- ICH GCP
- Registre américain des essais cliniques
- Essai clinique NCT01380080
REMEMBER: Reducing Early Mortality & Morbidity by Empiric Tuberculosis (TB) Treatment (REMEMBER)
Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER)
People with HIV have a high chance of becoming infected with TB, especially when they live in areas where TB infection is common. It can be difficult to diagnose TB in people who need to start HIV treatment right away. Within about 6 months after starting HIV treatment, some of these people can become very sick with TB and can even die from it.
This study was being done in people who were starting HIV treatment and who lived in areas where the TB infection rate is high. The purpose of this study was to test an experimental approach to TB treatment to see if it is better than the usual approach. The experimental approach was to start TB treatment at the same time as HIV treatment, even when TB infection had not been found. The usual approach was to start TB treatment only if TB infection was found.
In this study, half of the people started TB treatment at the same time as they started their HIV treatment. The other half started TB treatment only if TB infection was found.
The study also tested how safe and effective it was to start TB treatment at about the same time as HIV treatment even when TB infection had not been found. The study collected information about diet, whether (and when) people in the study became sicker or died, how well their HIV was controlled, how they were feeling, how they were taking their medications, whether it mattered where they lived or what kind of HIV and TB care was standard, how many people were diagnosed with TB while in the study, and how the cost of the two treatment options on a national level could be compared.
Aperçu de l'étude
Statut
Les conditions
Description détaillée
This was a randomized, open-label, phase IV strategy trial for participants from resource-limited settings (RLS) who presented with advanced HIV disease and no probable or confirmed tuberculosis (TB), and who were initiating antiretroviral treatment (ART).
Participants were randomized to one of two strategy arms: immediate, empiric TB treatment (Empiric arm) or local standard of care TB treatment (IPT arm).
Randomization was balanced by clinical trial unit and stratified according to CD4+ T cell count (<25 vs. ≥25 cells/mm^3) and presence of any of the following prognostic factors: reportable hospitalization within the past 30 days, BMI <18.5 kg/m^2, or anemia (hemoglobin <8 g/dl).
Participants were followed for 96 weeks. Participants attended study visits at screening, enrollment, and weeks 1, 2, 4, 8, 12, 16, 20, 24 and 48. Signs and symptoms, ART modifications, concomitant medications, and clinical events as defined by AIDS Clinical Trials Group (ACTG) Appendix 60 were collected at each visit. Blood was collected for CD4 and HIV-1 RNA at study entry, weeks 4, 24 and 48, and blood for safety laboratories (liver function, hematology, and renal function) was collected at all visits except week 1. A sputum sample was collected and stored at study entry. Phone contact was conducted at weeks 60, 72, 84 and 96 to obtain information about vital status, reportable hospitalization, TB status (including screening and follow-up), TB and HIV treatment modifications, and quality of life.
Type d'étude
Inscription (Réel)
Phase
- Phase 4
Contacts et emplacements
Lieux d'étude
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Johannesburg, Afrique du Sud
- Soweto ACTG CRS (12301)
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Gauteng
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Johannesburg, Gauteng, Afrique du Sud
- Wits HIV CRS
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KwaZulu-Natal
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Durban, KwaZulu-Natal, Afrique du Sud, 4011
- CAPRISA eThekwini CRS
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Durban, KwaZulu-Natal, Afrique du Sud
- Durban Adult HIV CRS
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Rio de Janeiro,, Brésil, 21045-900
- Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
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Port Au Prince, Haïti
- GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
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Port-au-Prince, Haïti, 6110
- Les Centres GHESKIO CRS
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Chennai
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Rajiv Gandhi Salai Taramani, Chennai, Inde, 600113
- YRG CARE Medical Ctr., VHS Chennai CRS
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Maharashtra
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Pune, Maharashtra, Inde, 411001
- BJ Medical College CRS
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Eldoret, Kenya, 30100
- AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS
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Kericho, Kenya, 20200
- Walter Reed Project - Kenya Med. Research Institute Kericho CRS
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Blantyre, Malawi
- College of Med. JHU CRS (30301)
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Lilongwe, Malawi
- University of North Carolina Lilongwe CRS (12001)
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Kampala, Ouganda
- Joint Clinical Research Centre (JCRC) (12401)
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Lima, Pérou, 18 PE
- Barranco CRS (11301)
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Lima
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San Miguel, Lima, Pérou
- San Miguel CRS
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Lusaka, Zambie
- Kalingalinga Clinic CRS (12801)
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Harare
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AIDS Research Unit P.O. Box A178, Harare, Zimbabwe
- UZ-Parirenyatwa CRS
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
- HIV-1 infection
- Willingness to start efavirenz-based ART as soon as possible and within no more than 3 days following randomization.
