BTZ-043 Dose Evaluation in Combination and Selection

NCT05926466 | Unknown Phase 2 DMC

• 2 other identifiers: LMU-IMPH-BTZ-043-04UNITE4TB-02
• Study Type: interventional
• Target: 90
• Locations: 2 countries
• Sites: 4

Brief Summary

This is a phase 2B, open label study, that will compare the safety and efficacy of three experimental regimens consisting of bedaquiline and delamanid in combination with different doses of BTZ-043, a novel antibiotic, in adult participants with newly diagnosed, drug-sensitive pulmonary tuberculosis. Participants will be assigned to receive either one of the three BTZ-043-containing regimens or a comparator regimen consisting of bedaquiline, delamanid and moxifloxacin. The objective is to find the optimal dose of BTZ-043 with the highest efficacy and safety to be used in subsequent studies.

Conditions

Tuberculosis, Pulmonary; Other Specified Pulmonary Tuberculosis

Keywords

Tuberculosis; BTZ-043; Bedaquiline; Delamanid; Moxifloxacin; Safety; Tolerability; Pharmacokinetics (PK); Benzothiazinones; Pulmonary Tuberculosis; Dose-finding; Antitubercular agents

Outcome Measures

Primary Outcomes (1)

• Time to positivity in BD MGIT liquid culture

  To evaluate which of the BTZ-043 containing experimental arms is superior, the change in mycobacterial load over time on treatment as quantified by time to positivity in BD MGIT 960® (Mycobacterium Growth Tube Indicator) liquid culture described by non-linear mixed-effects methodology

  Day 01- Day 112

Secondary Outcomes (15)

• Time to stable culture conversion to negative in liquid media

  Day 01- Day 112

• Proportion of participants converting to negative sputum culture in liquid media

  Day 01- Day 112

• Frequency of all adverse events (serious and non-serious)

  Day 01- Day 168

• Frequency of adverse events of Grade 3 severity (severe) or higher

  Day 01- Day 168

• Frequency of adverse events possibly, probably or definitely related to study drug

  Day 01- Day 168

Study Arms (4)

Arm 1

ACTIVE COMPARATOR

Drug: Moxifloxacin Moxifloxacin will be dosed at the licensed dose of 400 mg orally once daily for 16 weeks Drug: Bedaquiline Bedaquiline will be dosed at 400 mg orally once daily for the first 2 weeks, followed by 100 mg orally once daily for 14 weeks Drug: Delamanid Delamanid will be dosed at 300 mg orally once daily for 16 weeks

Drug: Bedaquiline; Drug: Delamanid; Drug: Moxifloxacin

Arm 2

EXPERIMENTAL

Drug: Bedaquiline Bedaquiline will be dosed at 400 mg orally once daily for the first 2 weeks, followed by 100 mg orally once daily for 14 weeks Drug: Delamanid Delamanid will be dosed at 300 mg orally once daily for 16 weeks Drug: BTZ-043 BTZ-043 will be dosed at 500 mg orally once daily for 16 weeks

Drug: BTZ-043; Drug: Bedaquiline; Drug: Delamanid

Arm 3

EXPERIMENTAL

Drug: Bedaquiline Bedaquiline will be dosed at 400 mg orally once daily for the first 2 weeks, followed by 100 mg orally once daily for 14 weeks Drug: Delamanid Delamanid will be dosed at 300 mg orally once daily for 16 weeks Drug: BTZ-043 BTZ-043 will be dosed at 1000 mg orally once daily for 16 weeks

Drug: BTZ-043; Drug: Bedaquiline; Drug: Delamanid

Arm 4

EXPERIMENTAL

Drug: Bedaquiline Bedaquiline will be dosed at 400 mg orally once daily for the first 2 weeks, followed by 100 mg orally once daily for 14 weeks Drug: Delamanid Delamanid will be dosed at 300 mg orally once daily for 16 weeks Drug: BTZ-043 BTZ-043 will be dosed at 1500 mg orally once daily for 16 weeks

