Ignite Creation Date:
2024-07-17 @ 11:14 AM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06498414
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-07-12
First Post:
2024-04-29
Brief Title:
An Adaptive Trial to Find the Safest And Shortest TB Preventive Regimens
Sponsor:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Organization:
McGill University Health CentreResearch Institute of the McGill University Health Centre
Study Overview
Official Title:
An Adaptive Trial to Find the Safest And Shortest TB Preventive Regimens
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
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:
Our study rationale is based on
1 Tuberculosis Preventive Treatment TPT is given to healthy people and needs to be safe
2 Tuberculosis Preventive Treatment TPT with shorter regimens are superior with respect to acceptance completion and costs
3 4 months of Rifampin 10mgkg 4R10 is the safest regimen but is completed by 80 of patients
4 The safety of 2 months of Rifampin 20mgkg 2R20 is similar to that of 4 months of Rifampin 10mgkg 4R10 but completion is a concern
5 1-month regimens have promising efficacy
6 Safety and tolerability must be carefully assessed with comparisons to 4 months of Rifampin 10mgkg 4R10 and head-to-head with each other
OBJECTIVES The investigator will use a Bayesian adaptive Phase 2 randomized open-label trial design to test at least three experimental Tuberculosis Preventive Treatment TPT regimens to identify at least one regimen of 2 months duration that has non-inferior safety completion and tolerability in adults and children relative to the reference Tuberculosis Preventive Treatment TPT regimen The shortest safest and best tolerated regimen identified in this Phase 2 trial will be tested for effectiveness and efficacy in a Phase 3 trial
Specific Tuberculosis Preventive Treatment TPT regimens All are daily and self-administered Reference Rifampin at a dose of 10 mgkgday for 4 months 4R10 Experimental 1 Rifampin at 20 mgkgday for 2 months 2R20 2 one month Levofloxacin and Rifapentine 1LP At a later stage a 3rd experimental regimen will be selected and added one another novel 1-2-month regimen identified from pre-clinical and clinical studies When selected this will be explained fully including preliminary data on safety and efficacy in an amended protocol and consent - which will be submitted for ethics and regulatory approval at that time
1 Tuberculosis Preventive Treatment TPT is given to healthy people and needs to be safe
2 Tuberculosis Preventive Treatment TPT with shorter regimens are superior with respect to acceptance completion and costs
3 4 months of Rifampin 10mgkg 4R10 is the safest regimen but is completed by 80 of patients
4 The safety of 2 months of Rifampin 20mgkg 2R20 is similar to that of 4 months of Rifampin 10mgkg 4R10 but completion is a concern
5 1-month regimens have promising efficacy
6 Safety and tolerability must be carefully assessed with comparisons to 4 months of Rifampin 10mgkg 4R10 and head-to-head with each other
OBJECTIVES The investigator will use a Bayesian adaptive Phase 2 randomized open-label trial design to test at least three experimental Tuberculosis Preventive Treatment TPT regimens to identify at least one regimen of 2 months duration that has non-inferior safety completion and tolerability in adults and children relative to the reference Tuberculosis Preventive Treatment TPT regimen The shortest safest and best tolerated regimen identified in this Phase 2 trial will be tested for effectiveness and efficacy in a Phase 3 trial
Specific Tuberculosis Preventive Treatment TPT regimens All are daily and self-administered Reference Rifampin at a dose of 10 mgkgday for 4 months 4R10 Experimental 1 Rifampin at 20 mgkgday for 2 months 2R20 2 one month Levofloxacin and Rifapentine 1LP At a later stage a 3rd experimental regimen will be selected and added one another novel 1-2-month regimen identified from pre-clinical and clinical studies When selected this will be explained fully including preliminary data on safety and efficacy in an amended protocol and consent - which will be submitted for ethics and regulatory approval at that time
Detailed Description:
