Ignite Creation Date:
2024-05-05 @ 4:47 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00310245
Status:
COMPLETED
Last Update Posted:
2006-07-24
First Post:
2006-03-31
Brief Title:
BASTA Study on STI in HIV Infected Patients
Sponsor:
AO Ospedale Papa Giovanni XXIII
Organization:
AO Ospedale Papa Giovanni XXIII
Study Overview
Official Title:
Strategic Long Term Immunologically Driven Treatment Interruptions in Patients on Effective HAART a Controlled Randomized Study
Status:
COMPLETED
Status Verified Date:
2005-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a single center independent study The primary objective is to compare efficacy and safety of continuing a conventional HAART in chronically infected HIV patients with a therapeutic strategy based on long term immunologically driven treatment interruptions Evaluation will be based on clinical immunological and virological response
Patients will be randomized in a ratio 12 to one of the two treatment arms
Control group continuing the ongoing therapy STI group performing long term CD4 guided structured treatment interruptions In the STI arm patients will stay off therapy until their CD4 count will drop 400 cellsmcL At that time point patients will resume the HAART regimen they were assuming before STI and will continue HAART until they CD4 count will raise 800 cellsmcL and their HIV-RNA will drop below the detection limit of 50 copiesml When both the CD4 count and the viral load will be within these pre-set values they will stop therapy again There is no limit to the number of interruptions and re-start cycles during the study period The study is powered to evaluate equivalence between the two strategies under the assumption of a failure proportion in the control arm at each time point not greater than 5 and a maximum allowed difference of 15
Patients will be randomized in a ratio 12 to one of the two treatment arms
Control group continuing the ongoing therapy STI group performing long term CD4 guided structured treatment interruptions In the STI arm patients will stay off therapy until their CD4 count will drop 400 cellsmcL At that time point patients will resume the HAART regimen they were assuming before STI and will continue HAART until they CD4 count will raise 800 cellsmcL and their HIV-RNA will drop below the detection limit of 50 copiesml When both the CD4 count and the viral load will be within these pre-set values they will stop therapy again There is no limit to the number of interruptions and re-start cycles during the study period The study is powered to evaluate equivalence between the two strategies under the assumption of a failure proportion in the control arm at each time point not greater than 5 and a maximum allowed difference of 15
Detailed Description:
Study objectives
Primary objective of the study is
To compare efficacy clinical and immunological and safety of continuing a conventional HAART in chronically infected HIV patients with a therapeutic strategy based on long term immunologically driven treatment interruptions To verify the risk of developing viral resistance
Secondary objectives are
To verify the effect of the two strategies on metabolic parameters To verify the possibility to steadily discontinue antiretroviral therapy in patients that started it with baseline immunological values higher than those currently recommended by international guidelines for HIV treatment To identify predictive variables of the possibility to safely discontinue antiretroviral therapy To verify the dynamic of CD4 loss and HIV replication after treatment interruption To verify costs connected to the strategy
Inclusion and exclusion criteria
a Inclusion i Age 17 years ii Informed consent signed iii Effective ongoing treatment HIV-RNA 50 copiesml Treatment must be based on any triple drug therapy Patients must be on the same steady therapy for at least 3 months
iv Current CD4 cell count above 800 cellsmcL b Exclusion i Childbearing or breastfeeding Women of childbearing potential will be asked to adopt effective contraceptive methods or behaviors ii Any ongoing grade 4 WHO AE or laboratory abnormality with the exclusion of cholesterol triglycerides for which a grade 3 AHA level will be considered an exclusion criteria
As the study wants to enroll patients strictly reflecting the population of HIV infected individuals previous mono or dual therapies as well as the presence of co-morbidities such as HBV and HCV co-infection do not constitute exclusion criteria but will be recorded
Study design
This is a randomized controlled open comparative study The trial will have a follow-up of 4 years
Patients will be monitored according to the international and local guidelines for HIV infection as far as timing and type of laboratory and clinical controls Laboratory exams will be decided locally and only a few key tests are required for the study The timing of laboratory evaluation will be 1 and 2 months after each treatment interruption and thereafter every 2 months All data will be stored in a computerized data-base
Study arms and management of the study
Patients will be randomized in the ratio 1 2 to one of the following treatment arms
1 Continuing their ongoing HAART control
2 Long term treatment interruption STI Randomization will be accomplished locally according to a pre-determined computer-generated random list
