Pharmacy and Poisons Board
Protocol No: ECCT/19/04/05 Date of Protocol: 25-09-2018
Study Title:

A5300B/I2003B/PHOENIx "Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients"

Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB)

Study Objectives:

 Primary Objectives:

Among HIV-infected and other child, adolescent, and adult HHCs of MDR-TB patients at high risk of developing TB:

  • To compare the efficacy of 26 weeks of DLM versus 26 weeks of INH for preventing confirmed or probable active TB during 96 weeks of follow-up.
  • To compare the safety (permanently stopping study drug due to treatment-related adverse events) of 26 weeks of DLM versus 26 weeks of INH for the treatment of presumed latent TB infection (LTBI) with MDR-TB.

 

Secondary Objectives:

  • To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in HHCs of MDR-TB patients by their HIV status (i.e., HIV-infected vs HIV-negative, indeterminate, or have unknown HIV status).
  • To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in each of the three high risk populations of HHCs enrolled (i.e., children aged <5 years; HIV-infected or non-HIV immunosuppressed adults, adolescents, and children ≥5 years; TST+ and/or IGRA+ adults, adolescents, and children aged ≥5 years who are HIV-negative, indeterminate, or have unknown HIV status and are not non-HIV immunosuppressed).
  • To compare the efficacy of DLM versus INH for preventing confirmed active MDR-TB.
  • To compare the efficacy of DLM versus INH in reducing all-cause mortality.
  • To compare the efficacy of DLM versus INH for reducing the composite outcome of confirmed or probable TB and all-cause mortality.
  • To compare the proportions of Grades 3 or higher events among HHCs receiving DLM versus INH.
  • To compare the drug-susceptibility pattern and whole genome sequence of the index case to that of confirmed incident TB cases among HHCs.
  • To evaluate factors, including index case characteristics, index case TB status at the end of HHC study treatment, household characteristics, and characteristics of HHCs, HHC medication adherence, and pharmacokinetic (PK) measures, as predictors of the risk of confirmed or probable TB among HHCs or possible modifiers of the difference in risk between randomized arms.
  • To describe the PK and safety of DLM administered once daily in children, 0 to <5 years old.
Laymans Summary:

This is a phase III, open-label, multicenter trial with a cluster-randomized superiority design (eligible contacts in the same household [HH] are a cluster), to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active TB during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years

The hypothesis is that treating child, adolescent, and adult household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) patients, including those with pre-extensively (pre-XDR) and extensively drug resistant (XDR) TB, who are at high risk of developing TB with delamanid (DLM), will substantially reduce the risk of developing TB compared with treatment with isoniazid (INH) preventive therapy.

The 2 primary objectives are to 1) compare the efficacy of 26 weeks of DLM versus 26 weeks of INH for preventing confirmed or probable active TB during 96 weeks of follow and 2) To compare the safety (permanently stopping study drug due to treatment-related adverse events) of 26 weeks of DLM versus 26 weeks of INH for the treatment of presumed latent TB infection (LTBI) with MDR-TB.
5 The changes, except for deletions, are noted in bold in the protocol document. Minor corrections were made in the protocol document for clarification and editorial purposes.
Abstract of Study:

DESIGN                      A Phase III, open-label, multicenter trial with a cluster-randomized superiority design (eligible contacts in the same household [HH] are a cluster), to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active TB during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.

Each site will have a run-in phase, where the site will demonstrate feasibility to identify adults with MDR-TB (index cases), access their HHs, screen HHCs, and enroll and follow eligible HHCs.

DURATION                 96 weeks for each participating HHC and index case.

SAMPLE SIZE            The preliminary estimate of the required sample size is 3452 high-risk HHCs to be enrolled from 1726 HHs with an index case confirmed as having MDR-TB (assuming a mean of two eligible contacts per HH). It is anticipated that about 20% of index cases enrolled won’t be from HHs with eligible high-risk HHCs, therefore, the number of index cases enrolled will be larger than 1726, and will be approximately 2158. Therefore, there will be approximately 5610 participants enrolled (approximately 2158 index cases and 3452 HHCs).

RANDOMIZATION     Randomization will be balanced by site with approximately equal numbers of HHs allocated to each of the study arms and no restriction on the number of HHs enrolled per site.

POPULATION            An index case is defined as an adult (18 years and older) with pulmonary MDR-TB who has started MDR-TB treatment within the past 90 days.

An HHC is defined as a person who currently lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the index case and who reports exposure within 90 days prior to the index case starting MDR-TB treatment. Also, shared >4 hours of indoor airspace with the index case during any one-week period prior to the index case starting MDR-TB treatment.

Following enrollment of an eligible index case with permission to complete an HH visit, HHCs will be screened for eligibility.

Only HHCs of index cases who are at high risk of developing TB will be enrolled into the study:

  • Children 0 to <5 years of age regardless of tuberculin skin test (TST)/interferon gamma release assay (IGRA), or HIV status;
  • Adults, adolescents, and children ≥5 years of age who are TST-positive (≥5 mm) and/or IGRA-positive and whose HIV status is negative, indeterminate, or unknown and who are not non-HIV immunosuppressed;
  • Adults, adolescents, and children ≥5 years of age who are HIV-infected or are non-HIV immunosuppressed (defined as receiving anti-tumor necrosis factor (TNF) treatment, or being solid organ or hematologic transplant recipients), regardless of TST/IGRA status.

