HIV-1 InfectionPhase 3REFLATE TB2NCT02273765
Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis
A Phase 3 study testing Tenofovir + lamivudine + raltegravir and Tenofovir + lamivudine + efavirenz in people with HIV-1 Infection and Tuberculosis, run by ANRS, Emerging Infectious Diseases at 5 sites in 5 countries.
Trial summary
Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV-1 Infection, Tuberculosis
- What is being tested?
- Tenofovir + lamivudine + raltegravir and Tenofovir + lamivudine + efavirenz
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 460 participants
- Where
- 5 sitesin 5 countries
- Study dates
- 11 Sep 2015to 28 Nov 2018
- Phase
- Phase 3
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed informed consent form
- Aged 18 years or more
- Confirmed HIV-1 infection as documented at any time prior to trial entry per national HIV testing procedures
- ART naïve
- For women of childbearing potential i.e. women of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
- Confirmed or probable active TB disease of any location, except neurological (meningitis or encephalitis), according to the following criteria based on WHO updated definitions:
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- Bacteriologically confirmed pulmonary TB (PTB) or extrapulmonary TB (EPTB), e.g. TB with a biological specimen positive by smear microscopy, culture or nucleic acid amplification test (such as Xpert MTB/RIF).
- Clinically diagnosed PTB or EPTB with typical histological evidence of TB (caseous or granulomatous) on biopsy specimen or positive urinary LAM test OR a significant improvement on TB treatment
- Ongoing standard rifampin-containing TB treatment for ≤8 weeks at inclusion
- For French patients, affiliation to a Social Security program
Who cannot join
- HIV-2 co-infection
- Impaired hepatic function (icterus or ALT (SGPT) > 5ULN)
- Hemoglobin < 6.5 g/dl
- Creatinine clearance <60ml/min (assessed by the Cockroft and Gault formula)
- Mycobacterium tuberculosis strain resistant to rifampin (current or past history).
- Neurological TB (meningitis or encephalitis)
Show all 16Show fewer
- Severe associated diseases requiring specific treatment (including all specific AIDS defining illnesses other than TB, and any severe sepsis)
- Any condition which might, in the investigator's opinion, compromise the safety of treatment and/or patient's adherence to trial procedures including very severe TB-related clinical condition
- Concomitant treatments including phenytoin or phenobarbital (compounds interacting with UGT1A1)
- For HCV co-infected patients, need to start specific treatment for hepatitis during the trial duration
- For women of childbearing potential:
- Pregnancy or breastfeeding
- Refusal to use a contraceptive method
- Any history of ARV intake for prevention of mother to child transmission of HIV (pMTCT)
- Subjects participating in another clinical trial evaluating therapies and including an exclusion period that is still in force during the screening phase
- Person under guardianship, or deprived of freedom by a judicial or administrative decision
Trial locations and contacts
5 sites in 5 countries.
5 sites in 5 countries
Brazil1 site
Laboratory of clinical research on STD/AIDS - IPEC/FIOCRUZ
Rio de Janeiro
Côte d’Ivoire1 site
PACCI / CePReF Centre de Prise en charge de Recherche et de Formation
Abidjan
Mozambique1 site
Instituto Nacional de Saude / Hospital Geral de Machava
Maputo
About this study
Official title: Phase III Open-label Randomized Multicenter Trial to Assess the Non-inferiority of Raltegravir Compared With EFavirenz, Both in Combination With LAmivudine and TEnofovir, in ART-naïve HIV-1-infected Patients Receiving Rifampin for Active TuBerculosis
Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis.
Read the detailed description
Phase III multicenter, international, open-label, randomized trial evaluating non-inferiority of raltegravir at dose of 400mg BID compared to efavirenz 600mg QD, both in association with tenofovir disoproxil fumarate and lamivudine in ART-naïve HIV-1 infected patients with active TB disease receiving a rifampin-based TB treatment initiated <8 weeks before inclusion. Patients will be randomized between 2 arms: the raltegravir (RAL) 400 mg bid arm or the efavirenz (EFV) 600 mg qd arm, each in combination with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) and will be followed for 48 weeks after entry in the trial (ART initiation).