In the control group patients will be allowed to change therapy for virological toxicological or personal reasons as well as to comply with new indications from international guidelines All variation will be recorded Patients changing therapy will be still included in the ITT analysis but will be considered failures in the AT analysis Patients stopping therapy for any reason and not resuming it within 3 months will be considered as failures for both the AT analysis In the STI arm patients will stay off therapy until their CD4 count drop 400 cellsmcL one measurement will be considered sufficient At that time point patients will resume the HAART regimen they were assuming before the STI period unless judged as no more of choice according to new international guidelines and will continue HAART until their CD4 count raises 800 cellsmcL and their plasma HIV-RNA drops below the detection limit of 50 copiesml one measurement will be considered sufficient When both the CD4 count and the viral load will be within these pre-set values they will stop therapy again There is no limit to the number of interruptions and re-start cycles during the study period 100 patients will be allocated in the STI arm and 30 patients in the control arm
End points and evaluation criteria
The primary end-points for the evaluation of the main objective of the study can be divided in short term end points and long term end points
The primary short term outcome measure will be the proportion of subjects maintaining at each time-point every 4 months a CD4 cell count above 400 cellsmcL The trial power is calculated on this end point
On the long term the primary outcome measure will be based on the occurrence of clinical end-points including disease progression defined as the occurrence of any AIDS defining event and death The occurrence of grade 4 WHO adverse events limiting the possibility to maintain the patient in the randomized arm will also be considered in AT analysis
Virologic failure with the selection of resistance conferring mutations is the second long-term primary end-point Genotypic tests will be performed in the case of HIV-RNA 1000 copiesml while on therapy for at least 6 months in either group
The secondary objectives of the study will be evaluated on the basis of
Mean variation of blood cholesterol and triglycerides from baseline values For these parameters the proportion of subjects with a value above grade 2 AHA will be also used as evaluation criteria
Development of lipodystrophy or modification of a pre-existing lipodystrophy Time off therapy Economic evaluation Genotypic tests to be performed in the case of HIV-RNA 1000 copiesml while on therapy for at least 4 months or one month after each treatment interruption
Duration of the study
Treatment will be continued for 4 years under the study conditions Patients completing the study period and still responding to therapy will be kept on the same regimen
Statistical evaluation of the study will be performed yearly
Monitoring
Laboratory tests during the study period will be performed in he fasting state The following tests and procedures are required and will be recorded in the electronic data base It is also advised to perform on regular basis haemogram renal function tests blood glucose and amylase Other test could be performed according to local needs or particular situations related to the specific management of single patients
Baseline all patients i Informed consent and treatment randomization ii Biochemical analysis ALT AST total cholesterol and HDL triglycerides iii CD4 count CD8 count iv Plasma HIV-RNA v Clinical evaluation anamnestic and demographic data sex age risk factor for HIV infection CDC AIDS classification time on ART time on current HAART previous antiretroviral drugs previous sub-optimal ARTs current antiretroviral drugs presence and grade of lipodystrophy time with HIV-RNA below detection nadir CD4 CD4 at start of antiretroviral therapy
1 month after each STI only STI group i CD4 count CD8 count HIV-RNA
2 months after each STI only STI group i Biochemical analysis ALT AST cholesterol total and HDL triglycerides ii CD4 count CD8 count iii Plasma HIV-RNA Genotype iv Clinical evaluation disease progression lipodystrophy assessment Every 2 months thereafter STI group and control group i Biochemical analysis ALT AST cholesterol total and HDL triglycerides ii CD4 count CD8 count iii Plasma HIV-RNA iv Clinical evaluation disease progression lipodystrophy assessment Additional tests
Additional tests will be requested in specific cases
i a second genotype after 4 months from the initiation of the STI period will be performed in all patients showing a major mutation in the genotype performed 2 months after STI start ii a genotype will be performed in all patients either in the STI or in the control group showing a viral load above 1000 copiesml after a continuous treatment period on drugs 5 months
Statistical considerations
The study is powered to evaluate equivalence between the two strategies under the assumption of a failure proportion in the control arm at each time point not greater than 5 and a maximum allowed difference of 15 Equivalence will be defined on the basis of the 95 confidence interval
According to this hypothesis with alfa 5 and 1-beta 80 a minimum of 70 patients will be needed The primary analysis will be made according to the intention-to-treat approach and therefore no correction for eventual drop outs is needed
