Pharmacy and Poisons Board
Protocol No: ECCT/23/05/01 Date of Protocol: 05-04-2021
Study Title:

A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of Two Linezolid Dosing Strategies in Combination with a Short Course Regimen for the Treatment of Drug-Resistant Pulmonary Tuberculosis

A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of Two Linezolid Dosing Strategies in Combination with a Short Course Regimen for the Treatment of Drug-Resistant Pulmonary Tuberculosis

 

Study Objectives:

 

   Primary Objectives

1. To compare time to sputum culture conversion in liquid media between treatment arms.

2. To estimate the occurrence of permanent discontinuation of at least one anti-TB drug due to AEs, intolerance, or death within each treatment arm.

 Secondary Objectives

1. To compare proportion with sputum culture conversion in liquid media at 8, 16, 26, and 38 weeks between treatment arms.

2.To compare permanent discontinuation of LZD due to AEs, intolerance, or death, temporary discontinuation of LZD for any reason, and dose reductions for LZD between treatment arms.

3. To compare the occurrence of treatment-related AEs between treatment arms.

4. To compare the occurrence of unfavorable TB treatment outcome at weeks 26, 38 (for those who extend treatment by 12 weeks), and 72 between treatment arms.

5. To determine LZD pharmacokinetic (PK) parameters for each LZD dosing strategy.

6.To determine DLM PK parameters within each treatment arm.

7. To compare adherence to LZD, BDQ, DLM, and CFZ between treatment arms as determined by recording of the number of observed doses based on directly observed therapy (DOT).

 
Laymans Summary:

This is a research study. Participants who will be  approached regarding this research study will have tuberculosis (TB) that is resistant to some of the drugs generally used to treat it. The purpose of the study is to evaluate the efficacy (how well the medicines work) and tolerability (the level and type of side effects from a drug or treatment) of two different treatment regimens that contain the same four anti-TB medicines: linezolid (LZD), bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study will also measure the level of these medicines in your blood.

Hypothesis;  Linezolid (LZD) administered at an initial dose of 1200 mg daily for 4 weeks followed by 1200 mg three times per week (TIW), plus bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) will be associated with more rapid sputum culture conversion and acceptable rates of treatment discontinuations due to adverse events (AEs), intolerance, and death compared to LZD administered at a dose of 600 mg daily in combination with BDQ, DLM, and CFZ.

The 2 primary objectives are to 1.Compare time to sputum culture conversion in liquid media between treatment arms. And 2 To estimate the occurrence of permanent discontinuation of at least one anti-TB drug due to AEs, intolerance, or death within each treatment arm.

 

 
 
 

 
1 To include additional information to the Rationale section to reflect the recently available ZeNix trial data. • To clarify co-enrollment guidelines. • To update the formulation of clofazimine from tablets to capsules. • To revise the TB Treatment Status Determination definitions and outcome measures to better align with the WHO’s new definitions of TB treatment outcome and with outcomes measured in other TB treatment trials. • To correct an intensive PK visit sampling time. • To revise the Sample Informed Consent for corrections • To incorporate revisions in some of the toxicity management subsections.
Abstract of Study:

DESIGN                   A5356 is a phase II, prospective, randomized, two-arm, open-label, multicenter clinical trial to evaluate the anti-tuberculosis (TB) activity, safety, and tolerability of an injectable-free short course regimen for treatment of multidrug-/rifampicin-resistant (MDR-/RR-), pre-extensively drug-resistant (pre-XDR-), and extensively drug-resistant (XDR-) TB comparing two dosing strategies of linezolid (LZD) combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ).

 

DURATION              72 weeks total: at least 26 weeks (6 months) of anti-TB treatment, with up to 46 weeks of follow-up.

 

SAMPLE SIZE         132 participants (66 per treatment arm)

 

POPULATION          Participants aged 18 years and older, with or without HIV, with newly diagnosed pulmonary MDR/RR-TB, pre-XDR-TB, or XDR-TB (collectively noted as DR-TB in the protocol).

 

Participants may be enrolled with a positive rapid diagnostic test for MDR/RR-TB such as Cepheid Xpert MTB/RIF, Cepheid Xpert MTB/RIF Ultra, Hain GenoType MTBDRplus, Hain GenoType MTBDRsl, or other World Health Organization (WHO)-endorsed rapid diagnostic test or with screening phenotypic drug susceptibility testing (DST) from a sputum specimen collected within 60 days prior to entry.