- CD4+ cell count <50 cells/mm^3 obtained within 45 days prior to study entry
- Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT), and total bilirubin ≤ 2.5 X ULN within 30 days prior to study entry.
- Creatinine clearance ≥30 mL/min either measured or estimated using values obtained within 30 days prior to study entry.
- Results from a hepatitis B surface antigen test performed within 30 days prior to study entry.
- Agreement not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).
- Female candidates of reproductive potential must have a negative serum or urine (15-25 mIU/mL) pregnancy test result within 7 days prior to study entry.
- Female candidates of reproductive potential who are participating in sexual activity that could lead to pregnancy must use two reliable methods of contraception while on study.
- Karnofsky performance score >/= 30 at time of study entry.
- Ability to swallow medications.
- Ability and willingness of participant or legal guardian/representative to provide informed consent.
- Intention to remain in the same general geographic region for the duration of study participation.
Exclusion Criteria:
- Presence of any confirmed or probable TB based on criteria listed in the current ACTG diagnosis appendix within 30 days prior to study entry and following completion of study-specific screening algorithm.
- Use of single-dose NVP for prevention of mother-to-child transmission (pMTCT) within 24 months prior to study entry.
- Use of prohibited medications within 30 days prior to study entry.
- Known allergy/sensitivity or any hypersensitivity to components of study-required ART or TB treatment.
- Current receipt of treatment for active TB or receipt of >14 days cumulative treatment for active TB within 96 weeks prior to study entry.
- Receipt of >30 days cumulative of INH prophylaxis within 48 weeks prior to study entry.
- Receipt at any time prior to study entry of >7 days cumulative treatment with any ARV or combination of ARVs (except for ARVs taken for any length of time during pregnancy for pMTCT, or ARVs taken for occupational exposure).
- Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- Current Grade ≥2 neuropathy.
- History of multi-drug-resistant (MDR) TB.
- Within 12 weeks prior to entry, exposure to a household member or co-worker with known MDR TB.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Expérimental: Arm A: Empiric
Study treatment for Arm A participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral treatment as soon as possible following randomization and within no more than 3 days following randomization plus a 4-drug anti-tuberculosis treatment (ATT) regimen (defined as rifampin/isoniazid/ethambutol/pyrazinamide) as soon as possible following randomization and within no more than 7 days following initiation of antiretroviral therapy.
After 2 months (or 8 weeks), the 4-drug ATT will be followed with 4 months (or 16 weeks) of 2-drug ATT (defined as rifampin/isoniazid).
All participants will be followed through week 96.
Drug provision by or through the study will be through week 48 only
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Patients are administered one tablet of Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF, Atripla) to taken be taken orally once daily at bedtime without food.
Participants will take one 600 mg tablet administered orally once daily without food.
Autres noms:
Participants will take one tablet of Emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (FTC/TDF, Truvada) administered orally once daily with or without food.
Participants will be administered Rifampin/isoniazid/pyrazinamide/ethambutol FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 of the protocol, for the first 8 weeks.
Participants will be administered rifampin/isoniazid FDC tablets orally, once daily; dose by weight as determined in Table 5.1-1 in the protocol, for 16 weeks following the first 8 weeks.
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Expérimental: Arm B: IPT
Study treatment for Arm B participants is the strategy of initiating study-provided or other FDA-approved or tentatively approved antiretroviral therapy as soon as possible following randomization and within no more than 3 days following randomization and of initiating anti-TB treatment (ATT) only when indicated according to local standard practice and at the discretion of the site investigator.
All participants will be followed through week 96.
Drug provision by or through the study will be through week 48 only.
Pyridoxine is provided by the sites to all participants while they are receiving isoniazid (INH).
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Patients are administered one tablet of Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (EFV/FTC/TDF, Atripla) to taken be taken orally once daily at bedtime without food.