In addition a secondary per-protocol analysis will be performed The primary outcome measure the proportion of patients with CD4 cell counts above 400 cellsmcL will be analyzed by means of Chi-square or Fishers exact test that will be used to analyze all other categorical variables too Time to treatment failure will be estimated using Kaplan-Meier product-limit estimates that will be presented graphically The log-rank test will be used to assess the difference between the survival curves for each arm while ANOVA test and Students t test will be used for continuous variables unless the variables will not be normally distributed in which case the Mann-Whitney U tests will be used Logistic regression analyses forward stepwise model will be used to evaluate the relationship between variables and outcome Comparisons between pairs of groups will bee performed only in the case of a multiple test yielding a statistically significant result
All tests will be two-sided and a P value inferior to 005 will be regarded as significant
The analysis of data will be performed by the proposing Study Center with the SPSS statistical software package for Windows version 100
Drugs
This is a spontaneous study It is proposed that all drugs will be dispensed according to standard procedures
Data use
Data will be used for scientific purposes only The analysis will be performed yearly The type and timing of publication of data will be agreed among the participants to the study The authorship of each presentation will be agreed among participants All participants will be acknowledged as members of the study group
Primary objective of the study is
To compare efficacy clinical and immunological and safety of continuing a conventional HAART in chronically infected HIV patients with a therapeutic strategy based on long term immunologically driven treatment interruptions To verify the risk of developing viral resistance
Secondary objectives are
To verify the effect of the two strategies on metabolic parameters To verify the possibility to steadily discontinue antiretroviral therapy in patients that started it with baseline immunological values higher than those currently recommended by international guidelines for HIV treatment To identify predictive variables of the possibility to safely discontinue antiretroviral therapy To verify the dynamic of CD4 loss and HIV replication after treatment interruption To verify costs connected to the strategy
Inclusion and exclusion criteria
a Inclusion i Age 17 years ii Informed consent signed iii Effective ongoing treatment HIV-RNA 50 copiesml Treatment must be based on any triple drug therapy Patients must be on the same steady therapy for at least 3 months
iv Current CD4 cell count above 800 cellsmcL b Exclusion i Childbearing or breastfeeding Women of childbearing potential will be asked to adopt effective contraceptive methods or behaviors ii Any ongoing grade 4 WHO AE or laboratory abnormality with the exclusion of cholesterol triglycerides for which a grade 3 AHA level will be considered an exclusion criteria
As the study wants to enroll patients strictly reflecting the population of HIV infected individuals previous mono or dual therapies as well as the presence of co-morbidities such as HBV and HCV co-infection do not constitute exclusion criteria but will be recorded
Study design
This is a randomized controlled open comparative study The trial will have a follow-up of 4 years
Patients will be monitored according to the international and local guidelines for HIV infection as far as timing and type of laboratory and clinical controls Laboratory exams will be decided locally and only a few key tests are required for the study The timing of laboratory evaluation will be 1 and 2 months after each treatment interruption and thereafter every 2 months All data will be stored in a computerized data-base
Study arms and management of the study
Patients will be randomized in the ratio 1 2 to one of the following treatment arms
1 Continuing their ongoing HAART control
2 Long term treatment interruption STI Randomization will be accomplished locally according to a pre-determined computer-generated random list
In the control group patients will be allowed to change therapy for virological toxicological or personal reasons as well as to comply with new indications from international guidelines All variation will be recorded Patients changing therapy will be still included in the ITT analysis but will be considered failures in the AT analysis Patients stopping therapy for any reason and not resuming it within 3 months will be considered as failures for both the AT analysis In the STI arm patients will stay off therapy until their CD4 count drop 400 cellsmcL one measurement will be considered sufficient At that time point patients will resume the HAART regimen they were assuming before the STI period unless judged as no more of choice according to new international guidelines and will continue HAART until their CD4 count raises 800 cellsmcL and their plasma HIV-RNA drops below the detection limit of 50 copiesml one measurement will be considered sufficient When both the CD4 count and the viral load will be within these pre-set values they will stop therapy again There is no limit to the number of interruptions and re-start cycles during the study period 100 patients will be allocated in the STI arm and 30 patients in the control arm
End points and evaluation criteria
The primary end-points for the evaluation of the main objective of the study can be divided in short term end points and long term end points
The primary short term outcome measure will be the proportion of subjects maintaining at each time-point every 4 months a CD4 cell count above 400 cellsmcL The trial power is calculated on this end point
