Official Title: “Cotrimoxazole Prophylaxis Cessation Study Among Stabilized HIV-Infected Adult Patients on HAART in Entebbe, Uganda”

According to the national guidelines in Uganda and to the World Health Organization guidelines, HIV-infected patients should receive cotrimoxazole prophylaxis indefinitely.

There are, however, concerns regarding the indefinite application of cotrimoxazole prophylaxis among patients immunologically stabilized on HAART (e.g. high pill burden, drug-drug interactions, toxicity and poor adherence because of treatment fatigue). To date no empirical evidence is available regarding the safety and optimal timing for the cessation of cotrimoxazole prophylaxis among HAART patients who successfully restored immunological competence.

Research question: Does morbidity significantly differ between continuation (orthodox) and cessation (experimental) of cotrimoxazole prophylaxis among immuno-competent patients stable HAART in the resource-limited setting of Uganda?

Study Type: Interventional

Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Factorial Assignment, Efficacy Study

Study Primary Completion Date: June 2011

Randomized double-blind placebo controlled equivalence trial to be conducted among consenting clinically healthy patients on HAART with 2 or more CD4 counts of 200 cells/ul or more for at least 3 months. The study will enable comparison of effects of randomized cessation of cotrimoxazole prophylaxis at 2 CD4-guided thresholds (200 Vs 350 cells/ul).

Rationale for inclusion of the placebo-controlled design - The double-blind placebo controlled approach is feasible and ethically justified in this equipoise situation to allow for concealment of allocated intervention among investigators and patients and avoids accidental unblinding of investigators to the allocated interventions by trial patients. - Maintenance of continued cotrimoxazole prophylaxis among patients randomized to this intervention will be easier if there is no awareness that those patients randomized to cessation of prophylaxis have a relative advantage of reduced pill burden. - It would be very difficult to maintain cessation of cotrimoxazole prophylaxis among patients randomized to do so in our setting where cotrimoxazole is readily and cheaply available in drug shops, drug stores and pharmacies.

First randomisation

Patients who have been on HAART for at least 3 months and who have a confirmed CD4 count between 200 and 349 cells/ul will be randomized to continue prophylaxis with active cotrimoxazole or to cease prophylaxis with active cotrimoxazole but continue with ingestion of the placebo cotrimoxazole daily.

Second randomization

Patients who achieve a confirmed CD4 count of 350 cells/ul or more while on HAART will be randomized to continue prophylaxis with active cotrimoxazole or to cease prophylaxis with active cotrimoxazole but continue with ingestion of placebo cotrimoxazole daily. Some patients will have participated already in 1st randomization but others will be entering the trial at this stage for the first time.

Rationale for 4 trial arms

In order to assess the separate effects of cessation of cotrimoxazole prophylaxis in trial patients at the 2 randomization stages above, those continuing with prophylaxis will be compared with those ceasing prophylaxis, necessitating 2 arms at each stage.

Intervention(s) in this Clinical Trial

• Drug: cotrimoxazole
  • cotrimoxazole 800/160 mg once daily as indicated by the start and end times of the specified arms for continued prevention of HIV-related infections
• Drug: Placebo
  • starch, magnesium stearate, sodium lauryl sulphate

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
  • It will comprise patients randomized to receive the placebo (stop cotrimoxazole prophylaxis) at CD4 counts of 200 or more but less than 350 cells/ul as they continue with HAART. Patients will be followed until they achieve a CD4 count of 350 cells/ul.
• Active Comparator: 2
  • It will comprise patients randomized to continue with cotrimoxazole prophylaxis and HAART at CD4 counts of 200 or more but less than 350 cells/ul. These patients will be followed until they achieve a CD4 count of 350 cells/ul and above, at which point they will be considered for the second randomization.
• Placebo Comparator: A
  • This arm will comprise patients who have achieved a CD4 count of 350 or more cells/ul either at the beginning of the study or once they have reached this threshold at the end of follow up in arms 1 and 2. They (including those previously in Arm 1) will receive the placebo (stop cotrimoxazole prophylaxis) after the second randomization but continue with HAART.
• Active Comparator: B
  • It will comprise patients randomized to continue or start with cotrimoxazole prophylaxis and HAART at CD4 of 350 or more cells/ul after second randomization. Some of them will have used cotrimoxazole prophylaxis whilst they were in arm 2 and others in arm 1 will restart cotrimoxazole prophylaxis at this stage.

Primary Measures

• all-cause morbidity such as pneumonia or malaria (presumptive and definitive diagnosis)
  • Time Frame: 3 years
    Safety Issue?: Yes

Secondary Measures

• sub-clinical laboratory abnormalities (such as neutropenia) and serious adverse events (such as death)
  • Time Frame: 3 years
    Safety Issue?: Yes

Inclusion Criteria:

• Consenting HIV-infected patient aged 16 years or older,
• Resident within 40 kms of study clinics
• Regularly attending clinics
• Documented HAART intake for at least 3 months
• Clinically healthy and stable
• Confirmed CD4 count of 200 cells/ul more.

Exclusion Criteria:

• Acutely ill patients with opportunistic or other infections
• Patients already enrolled in other HAART trials (e.g DART trial)
• First trimester pregnancy at enrolment
• Clinical and immunological evidence of HAART treatment failure
• Unable to attend study clinics regularly
• Hypersensitivity to cotrimoxazole

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: 59 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: MRC/UVRI Uganda Research Unit on Aids

Overall Clinical Trial Officials and Contacts

George Miiro, MSc, MBChB Principal Investigator MRC/UVRI Unit  

Overall Contact: George Mukalazi Miiro, MSc, MBChB 256-414-320-272 george.miiro@mrcuganda.org

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00674921

Study ID Number: 009/ESR/NDA/DID-01/2008

ClinicalTrials.gov Identifier: NCT00674921

Health Authority: Uganda: National Council for Science and Technology