HIVPhase 1NCT02832778
Pharmacokinetics of Efavirenz in the Presence of Rifampicin and Isoniazid
A Phase 1 study testing Efavirenz, tenofovir /emtricitabine and tenofovir/lamivudine in people with HIV, run by St Stephens Aids Trust at 2 sites in 2 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- HIV
- What is being tested?
- Efavirenz, tenofovir /emtricitabine and tenofovir/lamivudine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 35 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 21 Nov 2016to Feb 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Show all 25Show fewer
- 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.
- HIV-1-infected on an antiretroviral regimen containing 2 NRTIs plus efavirenz 600 mg once daily for at least 3 weeks.
- With a TB diagnosis and currently undergoing anti-TB treatment with rifampicin and isoniazid-containing regimens.
- 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 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)
- 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
Who cannot join
- 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
Show all 17Show fewer
- 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.
- 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).
- 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).
- 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.
- 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).
- 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).
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
Uganda1 site, 1 recruiting
- Not yet recruiting
Infectious Diseases Insitute
Kampala, P.O. Box 22418
Mohammed Lamorde, MBBS, MRCP, PhD, +256 312 307 000, mlamorde@idi.co.ug
United Kingdom1 site, 1 recruiting
- Recruiting
Chelsea and Westminster Hospital NHS Foundation Trust
London, SW10 9NH
Marta Boffito, 0208 846 6507, marta.boffito@chelwest.nhs.uk
About this study
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)
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.
Read more
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
Read the detailed description
Protocol Number: SSAT 062
EudraCT Number: 2014-002608-26
Name of Investigational Product: Sustiva/Stocrin/Atripla; Rifinah or local generic 300/150 Name of active ingredients: Efavirenz/ rifampicin/ isoniazid
Study title:Steady-state pharmacokinetics of efavirenz (Sustiva/Stocrin) 400 mg once daily in the presence of rifampicin and isoniazid (Rifinah or the local generics)
Name of Non Investigational Medicinal Product: 2 nucleoside reverse transcriptase inhibitors (Tenofovir/ emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine)
Phase of study: Phase I
Objectives: The objectives of this study are:
Primary:
- To evaluate the steady-state pharmacokinetics of efavirenz (Sustiva/Stocrin) 400 mg once daily during co-administration with rifampicin and isoniazid (Rifinah or local generic)
Secondary:
- To assess the safety and tolerability of efavirenz (Sustiva/Stocrin) 400 mg once daily during co-administration with rifampicin and isoniazid (Rifinah or local generic)
- To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure
- Exploratory: To investigate the impact of anti-retroviral drugs on platelet function in people living with HIV
Study design:
Two-centre, two-stage, 98/99 days in London (Stage 1) and 28 days in Kampala (Stage 2) (excluding screening and follow up), open-label, pharmacokinetic study
Indication:
London: HIV-1 infected patients (without tuberculosis infection) on established treatment with a combination based on 600 mg efavirenz dose Kampala: Patient 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
Methodology:
Measurements of efavirenz concentrations and efavirenz pharmacokinetic profiles in the absence (Stage 1 only) and in the presence of rifampicin and isoniazid in two populations of HIV-infected individuals:
- without TB (Stage 1, London)
- with TB (Stage 2, Kampala)
Planned sample size:
Stage 1, London: For this sequential design, a sample size of 25 patients would provide at least 80% power to detect a decrease in efavirenz Cmin of 20% during the combined rifampicin/isoniazid-efavirenz phase, compared to the efavirenz alone phase.
Up to 40 subjects may be screened and enrolled to have 25 HIV-infected patients completing the study.
Stage 2, Kampala: A pilot study in 10 patients in Uganda with HIV and TB co-infection and on anti-HIV treatment and anti-TB treatment will also be performed to validate findings of the London PK study in a TB-infected population.
Up to 25 subjects may be screened and enrolled to have 10 HIV/TB-co-infected patients completing the pilot sub-study
Summary of eligibility criteria:
Stage 1, London: HIV-1 infected males or females of at least 18 years, treated with a stable efavirenz based combination regimen (tenofovir/ emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine) for at least the preceding 12 weeks and with an undetectable viral load and a CD4+ T-cell count > 100 cell/mm3.