Drug: BTZ-043; Drug: Bedaquiline; Drug: Delamanid

Interventions

BTZ-043 DRUG

BTZ-043 belongs to the chemical class of benzothiazinones, and is a promising antibiotic for the treatment of Tuberculosis. Its mechanism of action is based on the covalent inhibition of the enzyme decaprenylphosphoryl-ß-D-ribose-2'-epimerase (DprE1), which is essential for the cell wall assembly of mycobacteria. . Formation of the covalent adduct between BTZ-043 and DprE1 results in inhibition of cell wall biosynthesis and loss of viability of Mycobacteria Tuberculosis. BTZ-043 has been evaluated in three clinical studies: a phase Ia, First Time in Human study (FTIH), a two-stage phase Ib multiple ascending dose (MAD) and phase IIa monotherapy early bactericidal activity (EBA) study, and a human ADME (Absorption/Distribution/Metabolism/Excretion) study.

Arm 2; Arm 3; Arm 4

Bedaquiline DRUG

Bedaquiline, is a diarylquinoline compound with a novel mechanism of action against MTB, the inhibition of mycobacterial adenosine triphosphate (ATP) synthase. On the 28th of December 2012, the Food and Drug Administration (FDA) granted accelerated approval to SIRTURO® (bedaquiline) tablets as a part of combination therapy in adults with MDR-TB. It is the first to be introduced specifically for the treatment of MDR-TB in combination with other drugs.

Also known as: SIRTURO®

Arm 1; Arm 2; Arm 3; Arm 4

Delamanid DRUG

Delamanid is a nitro-dihydro-imidazooxazole derivative that inhibits the synthesis of mycolic acids, a crucial component of the cell wall of MTB. Delamanid has received regulatory approvals in several countries and is currently recommended by WHO for for use in longer MDR- or RR-TB regimens in line with WHO recommendations.

Also known as: OPC-67683, Deltyba

Arm 1; Arm 2; Arm 3; Arm 4

Moxifloxacin DRUG

Moxifloxacin belongs to the group of fluoroquinolones (FQ). FQs are a mainstay of MDR-TB treatment, and Moxifloxacin is considered the most potent drug in second line MDR-TB therapy, recently reviewed by WHO, with only moderate pre-existing resistance in the community.

Also known as: Lonxave

Arm 1

Eligibility Criteria

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

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures, including HIV testing.
• Male or female, aged 18 up to (and including) 64 years.
• Body weight (in light clothing and with no shoes) within the range of 30 to 100kg and body mass index within the range of 15 to 40kg/m2.
• Newly diagnosed, previously untreated current episode of drug-susceptible pulmonary TB (presence of MTB complex with rapid molecular test result confirming susceptibility to rifampicin and isoniazid such as "GeneXpert" and/or "HAIN MTBDR plus").
• ≥ 1 sputum sample from concentrated spot sputum positive in GeneXpert MTB/RIF Ultra®, with semi-quantitative result at least "medium" or higher.
• FEMALE PARTICIPANTS: Inability to conceive AND/OR inability of partner(s) to father children OR consent to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:
• a. Non-childbearing potential: i) Bilateral oophorectomy AND/OR hysterectomy OR bilateral tubal ligation more than 12 months ago, AND/OR has been postmenopausal with a history of no menses for at least 12 consecutive months as per medical history.
• ii) Sexual partner(s) of female participant: vasectomy OR bilateral orchidectomy at least three months prior to screening as per medical history.
• b. Effective contraception methods: i) Two methods, including methods used by patient's sexual partner(s). At least one must be a barrier method. Contraception must be practised for at least until 12 weeks after the last dose of BTZ-043.
• \- MALE PARTICIPANTS: Inability to father children AND/OR inability of partner(s) to conceive, OR consent to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:
• c. Non-childbearing potential: i) Sexual partner(s) of male participant: Bilateral oophorectomy AND/OR hysterectomy OR bilateral tubal ligation more than 12 months ago, AND/OR has been postmenopausal with a history of no menses for at least 12 consecutive months as per medical history.
• ii) Vasectomy OR bilateral orchidectomy at least three months prior to screening as per medical history.
• iii) Female pregnant sexual partner of a male participant: agree to use at least one barrier method.
• iv) Male sexual partner of male participant: agree to use at least one barrier method for at least until 12 weeks after the last dose of BTZ-043 for protection of the partner.
• d. Effective contraception methods: ii) Two methods, including methods used by patient's female sexual partner(s). At least one must be a barrier method. Effective contraception must be ensured for at least 16 weeks after the last dose of BTZ-043

