Contact information
Type
Scientific
Contact name
Prof Janet Darbyshire
ORCID ID
Contact details
MRC Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom
+44 (0)20 7670 4780
dart@ctu.mrc.ac.uk
Additional identifiers
EudraCT/CTIS number
IRAS number
ClinicalTrials.gov number
Protocol/serial number
G0000068
Study information
Scientific 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
Acronym
DART
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.
Ethics approval(s)
Protocol approved in Uganda, Zimbabwe and United Kingdom
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Study setting(s)
Not specified
Study type
Treatment
Patient information sheet
Patient information can be found at: http://www.ctu.mrc.ac.uk/dart/faq.asp
Condition
Human Immunodeficiency Virus (HIV), Acquired Immunodeficiency Syndrome (AIDS)
Intervention
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.
Intervention type
Drug
Pharmaceutical study type(s)
Phase
Not Applicable
Drug/device/biological/vaccine name(s)
Primary outcome measure
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 measures
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)
Overall study start date
15/01/2003
Overall study end date
31/12/2007
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type(s)
Patient
Age group
Adult
Lower age limit
18 Years
Sex
Both
Target number of participants
3300
Participant 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 breastfeeding
Recruitment start date
15/01/2003
Recruitment end date
28/10/2004
Locations
Countries of recruitment
England, Uganda, United Kingdom, Zimbabwe
Study participating centre
MRC Clinical Trials Unit
London
NW1 2DA
United Kingdom
Sponsor information
Organisation
Medical Research Council (MRC) (UK)
Sponsor details
Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom
Sponsor type
Research council
Website
ROR
Funders
Funder type
Government
Funder name
Medical Research Council (UK)
Alternative name(s)
UK Medical Research Council, MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Department for International Development
Alternative name(s)
Department for International Development, UK, DFID
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
United Kingdom
Funder name
Rockefeller Foundation (USA)
Alternative name(s)
The Rockefeller Foundation, Rockefeller Fdn, RF
Funding Body Type
private sector organisation
Funding Body Subtype
Trusts, charities, foundations (both public and private)
Location
United States of America
Funder name
Antiretroviral drugs donated by Gilead (USA), GlaxoSmithKline (UK), Boehringer-Ingelheim (Germany)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Individual participant data (IPD) sharing plan
IPD sharing plan summary
Not provided at time of registration
Study outputs
Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
---|---|---|---|---|---|
Other publications | publication on prevalence, incidence and predictors of severe anaemia | 01/06/2006 | Yes | No | |
Other publications | publication on virological response | 26/06/2006 | Yes | No | |
Results article | results of pharmacokinetic sub-study | 30/03/2007 | Yes | No | |
Results article | results on interupted versus continous therapy | 11/01/2008 | Yes | No | |
Results article | results on demographics of poor adherence | 01/08/2008 | Yes | No | |
Results article | results on routine versus laboratory monitoring | 09/01/2010 | Yes | No | |
Results article | results of observational analysis | 10/04/2010 | Yes | No | |
Other publications | cost -effectiveness of routine versus laboratory monitoring | 01/04/2012 | Yes | No | |
Results article | results on pregnancy and infant outcomes | 01/04/2012 | Yes | No | |
Results article | secondary analysis results | 02/10/2013 | Yes | No | |
Results article | retrospective analysis results | 13/03/2014 | Yes | No | |
Results article | retrospective analysis results | 21/02/2017 | Yes | No |