Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00170209
Status:
COMPLETED
Last Update Posted:
2017-12-19
First Post:
2005-09-12
Brief Title:
Rifampin Versus Isoniazid for the Treatment of Latent Tuberculosis Infection in Children P4v9
Sponsor:
McGill University
Organization:
McGill University
Study Overview
Official Title:
A Randomized Trial to Compare Effectiveness of 4 Months Rifampin 4 RIF With 9 Months Isoniazid 9 INH in the Prevention of Active TB in Children The P4v9 Trial
Status:
COMPLETED
Status Verified Date:
2017-12
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:
Tuberculosis TB is spread by airborne transmission from adults with active contiguous TB to children especially those living in the same household Once children are exposed and infected they are at very high risk to develop active TB - which can be lethal if not detected and treated promptly This makes it very important to detect TB infection as soon as possible and treat this while it is still latent or dormant Current therapy for latent TB infection is 9 months of Isoniazid this is very effective if taken properly but because treatment is so long many children do not finish this Four months of Rifampin is a recommended alternative In adults this has been shown to be safer with much higher completion rates However the effectiveness of this treatment is unclear and is being studied in an ongoing study The investigators plan to compare the safety as well as the acceptability and effectiveness of 4 months Rifampin with 9 months Isoniazid standard treatment in children in several sites in Canada and other countries
It is hypothesized that among children at high risk for development of active TB intoleranceadverse events will not be worse non-inferiority among those randomized to 4RIF compared to those randomized to 9INH In addition completion of latent tuberculosis infection LTBI therapy will be significantly greater superiority and subsequent rates of active TB will not be significantly higher non-inferiority in children taking 4RIF
It is hypothesized that among children at high risk for development of active TB intoleranceadverse events will not be worse non-inferiority among those randomized to 4RIF compared to those randomized to 9INH In addition completion of latent tuberculosis infection LTBI therapy will be significantly greater superiority and subsequent rates of active TB will not be significantly higher non-inferiority in children taking 4RIF
Detailed Description:
On a global scale tuberculosis TB is the single most important infectious cause of morbidity and mortality in individuals aged 15-49 The World Health Organization has estimated that one third of the entire population of the world carries dormant or latent TB infection LTBI Of these 9 million develop active disease and 2 million die from TB each year In Canada and other industrialized countries TB continues to cause significant morbidity and mortality particularly in minorities immigrants and other disadvantaged populations
A key TB control strategy is therapy of LTBI The current standard regimen is 9 months of daily Isoniazid 9INH This has excellent efficacy if taken regularly but the long duration of treatment as well as potential for serious side effects substantially reduces provider prescription patient acceptance and completion A shorter alternative of 4 months of daily Rifampin 4RIF has been recommended based on limited evidence in LTBI but extensive experience using Rifampin for treatment of active TB However the efficacy of 4RIF in preventing active TB is not known especially in children
The investigators have initiated a research program to evaluate 4RIF for the treatment of LTBI In a first study 4RIF was associated with significant higher completion rates than 9INH In a second study all suspected adverse events were judged by an independent 3-member review panel who were blinded to study drug Incidence of Grade 3-4 serious adverse events was significantly lower among the 420 subjects randomized to 4RIF then among the 427 randomized to 9INH 24 vs 56 P02 Grade 3-4 hepatotoxicity was also significantly lower with 4RIF than 9INH 07 vs 38 P003 and completion rates were significantly higher with 4RIF
Therefore a large scale multi-center trial was launched with CIHR funding to compare the efficacy and effectiveness in preventing active TB of 4RIF and 9INH in adults see NCT00931736 In total 5850 adults will be randomized at 4 sites in Canada as well as sites in Australia Brazil Benin Ghana Indonesia Korea and Saudi Arabia The primary outcome of this trial is the occurrence of microbiologically confirmed active TB within 28 months after randomization
As an addition to this ongoing study the investigators are conducting an open label randomized trial in children at some of these same sites with the primary objectives of comparing tolerability and safety Secondary outcomes will be completion of therapy defined as taking more than 80 of planned doses and active TB Eligible children will be HIV infected household contacts of active pulmonary TB cases or other high risk group with a positive Tuberculin skin test TST reaction Active TB must be excluded before enrollment
