A Phase 2 Trial to Evaluate the EBA, Safety and Tolerability of Eto Alone and in Combination With BVL-GSK098 (BETO)

A Phase 2 Trial to Evaluate the EBA, Safety and Tolerability of Ethionamide Alone and in Combination With BVL-GSK098 Administered Orally to Adults With Newly Diagnosed, Rifampicin- and Isoniazid-Susceptible Pulmonary Tuberculosis

To evaluate the 7-day early bactericidal activity (EBA), pharmacokinetics (PK), safety and tolerability of ethionamide (Eto) with or without BVL-GSK098 in participants with rifampicin- and isoniazid-susceptible pulmonary TB.

Study Overview

• Status: Recruiting
• Conditions: Rifampicin- and Isoniazid-Susceptible Pulmonary Tuberculosis (TB)
• Intervention / Treatment: Drug: BVL-GSK098 9mg; Drug: Ethionamide 250mg; Drug: Isoniazid 300 MG; Drug: Ethionamide 250 mg

Detailed Description

A single-centre, open-label, clinical trial in two stages. All treatments will be administered orally (PO) on days 1-7.

Stage 1 will recruit 15 participants into arm 1 who will receive Eto and a low dose BVL-GSK098 combination (bEto), including 3 participants from the control arm (arm 2). Participants will be randomized 5:1. This will be followed by a recruitment pause and an interim analysis to evaluate safety of the combination.

Stage 1:

Arm Regimen Participants

1. BVL-GSK098 9 mg once daily (OD) plus ethionamide 250 mg OD (b9Eto250) 15
2. Isoniazid 300 mg po OD (INH) 3 * BVL-GSK098 9 mg will be given 12-hourly on Day one (loading dose), then once daily on Day 2-7.

An interim safety analysis will be performed after all Stage 1 participants complete the end of treatment visit (Day 8). If the b9Eto250 arm meets the predefined safety criteria (Section 9), the study will proceed to Stage 2. Recruitment will then continue with the remaining arms randomized in a 4:5:5:5:5:5 ratio.

Stage 2:

Arm Regimen Participants 2 Isoniazid 300 mg po OD (INH) 12 3 BVL-GSK098 27 mg OD plus ethionamide 125 mg po OD (b27Eto125) 15 4 BVL-GSK098 27 mg OD plus ethionamide 250 mg po OD (b27Eto250) 15 5 BVL-GSK098 27 mg OD plus ethionamide 500 mg po OD (b27Eto500) 15 6 Ethionamide 250 mg po OD (Eto250) 15 7 Ethionamide 750 mg po given in a single or divided dose daily (Eto750) 15

* BVL-GSK098 27 mg will be given 12-hourly on Day one (loading dose), then once daily on Day 2-7. Ethionamide 750 mg given in divided doses Day 1-3, and OD Day 4-7.

Participants on INH will serve as control for the EBA quantitative mycobacteriology. The study will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.

• Study Type: Interventional
• Enrollment (Anticipated): 105
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kim Nieuwenhout; Phone Number: +27211003606; Email: regulatory@task.org.za

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7530
      • Recruiting
      • Task Clinical Research Centre
      • Contact: Veronique de Jager, HBChB; Phone Number: +27219141044; Email: dr.veronique@task.org.za

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- Participants are required to meet all the following criteria in order to be randomized.

1. Provide written, informed consent prior to all trial-related procedures.
2. Male or female, aged between 18 and 65 years, inclusive.
3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
4. Newly diagnosed and untreated pulmonary TB.
5. Rifampicin- and isoniazid-susceptible pulmonary TB as determined by molecular testing (GeneXpert XDR or Genotype MTBDRplus for INH).
6. A chest X-ray taken during the screening period or up to 2 weeks before screening which, in the opinion of the investigator, is consistent with TB.
7. GeneXpert positive with a quantitative readout of medium or high.
8. Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
9. Be of non-childbearing potential or using effective methods of birth control.

10. For WOCBP, injectable or other contraceptive methods (per Appendix 1) need to be given prior to or during screening, and at least 2 days prior to first dose of IP.

    Exclusion Criteria:

    • Participants will be excluded from participation if they fulfil any of the following criteria.

    Medical History

11. Evidence of clinically significant conditions or findings, other than TB, that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
12. History of epilepsy, seizures or other neuropsychiatric disorders that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator
13. History of hypothyroidism
14. QTcF of >450 ms at baseline
15. Clinically significant evidence of extrathoracic TB, as judged by the investigator.
16. History of allergy to any of the trial IP as confirmed by the clinical judgement of the investigator.
17. Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.

18. HIV positive AND:

    1. CD4 < 250cells/mm3
    2. OR, on ART in stage 1 only. Participants established on ART (2 NRTIs and dolutegravir) for more than 30 days at start of screening are eligible for participation in stage 2.

    NOTE: ART permitted in Stage 2 is limited to the following in line with local guidelines for 1st line ART:

    • NRTIs selected from: Emtricitabine, Lamivudine, Tenofovir
    • PLUS Dolutegravir

    As the drug-drug interaction potential of ART has not been fully investigated with the IP, NNRTIs (efavirenz, nevirapine) and other protease inhibitors will not be permitted in this study.

19. Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of trial participation. Male participant planning to conceive a child for at least 90 days, after the last dose of study intervention in the trial.

    Treatment History

20. Participation in other clinical studies with investigational agents within 8 weeks prior to screening.
21. Treatment received for this episode of TB with any drug active against M.tb (including but not limited to isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides).
22. Treatment with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; BVL-GSK098 9 mg once daily (OD) plus ethionamide 250 mg OD (b9Eto250)	Drug: BVL-GSK098 9mg; BVL-GSK098 9 mg once daily po OD plus ethionamide 250 mg po OD (b9Eto250) BVL-GSK098 27 mg OD plus ethionamide 125 mg po OD (b27Eto125 BVL-GSK098 27 mg OD plus ethionamide 250 mg po OD (b27Eto250) BVL-GSK098 27 mg OD plus ethionamide 500 mg po OD (b27Eto500); Other Names: Ethionamide 125 and 250mg; Drug: Ethionamide 250mg; Ethionamide 250 mg po OD (Eto250)
Active Comparator: Arm 2; Isoniazid 300 mg po OD (INH)	Drug: Isoniazid 300 MG; Isoniazid 300 mg po OD (INH)
Experimental: Arm 3; BVL-GSK098 27 mg OD plus ethionamide 125 mg po OD (b27Eto125)	Drug: BVL-GSK098 9mg; BVL-GSK098 9 mg once daily po OD plus ethionamide 250 mg po OD (b9Eto250) BVL-GSK098 27 mg OD plus ethionamide 125 mg po OD (b27Eto125 BVL-GSK098 27 mg OD plus ethionamide 250 mg po OD (b27Eto250) BVL-GSK098 27 mg OD plus ethionamide 500 mg po OD (b27Eto500); Other Names: Ethionamide 125 and 250mg; Drug: Ethionamide 250mg; Ethionamide 250 mg po OD (Eto250)
Experimental: Arm 4; BVL-GSK098 27 mg OD plus ethionamide 250 mg po OD (b27Eto250)	Drug: BVL-GSK098 9mg; BVL-GSK098 9 mg once daily po OD plus ethionamide 250 mg po OD (b9Eto250) BVL-GSK098 27 mg OD plus ethionamide 125 mg po OD (b27Eto125 BVL-GSK098 27 mg OD plus ethionamide 250 mg po OD (b27Eto250) BVL-GSK098 27 mg OD plus ethionamide 500 mg po OD (b27Eto500); Other Names: Ethionamide 125 and 250mg; Drug: Ethionamide 250 mg; Ethionamide 750 mg po given in a single or divided dose (Eto750); Other Names: Ethionamide 250mg
Experimental: Arm 5; BVL-GSK098 27 mg OD plus ethionamide 500 mg po OD (b27Eto500)	Drug: Ethionamide 250mg; Ethionamide 250 mg po OD (Eto250)
Experimental: Arm 6; Ethionamide 250 mg po OD (Eto250)	Drug: Ethionamide 250 mg; Ethionamide 750 mg po given in a single or divided dose (Eto750); Other Names: Ethionamide 250mg
Experimental: Arm 7; Ethionamide 750 mg po given in a single or divided dose daily (Eto750)	Drug: Ethionamide 250mg; Ethionamide 250 mg po OD (Eto250)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EBA CFU	The EBA CFU(0-7) as determined by the predicted rate of change in log10CFU per ml sputum over the period day 0 to day 7 will be described using linear, bi-linear or non-linear functions using nonlinear mixed effects modelling as dictated by the data of log10CFU over time and relation to drug exposure. Predicted estimate of rates of change including uncertainties for the potential differences in treatment effects between the groups will be given and graphically illustrated.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EBA TTP	The EBA TTP(0-7) as determined by the predicted rate of change in TTP over the period day 0 to day 7 will be described using linear, bi-linear or non-linear functions using nonlinear mixed effects modelling of TTP over time and relation to drug exposure.	7 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	The incidence of the following events will be summarized by treatment group: Incidence of treatment-emergent adverse events (TEAEs);; Incidence of TEAEs by Severity;; Incidence of drug related TEAEs;; Incidence of Serious TEAEs;; Incidence of TEAEs leading to early withdrawal;; Incidence of TEAEs leading to death. Descriptive summary statistics will be presented for other safety variables: laboratory parameters, physical examination, vital signs, concomitant medication.	7 days

Collaborators and Investigators

• Sponsor: TASK Applied Science
• Investigators: Principal Investigator: Veronique de Jager, MBChB, TASK

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2022
• Primary Completion (Anticipated): October 1, 2023
• Study Completion (Anticipated): October 1, 2023

Study Registration Dates

• First Submitted: July 12, 2022
• First Submitted That Met QC Criteria: July 21, 2022
• First Posted (Actual): July 25, 2022

Study Record Updates

• Last Update Posted (Actual): January 19, 2023
• Last Update Submitted That Met QC Criteria: January 17, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Antitubercular Agents; Fatty Acid Synthesis Inhibitors; Isoniazid; Ethionamide
• Other Study ID Numbers: TASK-010-BETO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Plan not yet available
• IPD Sharing Time Frame: Immediately after publication.
• IPD Sharing Access Criteria: Not available yet
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No