Participants will take one 600 mg tablet administered orally once daily without food.
Autres noms:
Participants will take one tablet of Emtricitabine 200mg/tenofovir disoproxil fumarate 300mg (FTC/TDF, Truvada) administered orally once daily with or without food.
INH 300 mg orally once daily
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
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Cumulative Probability of Death or Unknown Vital Status by Week 24
Délai: From study entry to week 24
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The Kaplan-Meier estimate of the cumulative probability of death or unknown vital status by week 24. The vital status was considered unknown at week 24 if a participant prematurely discontinued from the study before week 24 and no vital status was obtained at week 48. |
From study entry to week 24
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
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Cumulative Probability of Death by Week 24
Délai: From study entry to week 24
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The Kaplan-Meier estimate of cumulative probability of death by week 24
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From study entry to week 24
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Cumulative Probability of First AIDS Progression by Week 96
Délai: From study entry to week 96
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The Kaplan-Meier estimate of the cumulative probability of first AIDS progression which was defined as the identification of a new World Health Organization (WHO) stage 3 or 4 condition
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From study entry to week 96
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Cumulative Probability of Death or AIDS Progression by Week 24
Délai: From study entry to week 24
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The Kaplan-Meier estimate of the cumulative probability of death or AIDS progression by week 24.
AIDS progression was defined as new WHO stage 3 or 4 conditions occurred after study entry.
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From study entry to week 24
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Proportion of Participants With HIV-1 RNA Level <400 Copies/mL
Délai: At weeks 0, 4, 24, and 48
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Proportion of participants with HIV-1 RNA level <400 copies/mL.
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At weeks 0, 4, 24, and 48
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CD4+ T-cell Count
Délai: At weeks 0, 4, 24, and 48
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The absolute levels of CD4+ T-cell counts (cells/mm^3)
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At weeks 0, 4, 24, and 48
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CD4+ T-cell Count Change From Baseline
Délai: Weeks 0, 4, 24 and 48
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Change was calculated as the CD4+ T-cell count at the later weeks (4, 24 and 48) minus the baseline (week 0) CD4+ T-cell count.
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Weeks 0, 4, 24 and 48
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Time to Initiation of TB Treatment by Week 96
Délai: From study entry to week 96
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Median time to TB treatment initiation since study entry
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From study entry to week 96
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Proportion of Participants With TB Diagnosis by Week 96
Délai: From study entry to week 96
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Proportion of participants with TB diagnosis per current ACTG Diagnosis Appendix 60 by week 96
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From study entry to week 96
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Proportion of Participants With at Least One New Grade 3 or 4 Adverse Event That is at Least a One-grade Increase From Baseline by Week 48
Délai: From study entry to week 48
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Proportion of participants with at least one new Grade 3 or 4 laboratory or sign or symptom that is at least a one-grade increase from baseline by Week 48.
Grade 3=Severe, Grade 4=Life-Threatening according to DAIDS AE Grading Table (see references).
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From study entry to week 48
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Proportion of Participants With at Least One New Grade 3 or 4 Targeted Laboratory Value That is at Least a One-grade Increase From Baseline by Week 48
Délai: From study entry to week 48. The lab events were collected at study entry, weeks 2, 4, 8, 12, 16, 20, 24, and 48.
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Proportion of participants with at least one new Grade 3 or 4 that is at least a one-grade increase from baseline for the following targeted laboratory values by Week 48 The targeted laboratory events include hemoglobin, serum creatinine, ALT and AST |
From study entry to week 48. The lab events were collected at study entry, weeks 2, 4, 8, 12, 16, 20, 24, and 48.
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Proportion of Participants With Immune Reconstitution Inflammatory Syndrome (IRIS) by Week 48
Délai: From study entry to week 48
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Proportion of participants with IRIS (using current ACTG definition Appendix 60, see References) by Week 48.
IRIS in participants with TB and other opportunistic infections may occur shortly after the initiation of potent combination ART, particularly in participants with advanced HIV disease.