DESIGN The investigator proposes to assess safety completion and tolerability of three experimental Tuberculosis Preventive Treatment TPT regimens in a Phase 2 adaptive trial The investigator will start the trial with the reference 4 months of Rifampin 10mgkg 4R10 and first two experimental regimens 2 months of Rifampin 20mgkg 2R20 one month Levofloxacin and Rifapentine 1LP if either experimental regimen does not meet pre-determined selection criteria the experimental regimen will be dropped if acceptable enrolment will be reduced so that a 3rd new experimental regimen may be tested This will be either one month of Isoniazid plus rifapentine 1HP or an entirely novel regimen this choice will be made on the basis of all available pre-clinical evidence and clinical studies Note that when this 3rd regimen is selected the protocol and informed consent will be revised to include a description of this regimen including results from all pre-clinical and clinical studies of efficacy tolerability and safety The revised consent and protocol will be submitted as an amendment for ethics and regulatory review Randomization will be adjusted as regimens are added or dropped Including new regimens and dropping those with unacceptable safety completion andor tolerability will improve trial efficiency and timeliness of results Regimens will be assessed for acceptability qualitatively health system and patient costs and drug exposure based on pharmacokinetics PK to understand potential trade-offs between dose duration acceptability tolerability and costs After the first 100 persons have completed treatment for each new Tuberculosis Preventive Treatment TPT regimen the investigators plan an early safety analysis to identify whether a regimen has substantially higher rates of severe Adverse Event AE if this were to occur enrolment to that arm will stop After 400 participants have completed each of the two initial experimental regimens the investigators plan an Initial regimen selection analysis Regimens will continue enrolment if the regimen meet the criteria for non-inferior safety completion and tolerability compFared to that of 4 months of Rifampin 10mgkg 4R10 Margins for non-inferiority are stricter for safety - our primary outcome -than for completion and tolerability our secondary outcomes see section 210 for non-inferiority margins and justification The investigators have planned for 24 months of enrolment to evaluate at least three experimental regimens Enrolment will stop after 400 persons have been enrolled to experimental regimen 3 the Final regimen selection analysis will determine which regimen will continue in a Phase 3 trial
STUDY SITES Calgary Edmonton Montreal Ottawa Toronto Vancouver and Winnipeg Canada Cotonou Benin Manaus Brazil Bandung Indonesia and Ho Chi Minh City Vietnam
PLANNED ENROLMENT The first regimen selection analysis will be conducted after 400 participants have completed treatment in each experimental arm The investigators anticipate enrolling 1000 total participants in 13-14 months on the basis of our past performance at all sites and adding three new sites in Canada plus Brazil and Benin which were high enrolling sites in our 4v9 trial After participant 1000 has been enrolled the 3rd experimental regimen will be added and randomization will be modified so that equal numbers are allocated to the 3rd regimen and to all continuing regimens ie a ratio of 3111 for 3rd experimental 4 months of Rifampin 10mgkg 4R10 2 months of Rifampin 20mgkg 2R20 and one month levofloxacin and rifapentine 1LP until the first regimen selection analysis is complete To ensure timely initiation this 3rd regimen must be selected by the end of Year 1 at the latest so that ethics and regulatory approval can be obtained for all sites After the first regimen selection analysis is complete enrolment to experimental regimens 1 andor 2 may stop The investigators expect 1800 total enrollees by mid-Year 3 providing 400 enrollees to the 3rd experimental regimen and an added 400 to be split between 4 months of Rifampin 10mgkg 4R10 and experimental regimens 1 andor 2
RANDOMIZATION Randomization will be by computer-generated random sequences in blocks of variable size and stratified by site to account for previously observed differences between sites in rates of completion and Adverse Events AEs The investigator will allocate all members of the same household for household contacts to the same arm The randomization program will be developed by the same group as for our prior Research Clinical Trials RCTs demo https2r2-demo-ltbcredca Identification 2r2-demo Password 2R2-demo123456789 This will verify eligibility and if another household member was randomized The investigator plan an initial randomization ratio of 122 for 4 months of Rifampin 4R10 2 months of Rifampin 2R20 and 1 month Levofloxacin and Rifapentine 1LP fewer participants need to be randomized to the 4 months of Rifampin 4R10 arm given the availability of results from our three prior 4 months of Rifampin 4R10 trials at the same sites with the same inclusionexclusion criteria similar participant characteristics and very consistent rates of Adverse Event AE and completion DURATION OF TREATMENT AND FOLLOW-UP The investigators wish to ensure that burden on participants of in-person follow-up visits is similar in all arms reduce effects of differential follow-up on treatment completion and also reflect usual care follow-up procedures for the standard arm Given the well-established safety of 4 months rifampin 4R most patients receiving this regimen outside of a study ie routine care are seen in-person only once after 4 weeks of treatment and are called by telephone