On the long term the primary outcome measure will be based on the occurrence of clinical end-points including disease progression defined as the occurrence of any AIDS defining event and death The occurrence of grade 4 WHO adverse events limiting the possibility to maintain the patient in the randomized arm will also be considered in AT analysis
Virologic failure with the selection of resistance conferring mutations is the second long-term primary end-point Genotypic tests will be performed in the case of HIV-RNA 1000 copiesml while on therapy for at least 6 months in either group
The secondary objectives of the study will be evaluated on the basis of
Mean variation of blood cholesterol and triglycerides from baseline values For these parameters the proportion of subjects with a value above grade 2 AHA will be also used as evaluation criteria
Development of lipodystrophy or modification of a pre-existing lipodystrophy Time off therapy Economic evaluation Genotypic tests to be performed in the case of HIV-RNA 1000 copiesml while on therapy for at least 4 months or one month after each treatment interruption
Duration of the study
Treatment will be continued for 4 years under the study conditions Patients completing the study period and still responding to therapy will be kept on the same regimen
Statistical evaluation of the study will be performed yearly
Monitoring
Laboratory tests during the study period will be performed in he fasting state The following tests and procedures are required and will be recorded in the electronic data base It is also advised to perform on regular basis haemogram renal function tests blood glucose and amylase Other test could be performed according to local needs or particular situations related to the specific management of single patients
Baseline all patients i Informed consent and treatment randomization ii Biochemical analysis ALT AST total cholesterol and HDL triglycerides iii CD4 count CD8 count iv Plasma HIV-RNA v Clinical evaluation anamnestic and demographic data sex age risk factor for HIV infection CDC AIDS classification time on ART time on current HAART previous antiretroviral drugs previous sub-optimal ARTs current antiretroviral drugs presence and grade of lipodystrophy time with HIV-RNA below detection nadir CD4 CD4 at start of antiretroviral therapy
1 month after each STI only STI group i CD4 count CD8 count HIV-RNA
2 months after each STI only STI group i Biochemical analysis ALT AST cholesterol total and HDL triglycerides ii CD4 count CD8 count iii Plasma HIV-RNA Genotype iv Clinical evaluation disease progression lipodystrophy assessment Every 2 months thereafter STI group and control group i Biochemical analysis ALT AST cholesterol total and HDL triglycerides ii CD4 count CD8 count iii Plasma HIV-RNA iv Clinical evaluation disease progression lipodystrophy assessment Additional tests
Additional tests will be requested in specific cases
i a second genotype after 4 months from the initiation of the STI period will be performed in all patients showing a major mutation in the genotype performed 2 months after STI start ii a genotype will be performed in all patients either in the STI or in the control group showing a viral load above 1000 copiesml after a continuous treatment period on drugs 5 months
Statistical considerations
The study is powered to evaluate equivalence between the two strategies under the assumption of a failure proportion in the control arm at each time point not greater than 5 and a maximum allowed difference of 15 Equivalence will be defined on the basis of the 95 confidence interval
According to this hypothesis with alfa 5 and 1-beta 80 a minimum of 70 patients will be needed The primary analysis will be made according to the intention-to-treat approach and therefore no correction for eventual drop outs is needed
In addition a secondary per-protocol analysis will be performed The primary outcome measure the proportion of patients with CD4 cell counts above 400 cellsmcL will be analyzed by means of Chi-square or Fishers exact test that will be used to analyze all other categorical variables too Time to treatment failure will be estimated using Kaplan-Meier product-limit estimates that will be presented graphically The log-rank test will be used to assess the difference between the survival curves for each arm while ANOVA test and Students t test will be used for continuous variables unless the variables will not be normally distributed in which case the Mann-Whitney U tests will be used Logistic regression analyses forward stepwise model will be used to evaluate the relationship between variables and outcome Comparisons between pairs of groups will bee performed only in the case of a multiple test yielding a statistically significant result
All tests will be two-sided and a P value inferior to 005 will be regarded as significant
The analysis of data will be performed by the proposing Study Center with the SPSS statistical software package for Windows version 100
Drugs
This is a spontaneous study It is proposed that all drugs will be dispensed according to standard procedures
Data use
Data will be used for scientific purposes only The analysis will be performed yearly The type and timing of publication of data will be agreed among the participants to the study The authorship of each presentation will be agreed among participants All participants will be acknowledged as members of the study group
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None