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Pharmacokinetics of Efavirenz in the Presence of Rifampicin and Isoniazid

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02832778
Recruitment Status : Unknown
Verified June 2017 by St Stephens Aids Trust.
Recruitment status was:  Recruiting
First Posted : July 14, 2016
Last Update Posted : June 21, 2017
Sponsor:
Collaborators:
Mylan Inc.
United States Agency for International Development (USAID)
Information provided by (Responsible Party):
St Stephens Aids Trust

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


Condition or disease Intervention/treatment Phase
HIV Drug: Efavirenz Drug: tenofovir /emtricitabine Drug: tenofovir/lamivudine Drug: lamivudine/zidovudine Drug: Rifinah or local generics Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Steady-state Pharmacokinetics of Efavirenz (Sustiva/Stocrin) 400 mg Once Daily in the Presence of Rifampicin and Isoniazid (Rifinah or the Local Generics)
Actual Study Start Date : November 21, 2016
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : February 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Stage 1 London

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
Efavirenz 400mg
Other Names:
  • Sustiva
  • Stocrin
  • Atripla

Drug: tenofovir /emtricitabine
tenofovir 245 mg/emtricitabine 200mg

Drug: tenofovir/lamivudine
tenofovir 245mg/lamivudine 300mg

Drug: lamivudine/zidovudine
lamivudine 300mg/zidovudine 600mg

Drug: Rifinah or local generics
Rifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if <50kg.)
Other Name: Rifampicin and isoniazid

Experimental: Stage 2 Kampala
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
Efavirenz 400mg
Other Names:
  • Sustiva
  • Stocrin
  • Atripla

Drug: tenofovir /emtricitabine
tenofovir 245 mg/emtricitabine 200mg

Drug: tenofovir/lamivudine
tenofovir 245mg/lamivudine 300mg

Drug: lamivudine/zidovudine
lamivudine 300mg/zidovudine 600mg

Drug: Rifinah or local generics
Rifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if <50kg.)
Other Name: Rifampicin and isoniazid




Primary Outcome Measures :
  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). [ Time Frame: 127 days ]
    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%.


Secondary Outcome Measures :
  1. Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and ison [ Time Frame: 127 days ]
    Safety and tolerability of medications will also be assessed by questions, physical examination, laboratory parameters and the DAIDS table for grading the severity of adult and pediatric adverse events. These will be performed at regular intervals during the drug study.

  2. 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 [ Time Frame: 127 days ]

    A candidate gene approach will be utilised to examine loci of interest. This procedure will provide potentially important information on genetic influences on plasma drug concentrations and give insight into how to improve the management of HIV-infected patients by individualising therapy. These studies will not be powered for genetic associations but will

    - Page 5 of 6 - enable us to build a data base of genotype-phenotype. Prospective genetic studies would need to be planned based on these preliminary data.


  3. Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV. [ Time Frame: 127 days ]
    To look at platelet function during antiretroviral intake in HIV positive individuals who take part in clinical trials



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - LONDON

  1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  2. Male or non-pregnant, non-lactating females.
  3. 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.
  4. With an undetectable viral load for at least 12 weeks (re-testing is allowed).
  5. CD4 count >100 cells/mm3.
  6. Between 18 to 60 years, inclusive.
  7. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.
  8. 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)
  9. 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
  10. TB negative according to the results of the ELISPOT testing (in case of history of treated TB, ELISPOT results can be positive).

Inclusion Criteria - KAMPALA

  1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  2. Male or non-pregnant, non-lactating females.
  3. HIV-1-infected on an antiretroviral regimen containing 2 NRTIs plus efavirenz 600 mg once daily for at least 3 weeks.
  4. With a TB diagnosis and currently undergoing anti-TB treatment with rifampicin and isoniazid-containing regimens.
  5. CD4 count >100 cells/mm3.
  6. Between 18 to 60 years, inclusive.
  7. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.
  8. Women of childbearing potential (WOCBP) must be using an adequate double method of contraception to avoid pregnancy throughout the study and for a period of at least 12 weeks after the last dose of study medication

    Adequate contraception methods are:

    • Condom and spermicides
    • Condom and Intra-uterine device (IUD/IUS)
  9. Heterosexually active males, must be using effective birth control methods and are willing to continue practising these birth control methods during the trial and until the follow-up visit

Exclusion criteria - LONDON

  1. Any significant acute or chronic medical illness that in the opinion of the investigator may influence the study results or patient safety.
  2. 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
  3. Hepatic transaminases (AST and ALT) > Grade 1 [1.25-2.5 x upper limit of normal (ULN)].
  4. Positive blood screen for hepatitis B surface antigen and/or positive hepatitis C PCR.
  5. 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.
  6. Exposure to any investigational drug or placebo within one month of first dose of study drug
  7. 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.
  8. Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 12 weeks after the end of the treatment period (See inclusion criteria number 8).
  9. Heterosexual males without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 12 weeks after the end of the treatment period. (See inclusion criteria number 9).

Exclusion criteria - KAMPALA

  1. 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)
  2. 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.
  3. Positive blood screen for hepatitis B surface antigen or hepatitis C antibodies.
  4. 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.
  5. Exposure to any investigational drug or placebo within one month of first dose of study drug.
  6. 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.
  7. Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 12 weeks after the end of the treatment period (see inclusion criteria number 8).
  8. Heterosexual males without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 12 weeks after the end of the treatment period (See inclusion criteria number 9 and appendix 4).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02832778


Contacts
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Contact: Freya Chapman, BSc (Hons) +44 (0) 7887 476178 freya.chapman@ststcr.com
Contact: Marta Boffito, MBBS,MD,PhD +44 (0) 203 315 6507 marta.boffito@chelwest.nhs.uk

Locations
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Uganda
Infectious Diseases Insitute Not yet recruiting
Kampala, P.O. Box 22418, Uganda
Contact: Mohammed Lamorde, MBBS, MRCP, PhD    +256 312 307 000    mlamorde@idi.co.ug   
United Kingdom
Chelsea and Westminster Hospital NHS Foundation Trust Recruiting
London, United Kingdom, SW10 9NH
Contact: Marta Boffito    0208 846 6507    marta.boffito@chelwest.nhs.uk   
Sponsors and Collaborators
St Stephens Aids Trust
Mylan Inc.
United States Agency for International Development (USAID)
Investigators
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Principal Investigator: Marta Boffito, MBBS,MD,PhD St. Stephen's AIDS Trust
Principal Investigator: Mohammed Lamorde, MBBS,MRCP,PhD Infectious Diseases Institute
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: St Stephens Aids Trust
ClinicalTrials.gov Identifier: NCT02832778    
Other Study ID Numbers: SSAT062
First Posted: July 14, 2016    Key Record Dates
Last Update Posted: June 21, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Tenofovir
Lamivudine
Zidovudine
Emtricitabine
Efavirenz
Lamivudine, zidovudine drug combination
Isoniazid
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
Antimetabolites
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
Antitubercular Agents
Anti-Bacterial Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents