Three Chemo Regimens as an Adjunct to ART for Treatment of Advanced AIDS-KS
- Conditions
- HIV-1 Infection
- Interventions
- Drug: Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
- Registration Number
- NCT01435018
- Lead Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Brief Summary
This study was done to compare the safety and efficacy of three combination treatments for Kaposi's Sarcoma (KS) and AIDS:
1. Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) (ET+ART),
2. Bleomycin and Vincristine (BV) plus co-formulated EFV/FTC/TDF (BV+ART),
3. Paclitaxel (PTX) plus co-formulated EFV/FTC/TDF (PTX+ART).
- Detailed Description
The study consisted of four steps. Study duration was up to 240 weeks.
At the study Step 1 entry, participants were randomized with equal probability to each of the three regimens (ET+ART, BV+ART, PTX+ART). The original target sample size was 706. Randomization was stratified by:
1. Screening CD4 lymphocyte cell count (\<100, \>=100 cells/mm³), and
2. Country.
For participants who had an initial Independent Endpoint Review Committee (IERC) confirmed KS response and subsequent IERC-confirmed KS progression, and who, in the opinion of the investigator and with concurrence of the protocol Clinical Management Committee (CMC), could potentially have benefitted from another course of the same chemotherapy utilized in Step 1, entered Step 2. (Please see details on Step 2 eligibility.)
In Step 3, participants were randomized with equal probability to one of the two chemotherapy arms not utilized in Step 1. (Please see details on Step 3 eligibility.)
In Step 4, participants were assigned to the remaining study-provided chemotherapy not given in Step 1, Step 2 or Step 3. (Please see details on Step 4 eligibility.)
Step 1 visits occurred at screening, entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from study entry. Visits for Steps 2, 3 and 4 were scheduled at entry and weeks 3, 6, 9, 12, 15, 18, 21,24, 27, 30, 33, 36, 39, 42, 45, 48, 60, 72, 84 and 96 from the corresponding step entry date. Key evaluations included targeted physical examination, clinical assessment, KS examination, hematology, chemistry, pregnancy testing (for women of reproductive potential), and pulse oximetry for participants on BV+ART. CD4 count and HIV viral load were obtained every 12 weeks. Assessment of peripheral neuropathy was done at screening, weeks 9 and 21, and for those on BV+ART or PTX+ART, additionally at weeks 3, 6, 15 and 18. KS tumor punch biopsy, serum, plasma and peripheral blood mononuclear cells (PBMCs) were obtained and stored for use in future analyses. Participants also completed ET and ART adherence evaluations and quality of life questionnaires.
Enrollment to ET+ART and initiation of ET+ART in subsequent steps were discontinued in March 2016, based on the recommendation of the Data and Safety Monitoring Board (DSMB) due to ET+ART being less effective than PTX+ART. No safety concerns were identified. ET+ART participants in Step 1 or Step 2, in discussion with the local investigator and in consultation with the protocol CMC, could discontinue ET and enter Step 3. ET+ART participants in Step 3 could discontinue ET and start the remaining chemotherapy regimen in Step 4 in discussion with the local investigator and in consultation with the protocol CMC. Unless otherwise indicated, comparison between ET+ART and PTX+ART was based on the March 2016 data. The study remained open to enrollment and the remaining participants were randomized at Step 1 entry between BV+ART and PTX+ART. The target total sample size was revised to 446.
The DSMB recommended stopping the study in March 2018 due to BV+ART being inferior to PTX+ART. No safety concerns were identified. Study accrual was stopped. Eligible Step 1 PTX+ART participants entered Step 2 to receive PTX+ART; Step 1 and Step 2 BV+ART participants eligible to receive PTX+ART moved to Step 3 to receive PTX+ART. Otherwise, participants permanently transitioned to local care upon arrangement of appropriate oncology and ART, and then went off study. Participants who received ET while on study were followed for 144 weeks after beginning the last cycle of ET.
Comparison between BV+ART and PTX+ART was based on the March 2018 data.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 334
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description ET+ART Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) BV+ART Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) BV+ART Bleomycin and Vincristine (BV) Bleomycin and Vincristine (BV) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) ET+ART Etoposide (ET) Etoposide (ET) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) PTX+ART Paclitaxel (PTX) Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) PTX+ART Co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Paclitaxel (PTX) plus co-formulated Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF)
- Primary Outcome Measures
Name Time Method Cumulative Rate of Progression-Free Survival by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 Progression-free survival (PFS) by week 48 is defined as a lack of the following events: (a) Independent Endpoint Review Committee (IERC)-confirmed KS progression, (b) death, (c) entry into an additional step, or (d) loss to follow-up, prior to week 48. PFS rate was estimated by the Kaplan-Meier survival probability at week 48. Time to event was computed as the number of weeks from study entry to the first among these events. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48. Overall KS outcome status (complete response, partial response, stable, disease progression) was based on comparing follow-up to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Cumulative Rate of Progression-Free Survival by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 Progression-free survival (PFS) by week 48 is defined as a lack of the following events: (a) Independent Endpoint Review Committee (IERC)-confirmed KS progression, (b) death, (c) entry into an additional step, or (d) loss to follow-up, prior to week 48. PFS rate was estimated by the Kaplan-Meier survival probability at week 48. Time to event was computed as the number of weeks from study entry to the first among these events. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48. Overall KS outcome status (complete response, partial response, stable, disease progression) was based on comparing follow-up to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
- Secondary Outcome Measures
Name Time Method Cumulative Rate of IERC-confirmed KS Progression by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of IERC-confirmed KS progression by week 48. IERC-confirmed KS progression was defined as KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Cumulative Rate of Death by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of death by week 48. Time to death was computed as the number of weeks from study entry to date of death. For participants who did have the event, time to death was censored at the week of last contact with the participant. Time to death above 48 were censored at week 48.
Cumulative Rate of Death by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of death by week 48. Time to death was computed as the number of weeks from study entry to the death date. For participants who did have the event, time to death was censored at the week of last contact with the participant. Time to death above 48 were censored at week 48.
Cumulative Rate of IERC-confirmed KS Progression by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of IERC-confirmed KS progression by week 48. IERC-confirmed KS progression was defined as KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48
Number of Participants With Objective Response for ET+ART vs. PTX+ART From study entry up to week 144 The number of participants with objective response (complete response or partial response) as best overall KS response in Step 1. Overall KS response status (complete response, partial response, stable, disease progression) was based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 4 From Step 4 study entry to Step 4 discontinuation, up to 96 weeks IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA \>=1000 copies/mL at week 12 to week 24 or RNA \>=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 4 treatment arm.
Cumulative Rate of Death for ET+ART vs. PTX+ART From study entry to week 240 The Kaplan-Meier estimate of the cumulative rate of death. Time to death was computed as the number of weeks between study entry and date of death. For participants who did not have the event, time to death was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.
Changes in CD4+ Lymphocyte Cell Count for BV+ART vs. PTX+ART Baseline, weeks 12, 24, 48 Baseline CD4 lymphocyte cell count is the mean of screening and Step 1 entry CD4 values. Absolute change in CD4+ lymphocyte cell count was calculated as value at a given visit minus the baseline CD4 lymphocyte cell count.
Cumulative Rate of AIDS-defining Event by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of AIDS-defining events by week 48. AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Time to event was computed as the number of weeks from study entry to the first AIDS-defining event. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48.
Cumulative Rate of AIDS-defining Event by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of AIDS-defining events by week 48. AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Time to event was computed as the number of weeks from study entry to the first AIDS-defining event. For participants who did not have any of the events, event time was censored at the week of last contact with the participant. Follow-up time beyond 48 was censored at week 48.
Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 Virologic failure is defined as two successive measurements of plasma HIV-1 RNA \>=1000 copies/mL at week 12 to week 24 or RNA \>=400 copies/mL at week 24 or later.
Cumulative Rate of HIV-1 RNA Virologic Failure by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 Virologic failure is defined as two successive measurements of plasma HIV-1 RNA \>=1000 copies/mL at week 12 to week 24 or RNA \>=400 copies/mL at week 24 or later.
Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for BV+ART vs. PTX+ART From study entry to week 12 KS-IRIS is defined as any IERC-confirmed KS-progression that occurs within 12 weeks of ART-initiation that is associated with an increase in CD4 cell count of at least 50 cells/mm\^3 above the study entry value and/or a decrease in the HIV-1 RNA level by at least 0.5 log below the study entry value prior to or at the time of documented KS progression.
Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, or Virologic Failure by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, or virologic failure by week 48
Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.
Cumulative Rate of KS Progression, Death, AIDS Defining Event, Virologic Failure, or KS-IRIS by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, AIDS defining event, virologic failure, or KS-IRIS.
Number of Participants With Kaposi's Sarcoma-Immune Reconstitution Inflammatory Syndrome (KS-IRIS) for ET+ART vs. PTX+ART From study entry to week 12 KS-IRIS is defined as any IERC-confirmed KS-progression that occurs within 12 weeks of ART-initiation that is associated with an increase in CD4 cell count of at least 50 cells/mm\^3 above the study entry value and/or a decrease in the HIV-1 RNA level by at least 0.5 log below the study entry value prior to or at the time of documented KS progression.
Cumulative Rate of Change in KS Treatment by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of change in KS treatment by week 48. Change in KS treatment was defined as stopping Step 1 randomized chemotherapy and initiating a different chemotherapy.
Time to IERC-confirmed KS Progression or Death for BV+ART vs. PTX+ART From study entry to week 240 Time to IERC-confirmed KS progression or death was computed as the number of weeks between study entry and the earlier between date of IERC-confirmed KS progression or date of death. For participants who did not have the event, event time was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.The 25-th percentile and hazard ratio are presented.
Duration of Objective Response for ET+ART vs. PTX+ART From study entry up to week 144 Duration of objective response is the number of weeks from first complete or partial response to the earliest among progression, death or off study week. The 25th percentile duration is presented.
Number of Participants With Peripheral Neuropathy (PN) Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of PN for ET+ART was only done at screening, weeks 9 and 21. Presence of PN is defined as having all of the following results: presence of symptomatic PN, abnormal perception of vibrations, and absent or hypoactive deep tendon reflexes.
Presence of Oral KS From study entry to week 240 Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.
Cumulative Rate of KS Progression, Death, or AIDS Defining Event by Week 48 for ET+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of KS progression, death, or AIDS defining event by week 48
Self-reported Adherence to ART Therapy At Weeks 6, 12, 18, 30 and 48 ART adherence is based on participant's recall of the number of missed ART doses for the past month. Perfect adherence is defined as having zero missed ART doses.
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 2 From Step 2 study entry to Step 2 discontinuation, up to 144 weeks IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA \>=1000 copies/mL at week 12 to week 24 or RNA \>=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 2 treatment arm.
Cumulative Rate of Change in KS Treatment by Week 48 for BV+ART vs. PTX+ART From study entry to week 48 The Kaplan-Meier estimate of the cumulative rate of change in KS treatment by week 48. Change in KS treatment was defined as stopping Step 1 randomized chemotherapy and initiating a different chemotherapy.
Cumulative Rate of Death for BV+ART vs PTX+ART From study entry to week 240 The Kaplan-Meier estimate of the cumulative rate of death. Time to death was computed as the number of weeks between study entry and date of death. For participants who did not have the event, time to death was censored at the week of last contact with the participant or at the participant's off study week, whichever is later.
Time to IERC-confirmed KS Progression or Death for ET+ART vs. PTX+ART From study entry to week 240 Time to IERC-confirmed KS progression or death was computed as the number of weeks between study entry and the earlier between date of IERC-confirmed KS progression or date of death. For participants who did not have the event, event time was censored at the week of last contact with the participant or the participant's off study week, whichever is later. The 25-th percentile and hazard ratio are presented.
