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Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis (Crypto)

Primary Purpose

Cryptococcal Meningitis, HIV Infections

Status

Completed

Phase

Phase 4

Locations

Botswana

Study Type

Interventional

Intervention

Early antiretroviral therapy

About this trial

This is an interventional treatment trial for Cryptococcal Meningitis focused on measuring HIV-1, Africa, Botswana, Highly active antiretroviral therapy, treatment naive

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

HIV 1 infection confirmed by licensed ELISA kit and/or detectable Viral load.
Confirmed Cryptococcal meningitis on the current admission by India ink or CSF cryptococcal antigen
ART naive at the time of enrollment
21 years old and above
Ability and willingness to give written informed consent to participate in the study
Able (as assessed by the patient's medical team)to initiate amphotericin B for cryptococcal meningitis
Initiated amphotericin B 72 hours or less prior to assessment for enrollment or not on amphotericin B at the time of assessment for enrollment
Agrees to obtain outpatient care after discharge within 50 kilometers from Princess Marina Hospital,Scottish Livingstone Hospital and Bamalete Lutheran Hospital

Exclusion Criteria:

Recent (within the past 4 weeks) antifungal use
Pregnant or breastfeeding
Initiated anti-tubercular therapy 2 weeks or less prior to assessment for enrollment.
Bacterial meningitis at the time of assessment for enrollment.
Recent (within the past 1 month) use of the following:systemic cancer chemotherapy,oral or intravenous corticosteroids or other immunomodulators.
Judged by study coordinator to be likely to initiate chemotherapy or any other immunomodulatory therapy prior to the 4 week LP.
Imprisoned.

Sites / Locations

Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Early antiretroviral therapy

Standard antiretroviral therapy

Arm Description

Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrollment.

Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrollment.

Outcomes

Primary Outcome Measures

Change in the CSF CFUs between the immediate and standard ART initiation groups

Secondary Outcome Measures

Grade 3 or 4 adverse events

each participant is followed up for 6 months after the initiation of HAART

Clearance of C. neoformans antigen from CSF and blood.

Change in the number of peripheral blood mononuclear cells responding to C. neoformans

Full Information

NCT ID

NCT00976040

First Posted

September 11, 2009

Last Updated

February 3, 2012

Sponsor

Botswana-UPenn Partnership

Collaborators

Doris Duke Charitable Foundation, University of Pennsylvania

1. Study Identification

Unique Protocol Identification Number

NCT00976040

Brief Title

Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis

Acronym

Crypto

Official Title

A Randomized Clinical Trial of Immediate Versus Standard Antiretroviral Therapy for HIV-infected Adults Presenting With Cryptococcal Meningitis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2012

Overall Recruitment Status

Completed

Study Start Date

September 2009 (undefined)

Primary Completion Date

November 2011 (Actual)

Study Completion Date

December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Botswana-UPenn Partnership

Collaborators

Doris Duke Charitable Foundation, University of Pennsylvania

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The goal of this randomized clinical trial is to compare early versus standard timing of initiation of antiretroviral therapy (ART) with respect to clearance of Cryptococcus neoformans from cerebrospinal fluid (CSF) among HIV-infected adults with Cryptococcal Meningitis. The investigators hypothesize that early ART mediates more rapid clearance of C. neoformans from CSF, as manifested by a greater rate of decrease in C. neoformans colony forming units (CFUs) during the first 28 days after initiating antifungal treatment. Secondary hypotheses are that recovery of pathogen specific cellular immunity directed at C. neoformans, as manifested by increases in the number and function of C. neoformans-specific peripheral blood mononuclear cells is associated with 1) ART and 2) pathogen clearance. In addition, patients randomized to the intervention arm will have more rapid clearance of antigen levels in CSF and serum and will have a lower incidence of grade 3 and 4 Adverse events.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cryptococcal Meningitis, HIV Infections

Keywords

HIV-1, Africa, Botswana, Highly active antiretroviral therapy, treatment naive

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

28 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Early antiretroviral therapy

Arm Type

Experimental

Arm Description

Subjects randomized to this arm will initiate antiretroviral therapy within 7 days of enrollment.

Arm Title

Standard antiretroviral therapy

Arm Type

No Intervention

Arm Description

Subjects randomized to this arm will initiate antiretroviral therapy approximately 4 weeks after enrollment.

Intervention Type

Other

Intervention Name(s)

Early antiretroviral therapy

Intervention Description

The intervention is early initiation of antiretroviral therapy after diagnosis of Cryptococcal meningitis. In the intervention/experimental arm, triple-drug highly active antiretroviral therapy regimens will be initiated within 7 days of diagnosis of Cryptococcal meningitis.

Primary Outcome Measure Information:

Title

Change in the CSF CFUs between the immediate and standard ART initiation groups

Time Frame

4 weeks

Secondary Outcome Measure Information:

Title

Grade 3 or 4 adverse events

Description

each participant is followed up for 6 months after the initiation of HAART

Time Frame

6 months

Title

Clearance of C. neoformans antigen from CSF and blood.

Time Frame

6 months

Title

Change in the number of peripheral blood mononuclear cells responding to C. neoformans

Time Frame

4 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: HIV 1 infection confirmed by licensed ELISA kit and/or detectable Viral load. Confirmed Cryptococcal meningitis on the current admission by India ink or CSF cryptococcal antigen ART naive at the time of enrollment 21 years old and above Ability and willingness to give written informed consent to participate in the study Able (as assessed by the patient's medical team)to initiate amphotericin B for cryptococcal meningitis Initiated amphotericin B 72 hours or less prior to assessment for enrollment or not on amphotericin B at the time of assessment for enrollment Agrees to obtain outpatient care after discharge within 50 kilometers from Princess Marina Hospital,Scottish Livingstone Hospital and Bamalete Lutheran Hospital Exclusion Criteria: Recent (within the past 4 weeks) antifungal use Pregnant or breastfeeding Initiated anti-tubercular therapy 2 weeks or less prior to assessment for enrollment. Bacterial meningitis at the time of assessment for enrollment. Recent (within the past 1 month) use of the following:systemic cancer chemotherapy,oral or intravenous corticosteroids or other immunomodulators. Judged by study coordinator to be likely to initiate chemotherapy or any other immunomodulatory therapy prior to the 4 week LP. Imprisoned.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Gregory P Bisson, MD,MSCE

Organizational Affiliation

Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Pablo Tebas, MD

Organizational Affiliation

Botswana-UPenn Partnership, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Official's Role

Principal Investigator

Facility Information:

Facility Name

Princess Marina Hospital,Bamalete Lutheran Hospital and Scottish Livingstone Hospital

City

Gaborone,Ramotswa,Molepolole

Country

Botswana

12. IPD Sharing Statement

Citations:

PubMed Identifier

23362285

Citation

Bisson GP, Molefi M, Bellamy S, Thakur R, Steenhoff A, Tamuhla N, Rantleru T, Tsimako I, Gluckman S, Ravimohan S, Weissman D, Tebas P. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis. 2013 Apr;56(8):1165-73. doi: 10.1093/cid/cit019. Epub 2013 Jan 29. Erratum In: Clin Infect Dis. 2013 Oct;57(7):1067.

Results Reference

derived

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Optimal Time to Start Antiretroviral Therapy in HIV-infected Adults With Cryptococcal Meningitis

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