Ignite Creation Date:
2024-05-05 @ 11:17 PM
Last Modification Date:
2024-10-26 @ 10:31 AM
Study NCT ID:
NCT01299948
Status:
COMPLETED
Last Update Posted:
2013-03-22
First Post:
2011-02-18
Brief Title:
Progression of HIV-Disease Under Low Dose Corticosteroids
Sponsor:
Medical Mission Institute Germany
Organization:
Medical Mission Institute Germany
Study Overview
Official Title:
A Phase II Clinical Trial to Assess Risk and Benefit of Oral Low Dose Prednisolone for HIV Infected People Prior to the Commencement of Antiretroviral Treatment
Status:
COMPLETED
Status Verified Date:
2013-03
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:
ProCort1
Brief Summary:
There has been reports that low dose prednisolone stabilizes CD4-counts in HIV infected individuals However until now there are no prospective randomized studies on the use of corticosteroids in latent HIV disease Furthermore low dose prednisolone 5 mgd is not sufficient tested for the risks and benefit for HIV patients especially for those living in poor settings with a higher risk of infections This study will assess the benefit and the safety profile for low dose prednisolone therapy for patients in a region with limited resources and high prevalence of infections
Detailed Description:
1 INTRODUCTION
1 1 BACKGROUND
For treatment in advanced HIV infection combination therapy with antiretroviral drugs ARVs is the best option under current international standards The benefit of ARVs is best if they are used relatively late in the course of the disease commonly after a progression of years However under a global perspective more than 90 of those who need ARVs world-wide have no access to them
ARVs are not used in early stages of infection without significant immunodeficiency Although a variable degree of immunodeficiency may be present even in early HIV disease there is no established treatment for this phase
Immunodeficiency is associated with a decline of a certain population of lymphocytes the CD4 cells or T-helper cells It seems to be a useful concept to postulate that a treatment which slows down this loss of CD4 cells could also slow down the progression of HIV disease
In vitro findings and clinical studies showed a CD4 cell stabilizing effect of corticosteroids First clinical studies were based on relatively high dosages Andrieu JM 1995 LU W 1995 Andrieu JM 2004 These are hardly justifiable for a longer time because of numerous side effects eg immunosuppression of the cellular immune system the manifestation of diabetes or the Cushing syndrome
In 2005 Ulmer et al reported in a mono-centric open label study a CD4- stabilizing effect under the administration of low dose prednisolone 5 mgd Ulmer A 2005 Patients with more than 300 CD4 cellsµl were included After two years the 28 patients on treatment presented 1761 more CD4 cells than those of 62 control patients in comparison to their baseline counts p 00009 and after three years the 15 patients on treatment presented 2362 more CD4 cellsµl than those of 33 control patients in comparison to their baseline counts p 00021 The initiation of treatment with the more expensive and toxic ARVs was delayed
Based on this study and an increasing amount of experience by Ulmer and others it seems to be justified to systematically investigate the effect of low dose prednisolone on the progression of HIV disease The costs of 5 mg prednisolone per day is in a range of 3 US per year Action Medeor If it turned out that low dose prednisolone prolongs the period until ARVs become indicated without imposing intolerable risks on the patient this approach could be a very attractive future option for countries with health systems in resource-poor settings
12 RATIONAL FOR THE STUDY
Until now there are no prospective randomized studies on the use of corticosteroids in latent HIV disease Furthermore low dose prednisolone 5 mgd is not sufficient tested for the risks and benefit for HIV patients especially for those living in poor settings with a higher risk of infections This study will assess the benefit and the safety profile for low dose prednisolone therapy for patients in a region with limited resources and high prevalence of infections
13 SITE DESCRIPTION
The study will be conducted at the Bugando Medical Centre in Mwanza Tanzania
2 STUDY OBJECTIVES
21 PRIMARY
The primary objective of the study is to assess the effect of the low dose prednisolone therapy on the time to progression of HIV disease The time to progression is defined as the time between the baseline and the change of staging to advanced disease CDC stage A3 B3 or C or death see Appendix Va
22 SECONDARY
The following secondary objectives will be evaluated in the same patient population
Amount of CD4 Cells
Overall survival
Safety profile
Quality of life
Immune system status co-infections
Virus characterization by sequencing
3 PATIENT DEFINITION
This is a mono-centred trial involving 400 eligible patients
