A Study of the Early Effects, Safety, and Acceptability of Oral Alpibectir in Combination With Ethionamide

NCT06748937 | Recruiting Phase 2 DMC

• 2 other identifiers: TASKUNITE4TB-03
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

A multi-centre, randomized, open-label clinical trial. All treatments will be administered orally (PO) on days 1-14. 15 participants will be recruited into each treatment arm in two sequential cohorts. Each cohort will have participants enrolled onto the experimental regimen(s) or the standard of care (SOC; HRZE) control arm.

• Cohort 1 aims to generate safety data for a higher dose of alpibectir plus ethionamide 125 mg and 250 mg (arm 1: A45E125 and arm2: A45E250). Once 5 participants have enrolled into arms 1 and 2 each, and completed 14 days of treatment, an interim safety review will be conducted to determine whether the study can advance to cohort 2.
• Cohort 2 will investigate safety of alpibectir and ethionamide (A45E250) in combination with rifampicin, pyrazinamide and ethambutol (A45E250RZE). Participants on HRZE will serve as control for the EBA quantitative mycobacteriology in each cohort, and additionally as a safety benchmark for the A45E250RZE arm. The study is not statistically powered to make between arm comparisons of activity or safety. The treatment will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.

Conditions

Tuberculosis

Keywords

Alpibectir; Ethionamide; Rifampicin; Pyrazinamide; Ethambutol; Adults; Newly Diagnosed; Drug- Susceptible; Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (1)

• EBA-TTP (0-14)

  The EBA TTP (0-14) as determined by the rate of change in log10TTP in sputum over the period day 0 (baseline sample) to Day 14 will be described using linear, bi-linear, or non-linear functions using nonlinear mixed effects modelling of log10TTP over time. Estimates of rates of change including uncertainties for each treatment group will be given and graphically illustrated.

  14 days

Secondary Outcomes (14)

• EBA CFU (0-14)

  14 days

• EBA (0-2) and EBA (2-14)

  2-14 days

• Safety and tolerability

  14 days

• PK analysis - Cmax

  14 days

• Biomarkers (Sputum)

  14 days

Study Arms (5)

Cohort 1 Arm 1 (A45E125)

EXPERIMENTAL

Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD

Drug: Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD

Cohort 1 Arm 2 (A45E250)

EXPERIMENTAL

Alpibectir 45 mg OD plus Ethionamide 250 mg OD

Drug: Alpibectir 45 mg OD plus Ethionamide 250 mg OD

Cohort 1 Arm 3 (HRZE)

ACTIVE COMPARATOR

Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based

Drug: Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based

Cohort 2 Arm 3 (HRZE)

ACTIVE COMPARATOR

Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based

Drug: Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based

Cohort 2 Arm 4 (A45E250RZE)

EXPERIMENTAL

Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD

Drug: Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD

Interventions

Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD DRUG

Cohort 1 Arm 1

Cohort 1 Arm 1 (A45E125)

Alpibectir 45 mg OD plus Ethionamide 250 mg OD DRUG

Cohort 1 Arm 2

Cohort 1 Arm 2 (A45E250)

Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based DRUG

Active Comparator

Cohort 1 Arm 3 (HRZE); Cohort 2 Arm 3 (HRZE)

Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD DRUG

Cohort 2 Arm 4

Cohort 2 Arm 4 (A45E250RZE)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures and willing to adhere to all required study procedures and restrictions for the duration of the trial.
• Male or female, aged between 18 and 65 years, inclusive.
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Newly diagnosed and untreated for this episode of pulmonary TB.
• Rifampicin- and isoniazid susceptible pulmonary TB as determined by molecular testing (GeneXpert XDR or Genotype MTBDRplus for INH).
• 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.
• GeneXpert positive with a quantitative readout of medium or high.
• Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
• Be of non-childbearing potential or of childbearing potential using effective methods of birth control, as defined in section 5.2 and in Appendix 1.
• Female Participants
• For WOCBP who are not already receiving contraception per Appendix 1 requirements, agree to receive injectable or other contraceptive methods (per Appendix 1), to be given during screening, and at least 1 day prior to first dose of IMP.
• Male Participants
• Agree to ALL of the following during the study intervention period and for at least 90 days, after the last dose of study intervention:
• Refrain from donating fresh unwashed semen
• Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.

You may not qualify if:

• 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.
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the investigator.
• History of epilepsy, seizures or other neuropsychiatric disorders that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
• Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• History of hypothyroidism
• QTcF of \>450 ms at baseline
• Clinically significant evidence of extra-thoracic TB, as judged by the investigator.
• History of allergy to any of the trial IMP as confirmed by the clinical judgement of the investigator.
• Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.
• HIV positive AND:
• CD4 \< 250cells/mm3
• On other ART regimen not listed below or, if not on ART they are not willing to wait to start treatment until completion of study regimen
• Note: ART regimens permitted is limited to the following in line with local guidelines for 1st line ART:
• NRTIs selected from: Emtricitabine, Lamivudine, Tenofovir
• PLUS Dolutegravir 50 mg daily, or 50 mg twice daily if randomized to a rifampicin containing arm.

Sponsors & Collaborators

• TASK Applied Science: lead
• Innovative Medicines Initiative: collaborator

Study Sites (1)

TASK

Cape Town, Western Cape, 7550, South Africa

RECRUITING

Related Links

• SANCTR

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Interventions

Ethionamide; Isoniazid; Rifampin; Pyrazinamide; Ethambutol

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Hydrazines; Organic Chemicals; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Gifty Okyere-Manu, MBChB

  TASK

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gifty Okyere-Manu, MBChB

CONTACT

0211002046; dr.gifty@task.org.za

Vani Govender, Masters Medical Science

CONTACT

0211002046; vani.g@task.org.za

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2024
• First Posted: December 27, 2024
• Study Start: March 3, 2025
• Primary Completion: March 30, 2026
• Study Completion: March 30, 2026
• Last Updated: March 7, 2025

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)