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| Development of AntiRetroviral Therapy in Africa - A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa |
| ISRCTN | ISRCTN13968779 |
| DOI | 10.1186/ISRCTN13968779 |
| ClinicalTrials.gov identifier | |
| EudraCT number | |
| Public title | Development of AntiRetroviral Therapy in Africa - A randomised trial of monitoring practice and structured treatment interruptions in the management of antiretroviral therapy in adults with HIV infection in Africa |
| Scientific title | |
| Acronym | DART |
| Serial number at source | G0000068 |
| Study hypothesis |
To compare, in terms of clinical HIV disease progression or death:
1. Clinical monitoring only (CMO) versus routine regular laboratory and clinical monitoring (LCM) 2. Structured Treatment Interruptions (STIs: 12 weeks on, 12 weeks off therapy) versus continuous ART, initiated if the CD4 count has increased to 200 cells/mm3 or above (after 24 or 48 weeks on ART) [updated June 2006 from 300 cells/mm3 or above (after 48 or 72 weeks on ART)] The hypothesis is that CMO will result in similar outcomes to LCM, and that ART administered as pulse therapy (STI) will result in similar outcomes to continuous ART, in terms of progression of clinical HIV disease or death. STI Pilot Study Objectives: The initial non-randomised pilot study of STIs will inform on the safety of the 12 weeks on, 12 weeks off STI strategy and only after the completion of this substudy will the second randomisation commence. Abacavir Safety Substudy Nevirapine OR Abacavir (NORA) Substudy Objectives: This randomised sub-study of 600 patients will address issues of safe administration of Abacavir in resource poor settings and will compare the safety of Abacavir with that of Nevirapine when used in combination with Combivir. |
| Lay summary | http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=12 |
| Ethics approval | Protocol approved in Uganda, Zimbabwe and United Kingdom |
| Study design | Randomised controlled trial |
| Countries of recruitment | Uganda, Zimbabwe |
| Disease/condition/study domain | Human Immunodeficiency Virus (HIV), Acquired Immunodeficiency Syndrome (AIDS) |
| Participants - inclusion criteria |
1. Documentation of HIV-1 infection: antibody positive serology by enzyme-linked immunosorbent
assay (ELISA) test (confirmed by licensed second ELISA or Western Blot) 2. Age ≥18 years 3. Symptomatic WHO stage 2, 3 or 4 HIV disease and CD4 <200 cells/mm3 4. ART naïve (except for ART use during pregnancy for the prevention of mother-to-child HIV transmission) 5. Agreement and documented informed consent to be randomised to CMO or LCM and to STI or continuous ART, if eligible 6. Life expectancy of at least 3 months |
| Participants - exclusion criteria |
1. Cannot or unlikely to attend regularly (e.g. usual residence too far from Study Centre)
2. Likelihood of poor compliance 3. Presence of acute infection (e.g. malaria, acute hepatitis, pneumococcal pneumonia, non-typhoid salmonella septicaemia, cryptococcal meningitis). Patients may be admitted after recovery of an acute infection. Patients with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART. Patients starting ART whilst on anti-tuberculosis therapy after the intensive phase will not receive NVP, nor will they be randomised into the NORA substudy. 4. On chemotherapy for malignancy 5. Laboratory abnormalities which are a contraindication for the patient to start ART (e.g. haemoglobin <8 g/dl, total white blood cell count [WBC] <0.75 x 10^9/l, aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >5 x the upper limit of normal [ULN], grade 3 renal dysfunction - creatinine >360 µmol/l and/or urea >5 x ULN) 6. Pregnancy or breast-feeding |
| Anticipated start date | 15/01/2003 |
| Anticipated end date | 31/12/2007 |
| Status of trial | Completed |
| Patient information material | Patient information can be found at: http://www.ctu.mrc.ac.uk/dart/faq.asp |
| Target number of participants | 3300 (recruitment completed 28 October 2004) |
| Interventions |