Stage 2, Kampala: HIV-1 infected males or females of at least 18 years, treated with a stable efavirenz based combination regimen (tenofovir /emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine) for at least the preceding 12 weeks, with a CD4+ T-cell count > 100 cell/mm3, co-infected with TB and undergoing anti-TB treatment with rifampicin and isoniazid-containing regimens.
Duration of treatment:
London: 98 / 99 (+/- 1) days (excluding screening and follow up visits) Kampala: 28 days (+/- 7) days (excluding screening and follow up visits)
Dose and route of administration:
All study drugs will be administered orally to subjects with the following schedule:
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.)
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).
Criteria for evaluation:
Stage 1, London: Pharmacokinetic (PK) parameters of efavirenz will be evaluated on blood drawn on days:
- 14/15 (2 weeks after reducing efavirenz dose from 600 mg to 400 mg)
- 42/43 (4 weeks after Rifinah or local generics initiation at start of phase 2) and
- 98/99 (12 weeks after Rifinah or local generics initiation)
- PK profile at 0 (pre-dose), 2, 4, 8, 12 and 24 hours post administered dose.
Stage 2, Kampala: Pharmacokinetic parameters of efavirenz will be evaluated on blood drawn on:
- days 28 +/- 7 days (while on anti-TB medications)
- PK profile at 0 (pre-dose), 2, 4, 8, 12 and 24 hours post last dose.
Safety and tolerability of medications will also be assessed by questioning to collect adverse event symptoms, physical examination and laboratory parameters, performed at regular intervals during the study, including efavirenz therapeutic drug monitoring (TDM) once/twice a week.
Endpoints:
Primary endpoint:
- Steady state plasma concentrations of efavirenz when administered at 400 mg once daily in the presence of rifampicin and isoniazid
Secondary endpoints:
- Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and isoniazid.
- Relationship between genetic polymorphisms and exposure to efavirenz.
- Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV.
- Conditions
- HIV
- Being tested
- Efavirenz, tenofovir /emtricitabine, tenofovir/lamivudine, lamivudine/zidovudine, Rifinah or local generics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EfavirenzDrug
Also called Sustiva, Stocrin, Atripla
Efavirenz 400mg
tenofovir /emtricitabineDrug
tenofovir 245 mg/emtricitabine 200mg
tenofovir/lamivudineDrug
tenofovir 245mg/lamivudine 300mg
lamivudine/zidovudineDrug
lamivudine 300mg/zidovudine 600mg
Rifinah or local genericsDrug
Also called Rifampicin and isoniazid
Rifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if <50kg.)
| Study group | Role | What they receive |
|---|---|---|
| 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.) Receives: 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). Receives: Drug: Efavirenz; Drug: tenofovir /emtricitabine; Drug: tenofovir/lamivudine; Drug: lamivudine/zidovudine; Drug: Rifinah or local generics |
What is being measured
The primary outcome is the main question the study is designed to answer.
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%.
Measured: 127 days
Secondary outcomes (3)
Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and ison
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.
Measured: 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
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.
Measured: 127 days
Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV.