A total of 822 children will be randomized in equal numbers to receive daily and self-administered 9INH or 4RIF Children will be followed by their usual providers during therapy
Intolerability and adverse events during therapy will be investigated according to a standardized protocol and reported in non-nominal fashion using a web-based system These reports will be reviewed by an independent 3-member panel blinded to study drug to judge severity and likely relationship to study drug Completion of therapy will be ascertained by dosage counts of pills or suspension at each follow-up visit and defined as taking 80 of doses within a defined maximum time
After therapy children will be followed every 3 months up to 16 months post-randomization for the occurrence of clinically diagnosed active TB this will also be detected and investigated following a standardized protocol The final diagnosis of active TB will be based on the judgment of an independent panel of two expert pediatricians who will review all clinical radiographic and microbiologic information while remaining blinded to study drug
The primary analysis will compare rates of Grade 1-5 adverse events judged probably due to study drug Planned secondary analysis will compare rates of study drug completion as well as rates of clinically diagnosed active TB in all children randomized to the two regimens intention to treateffectiveness and rates of clinical active TB in children who take more than 80 of planned doses per protocol-efficacy analysis
A key TB control strategy is therapy of LTBI The current standard regimen is 9 months of daily Isoniazid 9INH This has excellent efficacy if taken regularly but the long duration of treatment as well as potential for serious side effects substantially reduces provider prescription patient acceptance and completion A shorter alternative of 4 months of daily Rifampin 4RIF has been recommended based on limited evidence in LTBI but extensive experience using Rifampin for treatment of active TB However the efficacy of 4RIF in preventing active TB is not known especially in children
The investigators have initiated a research program to evaluate 4RIF for the treatment of LTBI In a first study 4RIF was associated with significant higher completion rates than 9INH In a second study all suspected adverse events were judged by an independent 3-member review panel who were blinded to study drug Incidence of Grade 3-4 serious adverse events was significantly lower among the 420 subjects randomized to 4RIF then among the 427 randomized to 9INH 24 vs 56 P02 Grade 3-4 hepatotoxicity was also significantly lower with 4RIF than 9INH 07 vs 38 P003 and completion rates were significantly higher with 4RIF
Therefore a large scale multi-center trial was launched with CIHR funding to compare the efficacy and effectiveness in preventing active TB of 4RIF and 9INH in adults see NCT00931736 In total 5850 adults will be randomized at 4 sites in Canada as well as sites in Australia Brazil Benin Ghana Indonesia Korea and Saudi Arabia The primary outcome of this trial is the occurrence of microbiologically confirmed active TB within 28 months after randomization
As an addition to this ongoing study the investigators are conducting an open label randomized trial in children at some of these same sites with the primary objectives of comparing tolerability and safety Secondary outcomes will be completion of therapy defined as taking more than 80 of planned doses and active TB Eligible children will be HIV infected household contacts of active pulmonary TB cases or other high risk group with a positive Tuberculin skin test TST reaction Active TB must be excluded before enrollment
A total of 822 children will be randomized in equal numbers to receive daily and self-administered 9INH or 4RIF Children will be followed by their usual providers during therapy
Intolerability and adverse events during therapy will be investigated according to a standardized protocol and reported in non-nominal fashion using a web-based system These reports will be reviewed by an independent 3-member panel blinded to study drug to judge severity and likely relationship to study drug Completion of therapy will be ascertained by dosage counts of pills or suspension at each follow-up visit and defined as taking 80 of doses within a defined maximum time
After therapy children will be followed every 3 months up to 16 months post-randomization for the occurrence of clinically diagnosed active TB this will also be detected and investigated following a standardized protocol The final diagnosis of active TB will be based on the judgment of an independent panel of two expert pediatricians who will review all clinical radiographic and microbiologic information while remaining blinded to study drug
The primary analysis will compare rates of Grade 1-5 adverse events judged probably due to study drug Planned secondary analysis will compare rates of study drug completion as well as rates of clinically diagnosed active TB in all children randomized to the two regimens intention to treateffectiveness and rates of clinical active TB in children who take more than 80 of planned doses per protocol-efficacy analysis
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