Number of Participants With Objective Response for BV+ART vs. PTX+ART From study entry up to week 144 The number of participants with objective response (complete response or partial response) as best overall KS response in Step 1. Overall KS response status (complete response, partial response, stable, disease progression) was based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002).
Duration of Objective Response for BV+ART vs. PTX+ART From study entry up to week 144 Duration of objective response is the number of weeks from first complete or partial response to the earliest among progression, death or off study week. The 25th percentile duration is presented.
Number of Participants With Symptomatic Peripheral Neuropathy (SPN) Screening, Weeks 3, 6, 9, 12, 15, 18, 21. Assessment of SPN for ET+ART was only done at screening, weeks 9 and 21. SPN consists of three assessments: (1) pain, aching or burning in feet, legs, (2) "pins and needles" in feet, legs, and (3) numbness (lack of feeling) in feet, legs. SPN is graded on a severity scale from 0 (not present), 1 (mild) to 10 (severe). Presence of SPN is defined as having grade \>=1 in at least one of the three assessments.
Number of Participants With Treatment-related Toxicities and Adverse Events (AEs) From study entry to week 240 Adverse events classified by the site personnel as possibly, probably or definitely related to ART or chemotherapy.
Changes in CD4+ Lymphocyte Cell Count for ET+ART vs. PTX+ART Baseline, weeks 12, 24, 48 Baseline CD4 lymphocyte cell count is the mean of screening and Step 1 entry CD4 values. Absolute change in CD4+ lymphocyte cell count was calculated as value at a given visit minus the baseline CD4 lymphocyte cell count.
Salivary KSHV Baseline, weeks 60, 120, 180, 240 Funding for oral KS objectives including data and sample collection was withdrawn during the study conduct.
Number of Participants With IERC-Confirmed KS Disease Progression, Dose-Limiting Toxicity, Death, AIDS-Defining Events, Virologic Failure and Objective Response in Step 3 From Step 3 study entry to Step 3 discontinuation, up to 144 weeks IERC-confirmed KS progression refers to KS disease progression confirmed by the IERC based on comparing follow-up KS response to study entry or best KS response with respect to clinical assessment of KS cutaneous lesions (count, character and marker lesion area), oral KS, visceral KS and tumor-associated edema and as described in the publications (Krown et al 1989, Cianfrocca et al 2002). AIDS-defining events refer to non-KS AIDS-defining diagnosis (WHO Stage 4 (2007), plus microsporidiosis, cyclospora gastroenteritis, Chagas disease and visceral leishmaniasis). Virologic failure is defined as two successive measurements of plasma HIV-1 RNA \>=1000 copies/mL at week 12 to week 24 or RNA \>=400 copies/mL at week 24 or later. Objective response refers to complete response or partial response as best overall KS response. Results are presented by Step 3 treatment arm.
Trial Locations
- Locations (11)
Instituto de Pesquisa Clinica Evandro Chagas (12101)
🇧🇷Rio de Janeiro, Brazil
Moi University International Clnical Trials Unit
🇰🇪Eldoret, Kenya
Kenya Medical Research Institute/Center for Disease Control (KEMRI/CDC) CRS (31460)
🇰🇪Kisumu, Kenya
Family Clinical Research Unit (FAM-CUR) CRS (8950)
🇿🇦Cape Town, West Cape, South Africa
University of Witwatersrand
🇿🇦Johannesburg, South Africa
Durban Adult HIV CRS (11201)
🇿🇦Durban, South Africa
UZ-Parirenyatwa CRS (30313)
🇿🇼Harare, Zimbabwe
Uganda Cancer Institute ACTG CRS
🇺🇬Kampala, Uganda
Univ. of Malawi, John Hopkins Project
🇲🇼Blantyre, Malawi
Malawi CRS (12001)
🇲🇼Lilongwe, Malawi
KMRI / Walter Reed Project Clinical Research Center
🇰🇪Kericho, Kenya