31 INCLUSION CRITERIA
Positive HIV antibody test The HIV infection has to be confirmed according to the WHO Guidelines see Appendix IX
Adult male or female patients age 18 years
Patients must have given an informed consent and signed a consent form prior to beginning protocol specific procedures Appendix VI
Patients in CDC Stage A 1 2 B 1 2 see Appendix Va not yet requiring ARVs
CD4 cell count 300 cellsµl for inclusion 300 cellsµl for reason of security
No AIDS defining symptoms
WHO Performance Status of 012 see Appendix II
32 EXCLUSION CRITERIA
No pregnancy Female patients of childbearing potential must have a negative pregnancy test at study entry
Prior therapy with ARVs
Active tuberculosis
Abnormal laboratory results especially glucose level 160 mgdl liver enzymes AST ALT 15 x ULN bilirubin 4 x ULN alkaline phosphatase 5 x ULN creatinine 20mgdL 1768 µmol
Serious other diseases including psychiatric disorders
4 PLAN OF STUDY
41 STUDY DESIGN
This is a double blinded randomized phase II placebo-controlled clinical trial of oral low dose prednisolone therapy for HIV infected patients with CDC Stage A12 or B12 see Appendix Va
The trial is a mono-centred and involves 400 eligible patients in Tanzania divided in
200 Patients in Study medication group
200 Patients in Placebo group
The study enrollment period will last for 12 month 30 patients per month A study period of 24 month will follow After 12 months the first intermediate analysis will be done In case of no significant negative safety aspects the study will continue for the next 12 month A follow-up period for further evaluation can be added
42 STUDY TREATMENT
The patients in the Treatment Group will get prednisolone 5 mg per os daily The placebo group will get one tablet of placebo per os daily
43 DOSE MODIFICATION AND DELAY
There is no dose modification planned in this study Study drug related reactions like hypersensitivity reactions fluid retention hypertension gastric ulcer and diabetes will be treated according to local standards
44 DISCONTINUATION
Patients will be removed from the study for the following reasons
disease progression upgrading of clinical stage andor CD4 cell count 200µl both requiring the start of HAART primary study objective study completed
development of unacceptable toxicity not manageable by symptomatic care
administration of antiretroviral treatment
significant protocol violation in the prednisolone group eg interruption of taking the study medication for more than four weeks compliance
pregnancy
consent withdrawn
investigators decision
Patients are always allowed to refuse the participation of study and will be withdrawn
The reason for removal for all patients will be documented on the case report form Patients who are not eligible or not valuables for the study analysis will be replaced
45 PRE-STUDY SCREEN
The following data will be obtained within two weeks prior to randomization
informed consent and signed consent form audio consent for illiterate persons
complete medical history including dates and description of initial diagnosis of HIV infection concurrent illnesses and concomitant medication
physical examination including weight height WHO performance status Appendix II
vital signs blood pressure pulse rate oral temperature
HIV staging according to CDC examination for AIDS defining signs and CD4 cell count
chest x-ray to exclude active tuberculosis
short quality of life score
clinical laboratory tests full blood count glucose liver enzymes AST andor ALT bilirubin alkaline phosphatase creatinine pregnancy test for female patients
46 RANDOMIZATION
After having checked the patients eligibility the investigator will request randomization A Randomization list will be provided to the BMC The randomization number will be given by the study nurse The study medication is double blind Block randomization may be used
47 EVALUATION DURING THE STUDY
471 EVALUATION EVERY VISIT MONTH 012345691215182124
The patient will be examined every month for the following parameters
medical history update including documentation of concurrent conditions hospitalization and concomitant medications
quality of life score
physical examination including weight and WHO performance status
vital signs blood pressure pulse rate and oral temperature
HIV staging according to CDC examination for AIDS defining signs and CD4 cell count
full haematological blood count
serum chemistry glucose level liver enzymes AST andor ALT bilirubin alkaline phosphatase creatinine
pregnancy test for female patients
toxicity evaluation Toxicity is defined as a study drug related adverse event AE grade 3 severe or 4 life threatening Toxicity will be recorded as it occurs and graded according to the NCI Common Toxicity Criteria see Appendix III Toxicities that can not be graded using the NCI Common Toxicity Criteria will be recorded as mild asymptomatic moderate symptomatic but not interfering significantly with function severe causing significant interference with function or life-threatening
472 EVALUATION EVERY 3 MONTH IN ADDITION
Sputum test for Tuberculosis
473 EVALUATION EVERY 6 MONTH IN ADDITION
Chest x-ray for Tuberculosis
Sputum test for Tuberculosis
5 STUDY ASSESSMENTS
51 EFFICACY ASSESSMENT
511 TIME TO PROGRESSION
The time to progression is defined as time period between the baseline and the change of staging see appendix Va
Progression is
CD4 cell count 200 cellsµl Stage A3 B3
CDC clinical stage C all counts
death
512 AMOUNT OF CD4 CELLS
The number of the CD4 cells at baseline 100 will be compared to the number during the study 100 increase 100 decrease
513 QUALITY OF LIFE
Some Quality of life questions will be completed for each patient during the visits
514 OVERALL SURVIVAL
The duration of survival will be determined by measuring the time interval between the initial dose of study medication and the date of death The overall survival will be evaluated in the prolonged follow up period of the study
52 SAFETY ASSESSMENT METHODS
521 SUSPECTED ADVERSE RESPONSE SUSAR ADVERSE EVENT AND TOXICITY
Toxicity is defined as a study drug related Suspected Adverse Response SUSAR and Adverse events AE Grade 3 severe or 4 life threatening It will be evaluated based on a graded scale of 0-4 using the NCI Common Toxicity Criteria see Appendix III Toxicities that can not be graded using the NCI Common Toxicity Criteria will be graded as mild asymptomatic moderate symptomatic but not interfering significantly with function severe causing significant interference with function or life-threatening
The SUSARs are
Abdominal pain Hypertension Diabetes Hyperglycaemia Fluid retention Pneumonia Gastritis Weight gain
The AEs are
Abdominal Pain Nausea Candidiasis Peptic ulcer Diarrhoea Pneumonia Fever Skin Herpes simplexzoster Vomiting Hepatitis liver function Urinary tract infection
AEs and SUSARs will be monitored during every visit using a hard coded page in the case report form
Additional AEs occurring can be added
522 LABORATORY MEASUREMENTS
Biochemical and haematological tests will be conducted on blood samples once a month at every visit If AEs occur additional tests have to be done according to local standards
For later additional laboratory analysis a small amount of plasma samples and T-Cells will be stored at the National Institute for Medical Research These samples will be analyzed in Germany Medical Mission Institute University of Wuerzburg for identifying the status of activation of the immune system co-infections and virus characterization
6 ETHICAL CONSIDERATIONS
The study was approved at ethic board committees at the 21022007 Approval Number NIMRHQR8aVolIX518 Board Name National Institute for Medical Research Tanzania Board Affiliation Tanzania Ministry of Health Phone 255222121400 Email headquartersnimrortz ethical and additionally at the 26012007 Approval Number CW 15048 Board Name Bugando Medical Center Ethic board Mwanza Tanzania Board Affiliation Bugando Medical Center Phone 2550282500799 Email infobmcbugandomedicalcentregotz
1 1 BACKGROUND
For treatment in advanced HIV infection combination therapy with antiretroviral drugs ARVs is the best option under current international standards The benefit of ARVs is best if they are used relatively late in the course of the disease commonly after a progression of years However under a global perspective more than 90 of those who need ARVs world-wide have no access to them
ARVs are not used in early stages of infection without significant immunodeficiency Although a variable degree of immunodeficiency may be present even in early HIV disease there is no established treatment for this phase
Immunodeficiency is associated with a decline of a certain population of lymphocytes the CD4 cells or T-helper cells It seems to be a useful concept to postulate that a treatment which slows down this loss of CD4 cells could also slow down the progression of HIV disease
In vitro findings and clinical studies showed a CD4 cell stabilizing effect of corticosteroids First clinical studies were based on relatively high dosages Andrieu JM 1995 LU W 1995 Andrieu JM 2004 These are hardly justifiable for a longer time because of numerous side effects eg immunosuppression of the cellular immune system the manifestation of diabetes or the Cushing syndrome
In 2005 Ulmer et al reported in a mono-centric open label study a CD4- stabilizing effect under the administration of low dose prednisolone 5 mgd Ulmer A 2005 Patients with more than 300 CD4 cellsµl were included After two years the 28 patients on treatment presented 1761 more CD4 cells than those of 62 control patients in comparison to their baseline counts p 00009 and after three years the 15 patients on treatment presented 2362 more CD4 cellsµl than those of 33 control patients in comparison to their baseline counts p 00021 The initiation of treatment with the more expensive and toxic ARVs was delayed