every month thereafter Hence persons randomized to 4 months of Rifampin 10mgkg 4R10 will be seen at 2 weeks called by telephone at 4 8 and 12-13 weeks then come for a final end-of-treatment in person visit Those randomized to one month levofloxacin and rifapentine 1LP will be seen for routine follow-up visits at 2 weeks of treatment and end-of-treatment 4 weeks Persons randomized to 2 months of Rifampin 20mgkg 2R20 will be seen in person at 2 weeks and end-of-treatment 8-9 weeks To allow detection and response to poor tolerability participants in both experimental arms will be called evaluated at 2 weeks if symptoms of intolerability are reported and if judged not an adverse event the participant will be offered the opportunity to switch to 4 months of Rifampin 10mgkg 4R10 Routine blood tests complete blood count alanine transaminase ALT bilirubin and blood sampling for population pharmacokinetics PK will be performed at 2 weeks for all persons For all regimens participants will be called 2 weeks after the last dose taken to detect possible late Adverse Events AEs During each in-person visit participants will complete an interviewer-administered symptom questionnaire pill counts will be performed and new pills dispensed During telephone follow-up visits the same symptom questionnaire will be administered and participants asked to report pills remaining If a participant wishes to stop therapy the benefits of Tuberculosis Preventive Treatment TPT will be re-emphasized but the participant may stop without negative consequences To reduce bias due to differential efforts to enhance adherence staff will follow Standard Operating Procedures SOPs written pre-trial
In summary safety monitoring will be the most intensive for persons allocated to one month levofloxacin and rifapentine 1LP for which the investigator have the least safety data still quite intensive monitoring for persons allocated to 2 month rifampin 2R20 for which the investigator have reassuring safety data from approximately 450 participants and much less monitoring for the standard regimen but which aligned with current practice In addition to routine visits and calls participants will also be encouraged to call the study coordinator the study participant will be given the study cell phone number which is carried by study personnel 247 or TB clinic nurses at any time if the participant experience symptoms or other problems the participant think might be related to the study medications The participant will also be encouraged to come as walk-ins to the clinic at any time if symptoms or concerns arise
Post-treatment follow-up to detect incident tuberculosis TB disease Participants will be contacted every 3 months until 26 months post-randomization and asked about current symptoms of active tuberculosis TB any intercurrent diagnoses of active tuberculosis TB or hospitalization for any reason Suspected active tuberculosis TB will be investigated At study end the investigators will also cross-check all participants with local nominal registries of tuberculosis TB disease notifications to detect other participants diagnosed with tuberculosis TB disease
PLANNED ANALYSES Safety Our primary analysis is performed within the Bayesian framework using a beta-binomial model that places a non-informative flat prior distribution on the rate parameter Statistical significance is defined with respect to the posterior probability of non-inferiority The investigators will use robust dynamic borrowing methods to incorporate the prior trial data available on the reference treatment into the analysis The weight assigned to previous data will be determined in a sensitivity analysis to ensure controlling the type I error Secondary analyses will include a Bayesian generalized mixed effect model to account for clustering
Regimen completion and tolerability The investigators will use the same beta-binomial model for these two secondary outcomes For both outcomes the investigators specify a larger non-inferiority margin of 10 as the maximum tolerated difference and a more permissive probability threshold of 90 for concluding non-inferiority This means an experimental treatment will be deemed non-inferior to 4R10 with respect to either tolerability or completion if the posterior probability of non-inferiority exceeds 90
Acceptability Transcribed translated and anonymized interview recordings will be thematically analyzed drawing on acceptability frameworks to elucidate participant-prioritized criteria for Tuberculosis Preventive Treatment TPT acceptability The investigators will use researcher reflexivity inter-rater reliability contextualization and gather thick descriptions to enhance rigor Qualitative findings will contextualize quantitative results be triangulated to inform treatment tolerability and adherence data and guide knowledge translation activities