You may not qualify if:

• Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. in a prisoner or person suffering from an intellectual disability).
• Poor general condition, where delay in treatment cannot be tolerated, or death within three months is likely, as assessed by the investigator.
• Poor social condition which would result in a high likelihood of not completing the trial until the final visit.
• The patient is pregnant or breast-feeding.
• The patient is HIV antibody positive (known, or on a test performed at screening), unless:
• The patient has a viral load (VL) \< 200 copies/mL on a test performed at screening
• The patient has a CD4 cell count \> 200 cells/mm3 at screening
• The patient is experienced on antiretroviral therapy (ART), and is on a combination of tenofovir, lamivudine and dolutegravir (TDF/3TC/DTG) for a minimum of 6 months prior to the screening visit.
• The patient has a known intolerance to any of the study drugs or concomitant disorders or conditions for which study drugs or standard TB treatment are contraindicated.
• The patient has received treatment with any other investigational drug within 1 month prior to enrolment, or is planning to be enrolled into other clinical (intervention) trials during participation.
• The patient has a history of or current evidence of clinically relevant cardiovascular, metabolic, gastrointestinal, neurological, ophthalmological, psychiatric or endocrine diseases, malignancy or any other condition, that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:
• Clinically significant evidence of severe or extra-thoracic TB (e.g., miliary TB, TB meningitis, excluding limited lymph node involvement)
• Serious lung conditions other than TB or significant respiratory impairment in the discretion of the investigator
• Peripheral neuropathy (as evaluated by the Brief Peripheral Neuropathy Score).
• Significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required in the last five years or is anticipated to be required.

Sponsors & Collaborators

• Michael Hoelscher: lead
• Radboud University Medical Center: collaborator
• University of California, San Francisco: collaborator
• University College, London: collaborator

Study Sites (4)

TASK Applied Sciences Clinical Research Centre

Cape Town, 7500, South Africa

RECRUITING

TASK Applied Science Eden

George, 6529, South Africa

NOT YET RECRUITING

National Institute for Medical Research (NIMR-MMRC)

Mbeya, Tanzania

RECRUITING

National Institute for Medical Research (NIMR-Mwanza),

Mwanza, Tanzania

RECRUITING

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; bedaquiline; OPC-67683; Moxifloxacin

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)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Michael Hoelscher, Prof Dr

  LMU University Hospital

  STUDY DIRECTOR

Central Study Contacts

Michael Hoelscher, Prof Dr

CONTACT

+49894400; michael.hoelscher@med.uni-muenchen.de

Norbert Heinrich, PD Dr

CONTACT

+49894400; norbert.heinrich@med.uni-muenchen.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director, Division for Infectious Diseases and Tropical Medicine

Model Details: The study will compare the efficacy, safety of 3 experimental regimens with a comparator regimen administered over 16 weeks, in participants with newly diagnosed, drug sensitive pulmonary tuberculosis.

Study Record Dates

• First Submitted: June 22, 2023
• First Posted: July 3, 2023
• Study Start: September 21, 2023
• Primary Completion: August 1, 2024
• Study Completion: August 1, 2024
• Last Updated: December 22, 2023

Record last verified: 2023-12

Locations

ZA (2); TA (2)