- Conditions
- HIV-1 Infection, Tuberculosis
- Being tested
- Tenofovir + lamivudine + raltegravir, Tenofovir + lamivudine + efavirenz
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tenofovir + lamivudine + raltegravirDrug
In this arm, patients will receive the following medications :
- Tenofovir disoproxil fumarate (TDF) 300 mg / Lamivudine (3TC) 300 mg FDC once a day (1 tablet qd)
- Raltegravir (RAL) 400 mg (Isentress®): twice daily (1 tablet bid), with food
In countries where TDF/3TC FDC is not available, the following separate drugs will be used:
- Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd)
- Lamivudine (3TC) : 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd)
- Raltegravir (RAL) 400 mg (Insentress®): twice daily (1 tablet bid), with food
Tenofovir + lamivudine + efavirenzDrug
In this arm, patients will receive the following medications, in accordance with treatment guidelines in all countries:
- Tenofovir disoproxil fumarate (TDF) 300 mg / lamivudine (3TC) 300 mg FDC once a day (1 tablet qd)
- Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd)
OR:
- Tenofovir disoproxil fumarate (TDF) 245 300 mg / lamivudine (3TC) 300 mg / efavirenz (EFV) 600 mg: once a day (1 tablet qd), at night, if possible without food
In countries where TDF/3TC FDC is not available, the following separate drugs will be used:
- Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd)
- Lamivudine (3TC): 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd)
- Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd), if possible without food. The dose will not be adapted to the patient's body weight.
| Study group | Role | What they receive |
|---|---|---|
| Raltegravir | Active comparator | Tenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID Receives: Drug: Tenofovir + lamivudine + raltegravir |
| Efavirenz | Experimental | Tenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD Receives: Drug: Tenofovir + lamivudine + efavirenz |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients in virologic success
Virologic success, defined as plasma HIV-1 RNA <50 copies/mL, at week 48 with a window period of 42 to 54 weeks (snapshot algorithm). Discontinuation of the strategy (ie. permanent discontinuation of EFV, RAL), missing values, loss to follow-up and death will be considered as failure.
Measured: Week 48
Secondary outcomes (12)
Time to death
Measured: Week 48
Frequency, type and time to new or recurrent AIDS-defining illnesses
Measured: Week 48
Frequency, type and time to severe HIV-associated non-AIDS defining illnesses
Measured: Week 48
Frequency, type and time to grade 3 or 4 adverse events
Measured: Week 48
Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption
Measured: Week 48
Change in plasma HIV-1 RNA from baseline to week 48
Measured: Week 48
Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)
Measured: Week 48
Time to virologic failure during follow-up
Measured: Week 48
Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure
Measured: Week 48
Change in CD4 cell counts from baseline to week 48
Measured: Week 48
Frequency, type and time to Immune Reconstitution Inflammatory Syndrome
Measured: Week 48
Frequency of tuberculosis treatment outcomes
Measured: Week 48
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Oct 2014 (estimated)
- Study start11 Sep 2015
- Primary completion28 Nov 2018
- Study completion28 Nov 2018
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 HIV-1 InfectionStudies of the same condition, open and under way.