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From study entry to week 48
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Proportion of Participants With Reportable Hospitalization by Week 48
Délai: From study entry to week 48
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Proportion of participants with reportable hospitalization reported by Week 48
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From study entry to week 48
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Proportion of Participants Who Prematurely Discontinued Any Component of TB Treatment by Week 48
Délai: From study entry to week 48
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Proportion of participants with premature discontinuation of any component of TB treatment by Week 48
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From study entry to week 48
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Proportion of Participants Who Prematurely Discontinued Antiretroviral Therapy by Week 48
Délai: From study entry to week 48
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Proportion of participants with premature discontinuation of antiretroviral therapy (ART) by Week 48
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From study entry to week 48
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Cumulative Probability of Death or AIDS Progression by Week 48
Délai: From study entry to week 48
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The Kaplan-Meier estimate of the cumulative probability of death or AIDS progression by week 48.
AIDS progression was defined as new WHO stage 3 or 4 conditions occurred after study entry.
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From study entry to week 48
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chaise d'étude: Mina C Hosseinipour, MD, University of North Carolina Lilongwe CRS
- Chaise d'étude: Johnstone Kumwenda, MBChB, FRCP, College of Med. JHU CRS
Publications et liens utiles
Publications générales
- M. Hosseinipour, G. Bisson, S., et al. Empiric TB therapy does not decrease early mortality compared to Isoniazid Preventive therapy in adults with advanced HIV initiating ART: Results of ACTG A5274 (REMEMBER study). Program and abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and prevention; July 19-22, 2015; Vancouver, Canada. Abstract A-729-0105-03495
- Johnstone Kumwenda, Amita Gupta, et al. Empiric TB therapy versus IPT in HIV-infected persons initiating ART (ACTG A5274 48 week results). Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 16-1383
- Gregory P. Bisson, Amita Gupta, et al. Urine LAM Testing in Advanced HIV-Infected Adults in a Trial of Empiric TB Therapy. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, Massachusetts. Abstract 16-1650
- Manabe YC, Andrade BB, Gupte N, Leong S, Kintali M, Matoga M, Riviere C, Samaneka W, Lama JR, Naidoo K, Zhao Y, Johnson WE, Ellner JJ, Hosseinipour MC, Bisson GP, Salgame P, Gupta A. A Parsimonious Host Inflammatory Biomarker Signature Predicts Incident Tuberculosis and Mortality in Advanced Human Immunodeficiency Virus. Clin Infect Dis. 2020 Dec 17;71(10):2645-2654. doi: 10.1093/cid/ciz1147.
- Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A; Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team. Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Estimation)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
- Infections
- Infections bactériennes
- Infections bactériennes et mycoses
- Infections bactériennes à Gram positif
- Infections à Actinomycétales
- Infections à mycobactéries
- Tuberculose
- Mécanismes moléculaires de l'action pharmacologique
- Agents anti-infectieux
- Agents antiviraux
- Inhibiteurs de la transcriptase inverse
- Inhibiteurs de la synthèse des acides nucléiques
- Inhibiteurs d'enzymes
- Agents anti-VIH
- Agents antirétroviraux
- Antimétabolites
- Agents hypolipidémiants
- Agents de régulation des lipides
- Agents antibactériens
- Inhibiteurs des enzymes du cytochrome P-450
- Agents léprostatiques
- Inducteurs enzymatiques du cytochrome P-450
- Inducteurs du cytochrome P-450 CYP3A
- Agents antituberculeux
- Antibiotiques, Antituberculeux
- Inducteurs du cytochrome P-450 CYP2B6
- Inducteurs du cytochrome P-450 CYP2C8
- Inducteurs du cytochrome P-450 CYP2C19
- Inducteurs du cytochrome P-450 CYP2C9
- Inhibiteurs du cytochrome P-450 CYP2C9
- Inhibiteurs du cytochrome P-450 CYP2C19
- Inhibiteurs de la synthèse des acides gras
- Rifampine
- Emtricitabine, combinaison médicamenteuse de fumarate de ténofovir disoproxil
- Éfavirenz
- Isoniazide
- Pyrazinamide
- Éthambutol
- Efavirenz, emtricitabine, combinaison de médicaments fumarate de ténofovir disoproxil
- Association médicamenteuse isoniazide, pyrazinamide, rifampicine
Autres numéros d'identification d'étude
- ACTG A5274
- 1U01AI068636 (Subvention/contrat des NIH des États-Unis)
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .
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