TB Disease This Phase 2 trial is underpowered for this outcome Hence the investigators will describe the incidence of TB disease by arm using total person-time of follow-up of the modified intention to treat MITT population
INTERIM SAFETY ANALYSES To optimize the safety of study participants and identify any major excess in Adverse Event AE rates the investigators plan safety analyses after the first 100 participants are randomized to each new regimen The data and safety monitoring board DSMB will be blinded to study arm during review If needed unblinding will be done The data and safety monitoring board DSMB will make judgments about the strength of the evidence and the absolute magnitude and seriousness of any safety signals rather than absolute stopping rules
PLANNED SUB-GROUP ANALYSES The investigators will examine the association of severe Adverse Events AEs with age sex country and comorbidities and completion and tolerability by age sex country and indication for Tuberculosis Preventive Treatment TPT
STUDY SITES Calgary Edmonton Montreal Ottawa Toronto Vancouver and Winnipeg Canada Cotonou Benin Manaus Brazil Bandung Indonesia and Ho Chi Minh City Vietnam
PLANNED ENROLMENT The first regimen selection analysis will be conducted after 400 participants have completed treatment in each experimental arm The investigators anticipate enrolling 1000 total participants in 13-14 months on the basis of our past performance at all sites and adding three new sites in Canada plus Brazil and Benin which were high enrolling sites in our 4v9 trial After participant 1000 has been enrolled the 3rd experimental regimen will be added and randomization will be modified so that equal numbers are allocated to the 3rd regimen and to all continuing regimens ie a ratio of 3111 for 3rd experimental 4 months of Rifampin 10mgkg 4R10 2 months of Rifampin 20mgkg 2R20 and one month levofloxacin and rifapentine 1LP until the first regimen selection analysis is complete To ensure timely initiation this 3rd regimen must be selected by the end of Year 1 at the latest so that ethics and regulatory approval can be obtained for all sites After the first regimen selection analysis is complete enrolment to experimental regimens 1 andor 2 may stop The investigators expect 1800 total enrollees by mid-Year 3 providing 400 enrollees to the 3rd experimental regimen and an added 400 to be split between 4 months of Rifampin 10mgkg 4R10 and experimental regimens 1 andor 2
RANDOMIZATION Randomization will be by computer-generated random sequences in blocks of variable size and stratified by site to account for previously observed differences between sites in rates of completion and Adverse Events AEs The investigator will allocate all members of the same household for household contacts to the same arm The randomization program will be developed by the same group as for our prior Research Clinical Trials RCTs demo https2r2-demo-ltbcredca Identification 2r2-demo Password 2R2-demo123456789 This will verify eligibility and if another household member was randomized The investigator plan an initial randomization ratio of 122 for 4 months of Rifampin 4R10 2 months of Rifampin 2R20 and 1 month Levofloxacin and Rifapentine 1LP fewer participants need to be randomized to the 4 months of Rifampin 4R10 arm given the availability of results from our three prior 4 months of Rifampin 4R10 trials at the same sites with the same inclusionexclusion criteria similar participant characteristics and very consistent rates of Adverse Event AE and completion DURATION OF TREATMENT AND FOLLOW-UP The investigators wish to ensure that burden on participants of in-person follow-up visits is similar in all arms reduce effects of differential follow-up on treatment completion and also reflect usual care follow-up procedures for the standard arm Given the well-established safety of 4 months rifampin 4R most patients receiving this regimen outside of a study ie routine care are seen in-person only once after 4 weeks of treatment and are called by telephone every month thereafter Hence persons randomized to 4 months of Rifampin 10mgkg 4R10 will be seen at 2 weeks called by telephone at 4 8 and 12-13 weeks then come for a final end-of-treatment in person visit Those randomized to one month levofloxacin and rifapentine 1LP will be seen for routine follow-up visits at 2 weeks of treatment and end-of-treatment 4 weeks Persons randomized to 2 months of Rifampin 20mgkg 2R20 will be seen in person at 2 weeks and end-of-treatment 8-9 weeks To allow detection and response to poor tolerability participants in both experimental arms will be called evaluated at 2 weeks if symptoms of intolerability are reported and if judged not an adverse event the participant will be offered the opportunity to switch to 4 months of Rifampin 10mgkg 4R10 Routine blood tests complete blood count alanine transaminase ALT bilirubin and blood sampling for population pharmacokinetics PK will be performed at 2 weeks for all persons For all regimens participants will be called 2 weeks after the last dose taken to detect possible late Adverse Events AEs During each in-person visit participants will complete an interviewer-administered symptom questionnaire pill counts will be performed and new pills dispensed During telephone follow-up visits the same symptom questionnaire will be administered and participants asked to report pills remaining If a participant wishes to stop therapy the benefits of Tuberculosis Preventive Treatment TPT will be re-emphasized but the participant may stop without negative consequences To reduce bias due to differential efforts to enhance adherence staff will follow Standard Operating Procedures SOPs written pre-trial
