| Protocol No: | ECCT/14/11/02 | Date of Protocol: | 29-02-2012 |
| Study Title: | An Open-Label, Proof of Concept, Randomized Trial Comparing a LPV/r-Based to an nNRTI-Based Antiretroviral Therapy Regimen for Clearance of Plasmodium falciparum Subclinical Parasitemia in HIV-infected Adults with CD4+ Counts >200 and < 500 cells/mm3 |
| Study Objectives: | |
| Laymans Summary: | |
| Abstract of Study: |
DESIGN A5297 is a phase I/II, open-label, proof of concept, two-step, two-arm, controlled randomized clinical trial (RCT) to test the superiority of lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) to non-nucleoside reverse transcriptase (nNRTI)-based ART for clearance of Plasmodium falciparum (Pf) subclinical parasitemia (SCP).
Participants will be followed for 30 days in order to evaluate parasitemia clearance, Pf parasitemia, gametocytemia, and plasmepsin sequencing. Participants will have blood collected twice at entry, day 3, 6, 9, 12, 20, and 25 and three times for day 15 and day 30. Therefore, on most study days, participants will need to either remain at the clinic for an extended period of time or be willing to return two or three times at approximately 8-hour intervals (see section 6.2 for details).
DURATION 30 days: Step 1= days 1-15; Step 2= days 16-30
SAMPLE SIZE 52 participants
POPULATION HIV infected adults at least 18 years of age with CD4+ counts >200 and < 350 cells/mm3 who will be starting ART and have Pf SCP. Individuals with signs or symptoms suggestive of concurrent opportunistic infections, pulmonary or gastrointestinal infections, or clinical malaria will be excluded.
REGIMENS Step 1
Participants will be randomized 1:1 to one of the following arms for 15 days:
Arm A: LPV/r-based ART
Arm B: nNRTI-based ART
Step 2
All participants will receive an nNRTI-based ART and TMP/SMX prophylaxis to take from day 16 through day 30.
1.0 HYPOTHESES AND STUDY OBJECTIVES
1.1 Primary Hypothesis
In HIV-infected participants with CD4+ counts >200 and <350 cells/mm3, lopinavir/ritonavir (LPV/r)-based ART will be superior to nNRTI-based ART in PCR-defined Plasmodium falciparum (Pf) subclinical parasitemia (SCP) clearance after 15 days of therapy.
1.2 Secondary Hypotheses
1.2.1 Pf parasite densities in participants with Pf SCP who have received 15 days (Step 1) of LPV/r-based ART will be lower than those receiving nNRTI-based ART.
1.2.2 Time to clearance in participants with Pf SCP will be shorter in participants who have received 15 days (Step 1) of LPV/r-based ART compared with those receiving nNRTI-based ART.
1.2.3 Participants who have cleared Pf SCP at entry to Step 2 will remain without Pf SCP at day 30 evaluation regardless of the arm to which they were randomized in Step 1.
1.2.4 Participants with continued Pf SCP at entry to Step 2 will have lower Pf parasite densities at day 30 evaluation compared to day 15 evaluation regardless of the arm they were randomized to in Step 1.
1.2.5 Gametocyte densities will be lower in participants with Pf SCP who have received 15 days (Step 1) of LPV/r-based compared with nNRTI-based ART.
1.2.6 Participants with continued Pf SCP at entry to Step 2 will have a higher Pf gametocyte density at day 30 evaluation compared to day 15 evaluation regardless of the arm to which they were randomized in Step 1.
1.2.7 Mutations in the Pf plasmepsin region in participants receiving LPV/r-based ART will be identified after 15 days (Step 1) of therapy.
1.3 Primary Objective
To compare the proportions of Pf SCP clearance between LPV/r-based and nNRTI based ART in participants after 15 days of therapy (Step 1).
1.4 Secondary Objectives
1.4.1 To compare time to Pf SCP clearance in participants with Pf SCP who have received 15 days of LPV/r-based and nNRTI-based ART.
1.4.2 To compare Pf parasite densities in participants with Pf SCP who have received 15 days of LPV/r-based and nNRTI-based ART.
1.4.3 To estimate changes in Pf parasite densities from day 1 to day 30 in four cohorts: (1) randomized to nNRTI-based ART with continued Pf SCP at day 15, (2) randomized to nNRTI-based ART with clearance of Pf SCP at day 15, (3)
randomized to LPV/r-based ART with continued Pf SCP at day 15, (4) randomized to LPV/r-based ART with clearance of Pf SCP at day 15.
1.4.4 To compare Pf gametocyte densities in participants with Pf SCP who have received 15 days of LPV/r-based and nNRTI-based ART.
1.4.5 To estimate changes in Pf gametocyte densities from day 1 to day 30 in four cohorts: (1) randomized to nNRTI-based ART with continued Pf SCP at day 15, (2) randomized to nNRTI-based ART with clearance of Pf SCP at day 15, (3) randomized to LPV/r-based ART with continued Pf SCP at day 15, (4) randomized to LPV/r-based ART with clearance of Pf SCP at day 15.
1.4.6 To describe safety and clinical outcomes in participants with Pf SCP who have received 15 days of LPV/r-based and nNRTI-based ART.
1.4.7 To describe safety and clinical outcomes in participants who enter Step 2 with and without Pf SCP.
1.4.8 To evaluate whether exposure of Pf parasites to LPV/r results in the selection of signature mutations within the plasmepsin region.
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