- More trials run by ANRS, Emerging Infectious DiseasesThe sponsor's other registered studies.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 460 participants (actual)
Sponsor and investigators
- Lead sponsor
- ANRS, Emerging Infectious Diseases
- Sponsor type
- Other government
- Collaborators
- Merck Sharp & Dohme LLC, Ministry of Health, Brazil
- Responsible party
- Sponsor
- Investigators
- Beatriz Grinsztejn, MD, PhD, Study chair, Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900Nathalie De Castro, MD, Study chair, AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02273765
- Sponsor's protocol ID
- ANRS 12300 REFLATE TB2
- Acronym
- REFLATE TB2
- Status last verified
- Dec 2018
- First submitted
- 20 Oct 2014
- Last updated
- 31 Dec 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
De Castro N, Marcy O, Chazallon C, Messou E, Eholie S, N'takpe JB, Bhatt N, Khosa C, Timana Massango I, Laureillard D, Chau GD, Domergue A, Veloso V, Escada R, Wagner Cardoso S, Delaugerre C, Anglaret X, Molina JM, Grinsztejn B; ANRS 12300 Reflate TB2 study group. Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect Dis. 2021 Jun;21(6):813-822. doi: 10.1016/S1473-3099(20)30869-0. Epub 2021 Mar 2.
PubMed 33667406
Study at a glance
From the registry record, last updated by the sponsor on 31 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase III Open-label Randomized Multicenter Trial to Assess the Non-inferiority of Raltegravir Compared With EFavirenz, Both in Combination With LAmivudine and TEnofovir, in ART-naïve HIV-1-infected Patients Receiving Rifampin for Active TuBerculosis
- ClinicalTrials.gov ID
- NCT02273765
- Acronym / sponsor ID
- REFLATE TB2 / ANRS 12300 REFLATE TB2
- Conditions
- HIV-1 Infection, Tuberculosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 460 participants (actual)
- Lead sponsor
- ANRS, Emerging Infectious DiseasesOther government
- Collaborators
- Merck Sharp & Dohme LLC, Ministry of Health, Brazil
- Study start
- 11 Sep 2015 (actual)
- Primary completion
- 28 Nov 2018 (actual)
- Study completion
- 28 Nov 2018 (actual)
- First posted
- 24 Oct 2014 (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.
Phase III trial evaluating raltegravir as an alternative to efavirenz for antiretroviral treatment of HIV-infected patients with tuberculosis.
Detailed description
Phase III multicenter, international, open-label, randomized trial evaluating non-inferiority of raltegravir at dose of 400mg BID compared to efavirenz 600mg QD, both in association with tenofovir disoproxil fumarate and lamivudine in ART-naïve HIV-1 infected patients with active TB disease receiving a rifampin-based TB treatment initiated <8 weeks before inclusion. Patients will be randomized between 2 arms: the raltegravir (RAL) 400 mg bid arm or the efavirenz (EFV) 600 mg qd arm, each in combination with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) and will be followed for 48 weeks after entry in the trial (ART initiation).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Raltegravir | Active comparator | Drug: Tenofovir + lamivudine + raltegravirTenofovir 300mg QD + lamivudine 300mg QD + raltegravir 400mg BID |
| Efavirenz | Experimental | Drug: Tenofovir + lamivudine + efavirenzTenofovir 300mg QD + lamivudine 300mg QD + efavirenz 600mg QD |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Signed informed consent form
- Aged 18 years or more
- Confirmed HIV-1 infection as documented at any time prior to trial entry per national HIV testing procedures
- ART naïve
- For women of childbearing potential i.e. women of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
Key exclusion criteria (16 listed)
- HIV-2 co-infection
- Impaired hepatic function (icterus or ALT (SGPT) > 5ULN)
- Hemoglobin < 6.5 g/dl
- Creatinine clearance <60ml/min (assessed by the Cockroft and Gault formula)
- Mycobacterium tuberculosis strain resistant to rifampin (current or past history).