Based on this study and an increasing amount of experience by Ulmer and others it seems to be justified to systematically investigate the effect of low dose prednisolone on the progression of HIV disease The costs of 5 mg prednisolone per day is in a range of 3 US per year Action Medeor If it turned out that low dose prednisolone prolongs the period until ARVs become indicated without imposing intolerable risks on the patient this approach could be a very attractive future option for countries with health systems in resource-poor settings
12 RATIONAL FOR THE STUDY
Until now there are no prospective randomized studies on the use of corticosteroids in latent HIV disease Furthermore low dose prednisolone 5 mgd is not sufficient tested for the risks and benefit for HIV patients especially for those living in poor settings with a higher risk of infections This study will assess the benefit and the safety profile for low dose prednisolone therapy for patients in a region with limited resources and high prevalence of infections
13 SITE DESCRIPTION
The study will be conducted at the Bugando Medical Centre in Mwanza Tanzania
2 STUDY OBJECTIVES
21 PRIMARY
The primary objective of the study is to assess the effect of the low dose prednisolone therapy on the time to progression of HIV disease The time to progression is defined as the time between the baseline and the change of staging to advanced disease CDC stage A3 B3 or C or death see Appendix Va
22 SECONDARY
The following secondary objectives will be evaluated in the same patient population
Amount of CD4 Cells
Overall survival
Safety profile
Quality of life
Immune system status co-infections
Virus characterization by sequencing
3 PATIENT DEFINITION
This is a mono-centred trial involving 400 eligible patients
31 INCLUSION CRITERIA
Positive HIV antibody test The HIV infection has to be confirmed according to the WHO Guidelines see Appendix IX
Adult male or female patients age 18 years
Patients must have given an informed consent and signed a consent form prior to beginning protocol specific procedures Appendix VI
Patients in CDC Stage A 1 2 B 1 2 see Appendix Va not yet requiring ARVs
CD4 cell count 300 cellsµl for inclusion 300 cellsµl for reason of security
No AIDS defining symptoms
WHO Performance Status of 012 see Appendix II
32 EXCLUSION CRITERIA
No pregnancy Female patients of childbearing potential must have a negative pregnancy test at study entry
Prior therapy with ARVs
Active tuberculosis
Abnormal laboratory results especially glucose level 160 mgdl liver enzymes AST ALT 15 x ULN bilirubin 4 x ULN alkaline phosphatase 5 x ULN creatinine 20mgdL 1768 µmol
Serious other diseases including psychiatric disorders
4 PLAN OF STUDY
41 STUDY DESIGN
This is a double blinded randomized phase II placebo-controlled clinical trial of oral low dose prednisolone therapy for HIV infected patients with CDC Stage A12 or B12 see Appendix Va
The trial is a mono-centred and involves 400 eligible patients in Tanzania divided in
200 Patients in Study medication group
200 Patients in Placebo group
The study enrollment period will last for 12 month 30 patients per month A study period of 24 month will follow After 12 months the first intermediate analysis will be done In case of no significant negative safety aspects the study will continue for the next 12 month A follow-up period for further evaluation can be added
42 STUDY TREATMENT
The patients in the Treatment Group will get prednisolone 5 mg per os daily The placebo group will get one tablet of placebo per os daily
43 DOSE MODIFICATION AND DELAY
There is no dose modification planned in this study Study drug related reactions like hypersensitivity reactions fluid retention hypertension gastric ulcer and diabetes will be treated according to local standards
44 DISCONTINUATION
Patients will be removed from the study for the following reasons
disease progression upgrading of clinical stage andor CD4 cell count 200µl both requiring the start of HAART primary study objective study completed
development of unacceptable toxicity not manageable by symptomatic care
administration of antiretroviral treatment
significant protocol violation in the prednisolone group eg interruption of taking the study medication for more than four weeks compliance
pregnancy
consent withdrawn
investigators decision
Patients are always allowed to refuse the participation of study and will be withdrawn
The reason for removal for all patients will be documented on the case report form Patients who are not eligible or not valuables for the study analysis will be replaced
45 PRE-STUDY SCREEN
The following data will be obtained within two weeks prior to randomization
informed consent and signed consent form audio consent for illiterate persons
complete medical history including dates and description of initial diagnosis of HIV infection concurrent illnesses and concomitant medication