In summary safety monitoring will be the most intensive for persons allocated to one month levofloxacin and rifapentine 1LP for which the investigator have the least safety data still quite intensive monitoring for persons allocated to 2 month rifampin 2R20 for which the investigator have reassuring safety data from approximately 450 participants and much less monitoring for the standard regimen but which aligned with current practice In addition to routine visits and calls participants will also be encouraged to call the study coordinator the study participant will be given the study cell phone number which is carried by study personnel 247 or TB clinic nurses at any time if the participant experience symptoms or other problems the participant think might be related to the study medications The participant will also be encouraged to come as walk-ins to the clinic at any time if symptoms or concerns arise
Post-treatment follow-up to detect incident tuberculosis TB disease Participants will be contacted every 3 months until 26 months post-randomization and asked about current symptoms of active tuberculosis TB any intercurrent diagnoses of active tuberculosis TB or hospitalization for any reason Suspected active tuberculosis TB will be investigated At study end the investigators will also cross-check all participants with local nominal registries of tuberculosis TB disease notifications to detect other participants diagnosed with tuberculosis TB disease
PLANNED ANALYSES Safety Our primary analysis is performed within the Bayesian framework using a beta-binomial model that places a non-informative flat prior distribution on the rate parameter Statistical significance is defined with respect to the posterior probability of non-inferiority The investigators will use robust dynamic borrowing methods to incorporate the prior trial data available on the reference treatment into the analysis The weight assigned to previous data will be determined in a sensitivity analysis to ensure controlling the type I error Secondary analyses will include a Bayesian generalized mixed effect model to account for clustering
Regimen completion and tolerability The investigators will use the same beta-binomial model for these two secondary outcomes For both outcomes the investigators specify a larger non-inferiority margin of 10 as the maximum tolerated difference and a more permissive probability threshold of 90 for concluding non-inferiority This means an experimental treatment will be deemed non-inferior to 4R10 with respect to either tolerability or completion if the posterior probability of non-inferiority exceeds 90
Acceptability Transcribed translated and anonymized interview recordings will be thematically analyzed drawing on acceptability frameworks to elucidate participant-prioritized criteria for Tuberculosis Preventive Treatment TPT acceptability The investigators will use researcher reflexivity inter-rater reliability contextualization and gather thick descriptions to enhance rigor Qualitative findings will contextualize quantitative results be triangulated to inform treatment tolerability and adherence data and guide knowledge translation activities
TB Disease This Phase 2 trial is underpowered for this outcome Hence the investigators will describe the incidence of TB disease by arm using total person-time of follow-up of the modified intention to treat MITT population
INTERIM SAFETY ANALYSES To optimize the safety of study participants and identify any major excess in Adverse Event AE rates the investigators plan safety analyses after the first 100 participants are randomized to each new regimen The data and safety monitoring board DSMB will be blinded to study arm during review If needed unblinding will be done The data and safety monitoring board DSMB will make judgments about the strength of the evidence and the absolute magnitude and seriousness of any safety signals rather than absolute stopping rules
PLANNED SUB-GROUP ANALYSES The investigators will examine the association of severe Adverse Events AEs with age sex country and comorbidities and completion and tolerability by age sex country and indication for Tuberculosis Preventive Treatment TPT
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None