comparison of efavirenz (Sustiva/Stocrin) Ctrough during combined treatment with efavirenz and rifampicin/isoniazid treatment for tuberculosis, versus efavirenz (Sustiva/Stocrin) treatment alone. The efavirenz (Sustiva/Stocrin) Ctrough from each patient will be compared between the two phases using geometric mean ratios (log10 transformed data). For this sequential design, a sample size of 25 patients would provide at least 80% power to detect a decrease in efavirenz Ctrough of 20% during the combined rifampicin/isoniazid-efavirenz (Sustiva/Stocrin) phase, compared to the efavirenz alone phase. This calculation assumes two-sided testing with a 5% significance level and a within-patient coefficient of variation in efavirenz levels of no more than 30%.

  127 days

Secondary Outcomes (3)

• Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and ison

  127 days

• Relationship between genetic polymorphisms and exposure to efavirenz in order to understand whether polymorphism of certain genes encoding for efavirenz metabolic enzymes are behind differences in efavirenz pharmacokinetics between people

  127 days

• Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV.

  127 days

Study Arms (2)

Stage 1 London

EXPERIMENTAL

Stage 1, London: * Phase 1 (2 weeks): tenofovir/emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine plus efavirenz (Sustiva/Stocrin) 400 mg once daily * Phase 2 (12 weeks): tenofovir/emtricitabine or tenofovir /lamivudine or zidovudine/lamivudine) plus efavirenz (Sustiva/Stocrin) 400 mg once daily plus Rifinah or local generics once daily (rifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if \<50kg.)

Drug: Efavirenz; Drug: tenofovir /emtricitabine; Drug: tenofovir/lamivudine; Drug: lamivudine/zidovudine; Drug: Rifinah or local generics

Stage 2 Kampala

EXPERIMENTAL

Tenofovir/emtricitabine or lamivudine or zidovudine/lamivudine plus efavirenz (Sustiva/Stocrin) 400 mg once daily plus Rifinah or local generics once daily (rifampicin 600 mg and isoniazid 300 mg if ≥ 50 kg or rifampicin 450 mg and isoniazid 300 mg if \<50kg).

Drug: Efavirenz; Drug: tenofovir /emtricitabine; Drug: tenofovir/lamivudine; Drug: lamivudine/zidovudine; Drug: Rifinah or local generics

Interventions

Efavirenz DRUG

Efavirenz 400mg

Also known as: Sustiva, Stocrin, Atripla

Stage 1 London; Stage 2 Kampala

tenofovir /emtricitabine DRUG

tenofovir 245 mg/emtricitabine 200mg

Stage 1 London; Stage 2 Kampala

tenofovir/lamivudine DRUG

tenofovir 245mg/lamivudine 300mg

Stage 1 London; Stage 2 Kampala

lamivudine/zidovudine DRUG

lamivudine 300mg/zidovudine 600mg

Stage 1 London; Stage 2 Kampala

Rifinah or local generics DRUG

Rifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if \<50kg.)

Also known as: Rifampicin and isoniazid

Stage 1 London; Stage 2 Kampala

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Male or non-pregnant, non-lactating females.
• HIV-1-infected on an antiretroviral regimen containing tenofovir, emtricitabine, lamivudine or zidovudine/lamivudine and efavirenz 600 mg once daily for at least 12 weeks.
• With an undetectable viral load for at least 12 weeks (re-testing is allowed).
• CD4 count \>100 cells/mm3.
• Between 18 to 60 years, inclusive.
• Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.
• Women of childbearing potential (WOCBP) must be using an adequate and effective double barrier method of contraception (appendix 4) and is willing to continue practising these birth control methods during the trial to avoid pregnancy and for a period of at least 12 weeks after the last dose of study medication. Note: Non-childbearing potential is defined as either post-menopausal (12 months of spontaneous amenorrhoea and ≥45 years) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy.
• Adequate contraception methods are:
• Condom and spermicides
• Condom and Intra-uterine device (IUD/IUS)
• Heterosexually active males, must be using effective birth control methods and is are willing to continue practising these birth control methods during the trial and until the follow-up visit
• TB negative according to the results of the ELISPOT testing (in case of history of treated TB, ELISPOT results can be positive).
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Male or non-pregnant, non-lactating females.

You may not qualify if:

• Any significant acute or chronic medical illness that in the opinion of the investigator may influence the study results or patient safety.
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations that in the opinion of the investigator may compromise participation into the study
• Hepatic transaminases (AST and ALT) \> Grade 1 \[1.25-2.5 x upper limit of normal (ULN)\].
• Positive blood screen for hepatitis B surface antigen and/or positive hepatitis C PCR.
• Clinically relevant alcohol or drug use (positive urine drug screen - cannabis is allowed) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events.
• Exposure to any investigational drug or placebo within one month of first dose of study drug
• Use of any other drugs (unless approved by the Investigator - see section 5.2), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Investigator as known not to interact with study drugs.
• Any significant acute or chronic medical illness (with the exception of TB) that in the opinion of the Investigator may affect the study results or patient safety (including other AIDS events)
• Evidence of severe organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations that on the opinion of the investigator may compromise participation into the study.
• Positive blood screen for hepatitis B surface antigen or hepatitis C antibodies.
• History of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events.
• Exposure to any investigational drug or placebo within one month of first dose of study drug.
• Use of any other drugs (unless approved by the Investigator - see section 5.2), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.

Sponsors & Collaborators

• St Stephens Aids Trust: lead
• Mylan Inc.: collaborator
• United States Agency for International Development (USAID): collaborator

Study Sites (2)

Infectious Diseases Insitute

Kampala, P.O. Box 22418, Uganda

NOT YET RECRUITING

Chelsea and Westminster Hospital NHS Foundation Trust

London, SW10 9NH, United Kingdom

RECRUITING

Related Publications (1)

• Cerrone M, Wang X, Neary M, Weaver C, Fedele S, Day-Weber I, Owen A, Hill A, McClure M, Boffito M. Pharmacokinetics of Efavirenz 400 mg Once Daily Coadministered With Isoniazid and Rifampicin in Human Immunodeficiency Virus-Infected Individuals. Clin Infect Dis. 2019 Jan 18;68(3):446-452. doi: 10.1093/cid/ciy491.

  PMID: 30084943 DERIVED

Related Links

• UNAIDS is the leading advocate for worldwide action against HIV/AIDS. It promotes partnerships among and between other UN agencies, governments, corporations, media, sports and religious organizations, community-based groups
• BHIVA (the British HIV Association) is an organisation that represents healthcare professionals working in HIV in the UK. Its guidelines set out the medical and other care people living with HIV can expect to receive in the UK

MeSH Terms

Interventions

efavirenz; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Tenofovir; Emtricitabine; Lamivudine; lamivudine, zidovudine drug combination; Rifampin; Isoniazid

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Drug Combinations; Pharmaceutical Preparations; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Zalcitabine; Dideoxynucleosides; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines

Study Officials

• Marta Boffito, MBBS,MD,PhD

  St. Stephen's AIDS Trust

  PRINCIPAL INVESTIGATOR

• Mohammed Lamorde, MBBS,MRCP,PhD

  Infectious Diseases Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Freya Chapman, BSc (Hons)

CONTACT

+44 (0) 7887 476178; freya.chapman@ststcr.com

Marta Boffito, MBBS,MD,PhD

CONTACT

+44 (0) 203 315 6507; marta.boffito@chelwest.nhs.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2016
• First Posted: July 14, 2016
• Study Start: November 21, 2016
• Primary Completion: January 1, 2018
• Study Completion: February 1, 2018
• Last Updated: June 21, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

UG (1); GB (1)