Randomisation to Clinical Monitoring Only (CMO) or Laboratory and Clinical Monitoring (LCM):
3300 patients will be randomised to CMO or LCM over a period of 1-2 years. Randomisation will be stratified by CD4 count (0-99, 100-199) clinical site and by third drug (Tenofovir DF, Nevirapine or NORA substudy). Structured Treatment Interruptions (STI): Because there were no data on STI in the African setting, where patients are likely to have low CD4 cell counts before starting ART, a non-randomised pilot study of the first 100 patients eligible for the STI randomisation was undertaken. Following the successful completion of this pilot a randomisation to STI or continuous antiretroviral therapy (ART) was opened to patients when they reached 52 or 76 weeks of DART if they had a CD4 count of ≥300 at week 48 or 72. NORA substudy: A randomised, double-blind, phase II (substudy) trial to evaluate the toxicity of Abacavir compared with Nevirapine, both in combination with Ziduvudine + Lamivudine (Combivir), as first-line antiretroviral therapy in patients participating in the DART trial. |
| Primary outcome measure(s) |
1. Efficacy: Progression to a new WHO stage 4 HIV event or death
2. Safety: Any serious adverse event, which is not HIV related |
| Secondary outcome measure(s) |
1. Progression to a new or recurrent WHO stage 4 HIV event or death
2. Progression to a new WHO stage 4 HIV event or death from 6 weeks after randomisation 3. Progression to a new or recurrent WHO stage 4 HIV event or death from 6 weeks after randomisation 4. Any grade 3 or 4 adverse events 5. Number and class of anti-HIV drugs received by 3 years 6. Time to cessation of first-line regimen for failure 7. Adherence as measured by questionnaire and pill counts 8. CD4 count at 3 years (provided that it is at least 2 months after restarting ART for those in the STI group) 9. HIV RNA viral load (performed retrospectively) at 3 years (providing that it is at least 2 months after restarting ART for those in the STI group) 10. HIV resistance profiles at 3 years in those with detectable viral load (providing that it is at least 2 months after restarting ART for those in the STI group) |
| Sources of funding |
1. Medical Research Council (UK)
2. UK Department for International Development (DFID) 3. Rockefeller Foundation (USA) 5. Antiretroviral drugs donated by Gilead (USA), GlaxoSmithKline (UK), Boehringer-Ingelheim (Germany) |
| Trial website | http://www.ctu.mrc.ac.uk/dart |
| Publications |
1. 2006 publication on virological response in http://www.ncbi.nlm.nih.gov/pubmed/16791013
2. 2006 publication on prevalence, incidence and predictors of severe anaemia in http://www.ncbi.nlm.nih.gov/pubmed/17310818 3. 2007 results of pharmacokinetic sub-study in http://www.ncbi.nlm.nih.gov/pubmed/17413694 4. 2008 results on interupted versus continous therapy in http://www.ncbi.nlm.nih.gov/pubmed/18097226 5. 2008 results on demographics of poor adherence in http://www.ncbi.nlm.nih.gov/pubmed/18614918 6. 2009 results on routine versus laboratory monitoring in http://www.ncbi.nlm.nih.gov/pubmed/20004464 7. 2010 results of observational analysis in http://www.ncbi.nlm.nih.gov/pubmed/20347483 8. 2012 cost -effectiveness of routine versus laboratory monitoring in http://www.ncbi.nlm.nih.gov/pubmed/22545079 9. 2012 results on pregnancy and infant outcomes in http://www.ncbi.nlm.nih.gov/pubmed/22615543 |
| Contact name | Prof Janet Darbyshire |
| Address |
MRC Clinical Trials Unit
222 Euston Road |
| City/town | London |
| Zip/Postcode | NW1 2DA |
| Country | United Kingdom |
| Tel | +44 (0)20 7670 4780 |
| Fax | +44 (0)20 7670 4814 |
| dart@ctu.mrc.ac.uk | |
| Sponsor | Medical Research Council (MRC) (UK) |
| Address |
Clinical Trials Unit
222 Euston Road |
| City/town | London |
| Zip/Postcode | NW1 2DA |
| Country | United Kingdom |
| Sponsor website: | http://www.ctu.mrc.ac.uk/ |
| Date applied | 18/10/2000 |
| Last edited | 05/09/2012 |
| Date ISRCTN assigned | 18/10/2000 |
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| © 2013 ISRCTN unless otherwise stated. | |
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