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 |
|---|---|---|
| Tenofovir + lamivudine + raltegravirIn this arm, patients will receive the following medications : * Tenofovir disoproxil fumarate (TDF) 300 mg / Lamivudine (3TC) 300 mg FDC once a day (1 tablet qd) * Raltegravir (RAL) 400 mg (Isentress®): twice daily (1 tablet bid), with food In countries where TDF/3TC FDC is not available, the following separate drugs will be used: * Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd) * Lamivudine (3TC) : 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd) * Raltegravir (RAL) 400 mg (Insentress®): twice daily (1 tablet bid), with food | Drug | Raltegravir |
| Tenofovir + lamivudine + efavirenzIn this arm, patients will receive the following medications, in accordance with treatment guidelines in all countries: * Tenofovir disoproxil fumarate (TDF) 300 mg / lamivudine (3TC) 300 mg FDC once a day (1 tablet qd) * Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd) OR: • Tenofovir disoproxil fumarate (TDF) 245 300 mg / lamivudine (3TC) 300 mg / efavirenz (EFV) 600 mg: once a day (1 tablet qd), at night, if possible without food In countries where TDF/3TC FDC is not available, the following separate drugs will be used: * Tenofovir disoproxil fumarate (TDF) 300 mg (Viread® 245 mg): once a day (1 tablet qd) * Lamivudine (3TC): 300 mg once a day (300 mg, 1 tablet qd or 150 mg 2 tablets qd) * Efavirenz (EFV) 600 mg: once a day, at night (1 tablet qd), if possible without food. The dose will not be adapted to the patient's body weight. | Drug | Efavirenz |
Primary outcome
Proportion of patients in virologic success
Time frame: Week 48
Virologic success, defined as plasma HIV-1 RNA <50 copies/mL, at week 48 with a window period of 42 to 54 weeks (snapshot algorithm). Discontinuation of the strategy (ie. permanent discontinuation of EFV, RAL), missing values, loss to follow-up and death will be considered as failure.
12 secondary outcomes
Time to death
Time frame: Week 48
Frequency, type and time to new or recurrent AIDS-defining illnesses
Time frame: Week 48
Frequency, type and time to severe HIV-associated non-AIDS defining illnesses
Time frame: Week 48
Frequency, type and time to grade 3 or 4 adverse events
Time frame: Week 48
Frequency, type and time to drug-induced clinical or biological adverse reactions of grade 3 or 4 or leading to treatment interruption
Time frame: Week 48
Change in plasma HIV-1 RNA from baseline to week 48
Time frame: Week 48
Proportion of patients in virologic success at each time point (HIV-1 RNA<50 copies/mL)
Time frame: Week 48
Time to virologic failure during follow-up
Time frame: Week 48
Frequency and time to new antiretroviral genotypic resistance in plasma RNA in patients with virologic failure
Time frame: Week 48
Change in CD4 cell counts from baseline to week 48
Time frame: Week 48
Frequency, type and time to Immune Reconstitution Inflammatory Syndrome
Time frame: Week 48
Frequency of tuberculosis treatment outcomes
Time frame: Week 48
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2018.
- Derived from this study: PubMed 33667406De Castro N, Marcy O, Chazallon C, Messou E, Eholie S, N'takpe JB, Bhatt N, Khosa C, Timana Massango I, Laureillard D, Chau GD, Domergue A, Veloso V, Escada R, Wagner Cardoso S, Delaugerre C, Anglaret X, Molina JM, Grinsztejn B; ANRS 12300 Reflate TB2 study group. Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect Dis. 2021 Jun;21(6):813-822. doi: 10.1016/S1473-3099(20)30869-0. Epub 2021 Mar 2.
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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.
Beatriz Grinsztejn, MD, PhD study chair
Laboratory on Clinical research on DST/AIDS-IPEC FIOCRUZ Av Brasil, 4365 Manguinhos Rio de Janeiro, Brazil CEP 21040-900
Nathalie De Castro, MD study chair
AP-HP Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010 Paris, France
5 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tenofovir + lamivudine + raltegravir and Tenofovir + lamivudine + efavirenz in people with HIV-1 Infection and Tuberculosis, run by ANRS, Emerging Infectious Diseases at 5 sites in 5 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 10 inclusion and 16 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: finished, as of the sponsor's last update on 31 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Brazil, Côte d’Ivoire, France, Mozambique, Vietnam. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients in virologic success (time frame: Week 48). 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 NCT02273765, 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 31 Dec 2018.