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

Plain English Summary

http://www.ctu.mrc.ac.uk/research_areas/study_details.aspx?s=12

Study website

http://www.ctu.mrc.ac.uk/dart

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

EudraCT/CTIS number

IRAS number

ClinicalTrials.gov number

Protocol/serial number

G0000068

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)

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

Countries of recruitment

England, Uganda, United Kingdom, Zimbabwe

Study participating centre

MRC Clinical Trials Unit
London
NW1 2DA
United Kingdom

Organisation

Medical Research Council (MRC) (UK)

Sponsor details

Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom

Sponsor type

Research council

Website

http://www.ctu.mrc.ac.uk/

ROR

https://ror.org/03x94j517

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

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