Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01299948 |
| Other study ID # |
ProCort1 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
February 18, 2011 |
| Last updated |
March 21, 2013 |
| Start date |
June 2007 |
| Est. completion date |
May 2012 |
Study information
| Verified date |
March 2013 |
| Source |
Medical Mission Institute, Germany |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Tanzania: Ministry of Health |
| Study type |
Interventional
|
Clinical Trial 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 mg/d) 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.
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, e.g. 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 mg/d) (Ulmer A 2005).
Patients with more than 300 CD4 cells/µl were included. After two years the 28 patients
on treatment presented 176.1 more CD4 cells than those of 62 control patients in
comparison to their baseline counts (p 0.0009) and after three years the 15 patients on
treatment presented 236.2 more CD4 cells/µl than those of 33 control patients in
comparison to their baseline counts (p = 0,0021). 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.
1.2 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 mg/d) 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.
1.3 SITE DESCRIPTION
The study will be conducted at the Bugando Medical Centre in Mwanza, Tanzania.
2. STUDY OBJECTIVES
2.1 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).
2.2 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.
3.1 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 cells/µl (for inclusion 300 cells/µl for reason of security).
- No AIDS defining symptoms,
- WHO Performance Status of 0,1,2 (see Appendix II).
3.2 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 mg/dl, liver enzymes
(AST, ALT) ≥ 1,5 x ULN, bilirubin ≥ 4 x ULN, alkaline phosphatase ≥ 5 x ULN,
creatinine > 2,0mg/dL (>176,8 µmol).
- Serious other diseases, including psychiatric disorders.
4. PLAN OF STUDY
4.1 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 A1,2 or
B1,2 (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.
4.2 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.
4.3 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.
4.4 DISCONTINUATION
Patients will be removed from the study for the following reasons:
- disease progression: upgrading of clinical stage and/or CD4 cell count < 200/µl,
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, e.g. interruption of
taking the study medication for more than four weeks (compliance);
- pregnancy;
- consent withdrawn;
- investigator's 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.
4.5 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 and/or
ALT), bilirubin, alkaline phosphatase , creatinine; pregnancy test for female
patients.
4.6 RANDOMIZATION
After having checked the patient's 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.
4.7 EVALUATION DURING THE STUDY
4.7.1 EVALUATION EVERY VISIT (MONTH 0,1,2,3,4,5,6,9,12,15,18,21,24)
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 and/or 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.
4.7.2 EVALUATION EVERY 3 MONTH (IN ADDITION)
• Sputum test for Tuberculosis.
4.7.3 EVALUATION EVERY 6 MONTH (IN ADDITION)
- Chest x-ray for Tuberculosis.
- Sputum test for Tuberculosis.
5. STUDY ASSESSMENTS
5.1 EFFICACY ASSESSMENT
5.1.1 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 cells/µl; (Stage A3, B3 )
- CDC clinical stage C; all counts;
- death.
5.1.2 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).
5.1.3 QUALITY OF LIFE
Some Quality of life questions will be completed for each patient during the visits.
5.1.4 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.
5.2 SAFETY ASSESSMENT METHODS
5.2.1 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 SUSAR´s 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
simplex,zoster 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.
5.2.2 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 21.02.2007 Approval Number:
NIMR/HQ/R.8a/Vol.IX/518 Board Name: National Institute for Medical Research Tanzania Board
Affiliation: Tanzania: Ministry of Health Phone: +255222121400 Email:
headquarters@nimr.or.tz ethical and additionally at the 26.01.2007 Approval Number: CW
150/48 Board Name: Bugando Medical Center, Ethic board, Mwanza, Tanzania Board Affiliation:
Bugando Medical Center Phone: +2550282500799 Email: infobmc@bugandomedicalcentre.go.tz