 

Participants living with HIV are required to either be on ART or be willing to start ART within 30 days after entry.

 

REGIMENS              At entry, all participants will be randomized 1:1 to one of two treatment arms (Arm A or Arm B). The only difference in treatment between the two arms is the dosing schedule for LZD, as shown below.

 

Arm A

Weeks 1-26: LZD 600 mg once daily (QD)

Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD

Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD

Weeks 9-26 or -38: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

 

Arm B

Weeks 1-4: LZD 1200 mg QD

Weeks 5-26: LZD 1200 mg three times per week (TIW)

Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD

Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD

Weeks 9-26 or -38: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

 

Participants who do not achieve sputum culture conversion by 16 weeks of treatment will extend their treatment by an additional 12 weeks for a total treatment duration of 38 weeks.

 
1
  1. The protocol team roster, glossary of protocol-specific terms, and references have been updated. 
  2. The following revisions implemented via previous LOA (LOA #1, dated 22Oct2021) have been incorporated in several sections.
  • Additional information has been added to the Rationale section to reflect the available ZeNix trial data.
  • In section 4.4, co-enrollment guidelines have been clarified.
  • In sections 5.1.2 and 5.2.4, formulation of clofazimine has been corrected from tablets to capsules.
  • Section 6.3.18 has been revised to better align with the World Health Organization’s (WHO) new definitions of TB treatment outcome and with outcomes measured in other TB treatment trials.
  • In section 11.2.1.1, a correction has been made to intensive PK visit sampling time.
  • The Sample Informed Consent has been revised for corrections – to remove the 12-hour time point and to remove reference to whole genome sequencing.
  1. In the Schema and other sections (4.1.2, 6.1-1, and 6.3.11), Cepheid Xpert MTB/XDR has been added as a possible diagnostic test method.
  2. Additional information has been made to the Background and Rationale sections (sections 2.1 and 2.2).
  3. In sections 4.1.9 and 6.3.10, method for calculating creatinine clearance (CrCl) has been updated to add “or other ACTG-accepted equation or algorithm”.
  4. Exclusion criterion 4.2.5 has been modified for clarity. For clarity, a note below previous 4.2.5 has been added as exclusion 4.2.6.
  5. In section 4.3.1, an addition is made in the context of protocol amendment implementation timeline.
  6. In section 5.1.3, a revision has been made to the intake of study drugs within a specified window with respect to meal consumption.
  7. In section 6.1, Schedule of Evaluations footnotes have been revised for clarity and consistency.
  8. In section 6.2.4, a revision has been made to the Premature TB Treatment Discontinuation Evaluations subsection.
  9. Section 6.3.5 has been revised for consistency and clarity.
  10. In section 6.3.10, a note has been added obtaining lactate levels.
  11. Revisions have been made in section 6.3.11 for consistency and clarity.
  12. Section 7.2 has been updated to make a revision to AE reporting criteria and to provide a specific grading table for creatinine values for the study.
  13. In section 7.3.1, a website link has been added for the DAIDS EAE form.
  14. Section 7.4 has been revised to reflect an update to the monitoring plan.
  15. In section 8.1, Grade 3 and Grade 4 subsections have been revised.
  16. Revisions have been incorporated in specific toxicities management subsections – sections 8.2.4, 8.2.6, 8.2.7, 8.2.8, 8.2.11, and 8.2.13.
  17. Section 10.6.1 has been added to outline analysis sets. Information has been added to sections 10.6.2, 10.6.3, and 10.6.4 to reflect the definitions outlined in 10.6.1.
  18. In section 12.3.1, additional info regarding monitoring visits has been added.
  19. In the Sample Informed Consent WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? subsection, a revision has been made regarding the intake of study drugs within a specified window with respect to meal consumption.
  20. In APPENDIX III: SAMPLE CONSENT FORM FOR USE OF SAMPLES AND INFORMATION IN OTHER STUDIES, information has been added about ACTG study A5302.
  21. For consistency, where applicable, entry/baseline has been used. Thus, instances of baseline/entry have been changed to entry/baseline. To avoid confusion, these are not noted in bold.