To look at platelet function during antiretroviral intake in HIV positive individuals who take part in clinical trials
Measured: 127 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2016 (estimated)
- Study start21 Nov 2016
- Primary completionJan 2018 (estimated)
- Study completionFeb 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 35 participants (estimated)
Sponsor and investigators
- Lead sponsor
- St Stephens Aids Trust
- Sponsor type
- University, hospital or other
- Collaborators
- Mylan Inc., United States Agency for International Development (USAID)
- Responsible party
- Sponsor
- Investigators
- Marta Boffito, MBBS,MD,PhD, Principal investigator, St. Stephen's AIDS TrustMohammed Lamorde, MBBS,MRCP,PhD, Principal investigator, Infectious Diseases Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02832778
- Sponsor's protocol ID
- SSAT062
- Status last verified
- Jun 2017
- First submitted
- 11 Jul 2016
- Last updated
- 21 Jun 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 30084943
Study at a glance
From the registry record, last updated by the sponsor on 21 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02832778
- Acronym / sponsor ID
- SSAT062
- Conditions
- HIV
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 35 participants (estimated)
- Lead sponsor
- St Stephens Aids TrustUniversity, hospital or other
- Collaborators
- Mylan Inc., United States Agency for International Development (USAID)
- Study start
- 21 Nov 2016 (actual)
- Primary completion
- Jan 2018 (estimated)
- Study completion
- Feb 2018 (estimated)
- First posted
- 14 Jul 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
Protocol Number: SSAT 062
EudraCT Number: 2014-002608-26
Name of Investigational Product: Sustiva/Stocrin/Atripla; Rifinah or local generic 300/150 Name of active ingredients: Efavirenz/ rifampicin/ isoniazid
Study title:Steady-state pharmacokinetics of efavirenz (Sustiva/Stocrin) 400 mg once daily in the presence of rifampicin and isoniazid (Rifinah or the local generics)
Name of Non Investigational Medicinal Product: 2 nucleoside reverse transcriptase inhibitors (Tenofovir/ emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine)
Phase of study: Phase I
Objectives: The objectives of this study are:
Primary:
- To evaluate the steady-state pharmacokinetics of efavirenz (Sustiva/Stocrin) 400 mg once daily during co-administration with rifampicin and isoniazid (Rifinah or local generic)
Secondary:
- To assess the safety and tolerability of efavirenz (Sustiva/Stocrin) 400 mg once daily during co-administration with rifampicin and isoniazid (Rifinah or local generic)
- To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure
- Exploratory: To investigate the impact of anti-retroviral drugs on platelet function in people living with HIV
Study design:
Two-centre, two-stage, 98/99 days in London (Stage 1) and 28 days in Kampala (Stage 2) (excluding screening and follow up), open-label, pharmacokinetic study
Indication:
London: HIV-1 infected patients (without tuberculosis infection) on established treatment with a combination based on 600 mg efavirenz dose Kampala: Patient 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
Methodology:
Measurements of efavirenz concentrations and efavirenz pharmacokinetic profiles in the absence (Stage 1 only) and in the presence of rifampicin and isoniazid in two populations of HIV-infected individuals:
- without TB (Stage 1, London)
- with TB (Stage 2, Kampala)
Planned sample size:
Stage 1, London: For this sequential design, a sample size of 25 patients would provide at least 80% power to detect a decrease in efavirenz Cmin of 20% during the combined rifampicin/isoniazid-efavirenz phase, compared to the efavirenz alone phase.
Up to 40 subjects may be screened and enrolled to have 25 HIV-infected patients completing the study.
Stage 2, Kampala: A pilot study in 10 patients in Uganda with HIV and TB co-infection and on anti-HIV treatment and anti-TB treatment will also be performed to validate findings of the London PK study in a TB-infected population.
Up to 25 subjects may be screened and enrolled to have 10 HIV/TB-co-infected patients completing the pilot sub-study
Summary of eligibility criteria:
Stage 1, London: HIV-1 infected males or females of at least 18 years, treated with a stable efavirenz based combination regimen (tenofovir/ emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine) for at least the preceding 12 weeks and with an undetectable viral load and a CD4+ T-cell count > 100 cell/mm3.
Stage 2, Kampala: HIV-1 infected males or females of at least 18 years, treated with a stable efavirenz based combination regimen (tenofovir /emtricitabine or tenofovir/lamivudine or zidovudine/lamivudine) for at least the preceding 12 weeks, with a CD4+ T-cell count > 100 cell/mm3, co-infected with TB and undergoing anti-TB treatment with rifampicin and isoniazid-containing regimens.
Duration of treatment:
London: 98 / 99 (+/- 1) days (excluding screening and follow up visits) Kampala: 28 days (+/- 7) days (excluding screening and follow up visits)
Dose and route of administration:
All study drugs will be administered orally to subjects with the following schedule:
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.)
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).
