Cotrimoxazole Prophylaxis Cessation Study Among Stabilized HIV-Infected Adult Patients on HAART in Entebbe, Uganda

NCT ID: NCT00674921

Last Updated: 2008-06-05

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

1650 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-06-30

Study Completion Date

2011-06-30

Brief Summary

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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?

Detailed Description

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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.

Conditions

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HIV Infections

Keywords

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Opportunistic Infections AIDS HIV Treatment Experienced

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

starch, magnesium stearate, sodium lauryl sulphate

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.

Group Type ACTIVE_COMPARATOR

cotrimoxazole

Intervention Type DRUG

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

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

starch, magnesium stearate, sodium lauryl sulphate

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.

Group Type ACTIVE_COMPARATOR

cotrimoxazole

Intervention Type DRUG

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

Interventions

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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

Intervention Type DRUG

Placebo

starch, magnesium stearate, sodium lauryl sulphate

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

16 Years

Maximum Eligible Age

59 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Medical Research Council

OTHER_GOV

Sponsor Role collaborator

MRC/UVRI and LSHTM Uganda Research Unit

OTHER

Sponsor Role lead

Responsible Party

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MRC/UVRI Uganda Research Unit on Aids

Principal Investigators

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George Miiro, MSc, MBChB

Role: PRINCIPAL_INVESTIGATOR

MRC/UVRI Unit

Heiner Grosskurth, PhD, MD

Role: STUDY_DIRECTOR

MRC/UVRI Unit

Paula Munderi, MRCP, MBChB

Role: PRINCIPAL_INVESTIGATOR

MRC/UVRI Unit

Locations

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MRC/UVRI Uganda Research Unit on Aids

Entebbe, , Uganda

Site Status

Countries

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Uganda

Central Contacts

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George Mukalazi Miiro, MSc, MBChB

Role: CONTACT

Phone: 256-414-320-272

Email: [email protected]

Heiner Grosskurth, PhD, MD

Role: CONTACT

Phone: 256-414-320-272

Email: [email protected]

References

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Zellweger C, Opravil M, Bernasconi E, Cavassini M, Bucher HC, Schiffer V, Wagels T, Flepp M, Rickenbach M, Furrer H; Swiss HIV Cohort Study. Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study. AIDS. 2004 Oct 21;18(15):2047-53. doi: 10.1097/00002030-200410210-00009.

Reference Type RESULT
PMID: 15577626 (View on PubMed)

Mussini C, Pezzotti P, Antinori A, Borghi V, Monforte Ad, Govoni A, De Luca A, Ammassari A, Mongiardo N, Cerri MC, Bedini A, Beltrami C, Ursitti MA, Bini T, Cossarizza A, Esposito R; Changes in Opportunistic Prophylaxis (CIOP) Study Group. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis. 2003 Mar 1;36(5):645-51. doi: 10.1086/367659. Epub 2003 Feb 12.

Reference Type RESULT
PMID: 12594647 (View on PubMed)

Ledergerber B, Mocroft A, Reiss P, Furrer H, Kirk O, Bickel M, Uberti-Foppa C, Pradier C, D'Arminio Monforte A, Schneider MM, Lundgren JD; Eight European Study Groups. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med. 2001 Jan 18;344(3):168-74. doi: 10.1056/NEJM200101183440302.

Reference Type RESULT
PMID: 11188837 (View on PubMed)

Esposito S, Bojanin J, Porta A, Cesati L, Gualtieri L, Principi N. Discontinuation of secondary prophylaxis for Pneumocystis pneumonia in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J. 2005 Dec;24(12):1117-20. doi: 10.1097/01.inf.0000190038.53813.d2.

Reference Type RESULT
PMID: 16371882 (View on PubMed)

Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, Podzamczer D, Alberdi JC, Martinez E, Cosin J, Claramonte X, Gonzalez J, Domingo P, Casado JL, Ribera E; Grupo de Estudio del SIDA 04/98. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med. 2001 Jan 18;344(3):159-67. doi: 10.1056/NEJM200101183440301.

Reference Type RESULT
PMID: 11172138 (View on PubMed)

Furrer H, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, Telenti A, Vernazza PL, Rickenbach M, Flepp M, Malinverni R. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med. 1999 Apr 29;340(17):1301-6. doi: 10.1056/NEJM199904293401701.

Reference Type RESULT
PMID: 10219064 (View on PubMed)

Weverling GJ, Mocroft A, Ledergerber B, Kirk O, Gonzales-Lahoz J, d'Arminio Monforte A, Proenca R, Phillips AN, Lundgren JD, Reiss P. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group. Lancet. 1999 Apr 17;353(9161):1293-8. doi: 10.1016/s0140-6736(99)03287-0.

Reference Type RESULT
PMID: 10218526 (View on PubMed)

Other Identifiers

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009/ESR/NDA/DID-01/2008

Identifier Type: -

Identifier Source: org_study_id