physical examination including weight height WHO performance status Appendix II
vital signs blood pressure pulse rate oral temperature
HIV staging according to CDC examination for AIDS defining signs and CD4 cell count
chest x-ray to exclude active tuberculosis
short quality of life score
clinical laboratory tests full blood count glucose liver enzymes AST andor ALT bilirubin alkaline phosphatase creatinine pregnancy test for female patients
46 RANDOMIZATION
After having checked the patients eligibility the investigator will request randomization A Randomization list will be provided to the BMC The randomization number will be given by the study nurse The study medication is double blind Block randomization may be used
47 EVALUATION DURING THE STUDY
471 EVALUATION EVERY VISIT MONTH 012345691215182124
The patient will be examined every month for the following parameters
medical history update including documentation of concurrent conditions hospitalization and concomitant medications
quality of life score
physical examination including weight and WHO performance status
vital signs blood pressure pulse rate and oral temperature
HIV staging according to CDC examination for AIDS defining signs and CD4 cell count
full haematological blood count
serum chemistry glucose level liver enzymes AST andor ALT bilirubin alkaline phosphatase creatinine
pregnancy test for female patients
toxicity evaluation Toxicity is defined as a study drug related adverse event AE grade 3 severe or 4 life threatening Toxicity will be recorded as it occurs and graded according to the NCI Common Toxicity Criteria see Appendix III Toxicities that can not be graded using the NCI Common Toxicity Criteria will be recorded as mild asymptomatic moderate symptomatic but not interfering significantly with function severe causing significant interference with function or life-threatening
472 EVALUATION EVERY 3 MONTH IN ADDITION
Sputum test for Tuberculosis
473 EVALUATION EVERY 6 MONTH IN ADDITION
Chest x-ray for Tuberculosis
Sputum test for Tuberculosis
5 STUDY ASSESSMENTS
51 EFFICACY ASSESSMENT
511 TIME TO PROGRESSION
The time to progression is defined as time period between the baseline and the change of staging see appendix Va
Progression is
CD4 cell count 200 cellsµl Stage A3 B3
CDC clinical stage C all counts
death
512 AMOUNT OF CD4 CELLS
The number of the CD4 cells at baseline 100 will be compared to the number during the study 100 increase 100 decrease
513 QUALITY OF LIFE
Some Quality of life questions will be completed for each patient during the visits
514 OVERALL SURVIVAL
The duration of survival will be determined by measuring the time interval between the initial dose of study medication and the date of death The overall survival will be evaluated in the prolonged follow up period of the study
52 SAFETY ASSESSMENT METHODS
521 SUSPECTED ADVERSE RESPONSE SUSAR ADVERSE EVENT AND TOXICITY
Toxicity is defined as a study drug related Suspected Adverse Response SUSAR and Adverse events AE Grade 3 severe or 4 life threatening It will be evaluated based on a graded scale of 0-4 using the NCI Common Toxicity Criteria see Appendix III Toxicities that can not be graded using the NCI Common Toxicity Criteria will be graded as mild asymptomatic moderate symptomatic but not interfering significantly with function severe causing significant interference with function or life-threatening
The SUSARs are
Abdominal pain Hypertension Diabetes Hyperglycaemia Fluid retention Pneumonia Gastritis Weight gain
The AEs are
Abdominal Pain Nausea Candidiasis Peptic ulcer Diarrhoea Pneumonia Fever Skin Herpes simplexzoster Vomiting Hepatitis liver function Urinary tract infection
AEs and SUSARs will be monitored during every visit using a hard coded page in the case report form
Additional AEs occurring can be added
522 LABORATORY MEASUREMENTS
Biochemical and haematological tests will be conducted on blood samples once a month at every visit If AEs occur additional tests have to be done according to local standards
For later additional laboratory analysis a small amount of plasma samples and T-Cells will be stored at the National Institute for Medical Research These samples will be analyzed in Germany Medical Mission Institute University of Wuerzburg for identifying the status of activation of the immune system co-infections and virus characterization
6 ETHICAL CONSIDERATIONS
The study was approved at ethic board committees at the 21022007 Approval Number NIMRHQR8aVolIX518 Board Name National Institute for Medical Research Tanzania Board Affiliation Tanzania Ministry of Health Phone 255222121400 Email headquartersnimrortz ethical and additionally at the 26012007 Approval Number CW 15048 Board Name Bugando Medical Center Ethic board Mwanza Tanzania Board Affiliation Bugando Medical Center Phone 2550282500799 Email infobmcbugandomedicalcentregotz
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