REGIMEN                   If at least one HHC within an HH is found to be eligible, the HH will be randomized in approximately equal numbers, to one of the following:

Arm A:

  • DLM daily for adults, adolescents, and children, given for 26 weeks

Arm B:

  • INH daily for adults, adolescents, and children, given for 26 weeks  
  • Pyridoxine (vitamin B6) daily for adults, adolescents, and children, given for 26 weeks

All high-risk HHCs in the same HH will receive the same randomized regimen.

 
5
  1. The Protocol Title Page, Team Roster, Study Management Section, Glossary of Protocol-Specific Terms, and References in Section 17 have been updated.
  2. Exploratory objective for children aged <15 years added. (Section 1.4.9)
  3. WHO recommendation for the use of delamanid (DLM) to treat RR-TB disease in children 0-17 years of age added. (Section 2.4.1.2)
  4. Safety of DLM information added. (Section 2.4.1.5)
  5. History of major psychiatric disorders was added as an exclusion criterion. (Section 4.2.9)
  6. DLM and Isoniazid weight-based dosing information for children has been revised. (Section 5.1.1, and APPENDIX V: DELAMANID DOSING TABLES)
  7. Missed dosing information has been revised. (Section 5.1.3)
  8. Study drug provision and evaluation window information has been updated to account for potential unsafe conditions for study staff and/or participants. (Sections 5.1.4, 6.2.4, Table 6.1-2)
  9. Clarification has been made regarding DST on the mycobacterial isolate. (Table 6.1-1, Section 6.3.1.7, 6.3.1.8)
  10. Targeted Neuropsychiatric Signs & Symptoms evaluation has been added. (Table 6.1-2, Sections 6.3.3.4, 8.2.8)
  11. Evaluations for a Neuropsychiatric Adverse Event has been added. (Table 6.1-2, Section 6.2.4)
  12. Information on AE reporting and frequency of liver function, serum creatinine (a component of Blood Chemistries), and ECG evaluations added for HHCs who enrolled before or after November 1, 2021. (Table 6.1-2)
  13. Maximum total blood volume for children <5 years of age, and ≥5 years to <15 years of age has been revised. (Table 6.1-2)
  14. Details on discontinuation study visits/evaluations for household contacts (HHCs) has been revised. (Table 6.1-2, Section 6.2.5)
  15. ACTG protocol template language has been updated. (Sections 6.3, and 13.3.3, APPENDIX I: SAMPLE INFORMED CONSENT – INDEX CASE, APPENDIX II: SAMPLE INFORMED CONSENT – HOUSEHOLD CONTACT, and APPENDIX III: SAMPLE INFORMED CONSENT – PARENT OF CHILD AND ADOLESCENT HOUSEHOLD CONTACTS, WHAT ABOUT CONFIDENTIALITY?, WHAT HAPPENS IF I AM INJURED?)
  16. HHC pharmacokinetic sample information clarified to note HHCs currently taking study drug. (Section 6.3.3.22)
  17. HHC cost and quality of life assessment has been revised. (Section 6.3.3.32)
  18. Adverse Event (AE) collection and reporting requirements for this protocol has been updated. (Sections 7.2 and 7.3.2)
  19. Monitoring of Grade 2 or higher AEs and all neuropsychiatric AEs has been added. (Section 7.4.1)
  20. DSMB review of HHCs with Grade 1 or higher hallucinations related to study drug has been updated. (Section 7.4.3)
  21. Grading and management of neuropsychiatric symptoms in children and adults added. (Section 8.1, Appendix VI)
  22. AST and ALT elevation has been updated. (Section 8.2.2)
  23. Elevated Total Bilirubin has been updated. (Section 8.2.3)
  24. All enrolled HHCs have gone off study has been added to index case premature study discontinuation. (Section 9.1 and APPENDIX I: SAMPLE INFORMED CONSENT – INDEX CASE, WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY?)
  25. Efficacy primary outcome measure has been updated. (Section 10.2.1)
  26. An exploratory outcome measure has been added. (Sections 10.2.3 and 10.6.7)
  27. Statistical stopping guideline for evaluating efficacy has been revised. (Section 10.5.1)
  28. Information on sensitivity and supplementary analyses has been added. (Sections 10.6.1, 10.6.2, 10.6.3, and 10.6.4)
  29. Sparse PK sample information has been clarified. (Sections 11.3.1, 11.3.1.3)
  30. APPENDIX I: SAMPLE INFORMED CONSENT – INDEX CASE
    • Clarification has been made regarding study treatment not being provided for MDR-TB participants.
  31. APPENDIX II: SAMPLE INFORMED CONSENT – HOUSEHOLD CONTACT, and APPENDIX III: SAMPLE INFORMED CONSENT – PARENT OF CHILD AND ADOLESCENT HOUSEHOLD CONTACTS
    • Study Treatment information has been added and risks updated.
    • Asking the participant about difficulty sleeping, anxiety, or hallucinations has been added.
    • Evaluations if participant is having difficulty sleeping, anxiety, or hallucinations has been added.
    • Breastfeeding information has been revised.
    • Clarifying that DLM is approved in various countries for treating MDR-TB in adults has been added.
  32. APPENDIX II: SAMPLE INFORMED CONSENT – HOUSEHOLD CONTACT, APPENDIX III: SAMPLE INFORMED CONSENT – PARENT OF CHILD AND ADOLESCENT HOUSEHOLD CONTACTS, and APPENDIX IV: SAMPLE ASSENT FORM
  • Adjusting DLM and INH dose for children based on weight during the study has been added.