Criteria for evaluation:
Stage 1, London: Pharmacokinetic (PK) parameters of efavirenz will be evaluated on blood drawn on days:
- 14/15 (2 weeks after reducing efavirenz dose from 600 mg to 400 mg)
- 42/43 (4 weeks after Rifinah or local generics initiation at start of phase 2) and
- 98/99 (12 weeks after Rifinah or local generics initiation)
- PK profile at 0 (pre-dose), 2, 4, 8, 12 and 24 hours post administered dose.
Stage 2, Kampala: Pharmacokinetic parameters of efavirenz will be evaluated on blood drawn on:
- days 28 +/- 7 days (while on anti-TB medications)
- PK profile at 0 (pre-dose), 2, 4, 8, 12 and 24 hours post last dose.
Safety and tolerability of medications will also be assessed by questioning to collect adverse event symptoms, physical examination and laboratory parameters, performed at regular intervals during the study, including efavirenz therapeutic drug monitoring (TDM) once/twice a week.
Endpoints:
Primary endpoint:
- Steady state plasma concentrations of efavirenz when administered at 400 mg once daily in the presence of rifampicin and isoniazid
Secondary endpoints:
- Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and isoniazid.
- Relationship between genetic polymorphisms and exposure to efavirenz.
- Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Stage 1 London | Experimental | Drug: Efavirenz, Drug: tenofovir /emtricitabine, Drug: tenofovir/lamivudine, Drug: lamivudine/zidovudine, Drug: Rifinah or local genericsStage 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.) |
| Stage 2 Kampala | Experimental | Drug: Efavirenz, Drug: tenofovir /emtricitabine, Drug: tenofovir/lamivudine, Drug: lamivudine/zidovudine, Drug: Rifinah or local genericsTenofovir/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). |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (25 listed)
- 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.
Key exclusion criteria (17 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EfavirenzAlso: Sustiva, Stocrin, AtriplaEfavirenz 400mg | Drug | Stage 1 London, Stage 2 Kampala |
| tenofovir /emtricitabinetenofovir 245 mg/emtricitabine 200mg | Drug | Stage 1 London, Stage 2 Kampala |
| tenofovir/lamivudinetenofovir 245mg/lamivudine 300mg | Drug | Stage 1 London, Stage 2 Kampala |
| lamivudine/zidovudinelamivudine 300mg/zidovudine 600mg | Drug | Stage 1 London, Stage 2 Kampala |
| Rifinah or local genericsAlso: Rifampicin and isoniazidRifampicin 600 mg and isoniazid 300 mg if ≥50kg or rifampicin 450 mg and isoniazid 300 mg if <50kg.) | Drug | Stage 1 London, Stage 2 Kampala |
Primary outcome
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%.
3 secondary outcomes
Safety and tolerability of efavirenz when administered at 400 mg once daily in the presence of rifampicin and ison
Time frame: 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
Time frame: 127 days
Exploratory: impact of anti-retroviral drugs or platelet function in people living with HIV.
Time frame: 127 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jun 2017.
- Derived from this study: PubMed 30084943Cerrone 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.
- 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 groupsLink provided by the sponsor.
- 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 UKLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for HIV
Not yet recruiting
HealthMpowerment Korea: Pilot Testing the Cultural Adaptation of a Digital HIV Intervention for Men Who Have Sex With Men in South Korea
HIV Infections, HIV Prevention and Care
Not yet recruiting
Prescribe to Prevent HIV: A Hybrid Trial Helping Addiction Clinics Prevent HIV & Infections Through Safer Drug Use Support
People Who Use Opioids/People With Opioid Use Disorder (OUD)
Recruiting
Evaluating the Impact of Using the B-OK Bottles for HIV and ART Literacy in South Africa
HIV, HIV Treatment
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
RecruitingObservational study
Olfactory Function and Model-Based Behavior in People Living With HIV and SUD
HIV, Substance Use Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marta Boffito, MBBS,MD,PhD principal investigator
St. Stephen's AIDS Trust
Mohammed Lamorde, MBBS,MRCP,PhD principal investigator
Infectious Diseases Institute
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Efavirenz, tenofovir /emtricitabine and tenofovir/lamivudine in people with HIV, run by St Stephens Aids Trust at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Uganda, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Freya Chapman, BSc (Hons) (+44 (0) 7887 476178, freya.chapman@ststcr.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02832778, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jun 2017.