BTZ-043 - Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)

Sponsor

Michael Hoelscher (Other)

Overall Status

Completed

CT.gov ID

NCT04044001

Collaborator

European and Developing Countries Clinical Trials Partnership (EDCTP) (Other), Radboud University Medical Center (Other), German Federal Ministry of Education and Research (Other)

Enrollment

Locations

Arms

30.5

Actual Duration (Months)

38.5

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective, open label, two-centre, randomized, controlled, two-stage, phase Ib/IIa study to evaluate the safety, tolerability, PK, drug-drug interaction and bactericidal activity of BTZ-043 administered orally once daily over 14 days to participants with newly diagnosed, uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis.

The primary objective is to assess the safety and tolerability of BTZ-043 given over 14 days by evaluation of adverse events during treatment and follow-up period in patients with newly diagnosed, uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Tuberculoses Other Specified Pulmonary Tuberculosis	Drug: BTZ-043 Drug: Rifafour e-275® Drug: Probe Drug Cocktail Drug: Dolutegravir 50mg Tab	Phase 1/Phase 2

Detailed Description

Stage 1 is an escalating dose design in up to eight cohorts receiving different doses of BTZ-043 to define a safe dose corridor for BTZ-043. The focus of this stage is on adverse events, PK and a food-effect PK-evaluation .

Stage 2 is a parallel group comparison of 4 arms receiving different treatment regimens:

three arms to receive BTZ-043 in different doses within the safe corridor defined in stage 1, compared to one arm receiving Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol as a control. This stage is focusing on adverse effects, early bactericidal activity (EBA), PK and an evaluation of PK drug-drug interaction potential.

A total of up to 77 male and female patients, aged ≥ 18 - 64 years, with newly diagnosed, smear positive, drug sensitive pulmonary tuberculosis will be enrolled.

Allocation of patients will be carried out in two stages:

Stage 1: for each cohort 3 patients will be enrolled, treated and followed-up accordingly, starting with cohort 1. In a Trial Steering Committee (TSC) meeting, decision will be made on the dose in the next cohort.

Dose escalation steps to be followed, if no safety concerns arise:

Cohort 1: patients to receive 250 mg BTZ-043
Cohort 2: patients to receive 500 mg BTZ-043
Cohort 3: patients to receive 750 mg BTZ-043
Cohort 4: patients to receive 1000 mg BTZ-043
Cohort 5: patients to receive 1250 mg BTZ-043
Cohort 6: patients to receive 1500 mg BTZ-043
Cohort 7: patients to receive 1750 mg BTZ-043
Cohort 8: patients to receive 2000 mg BTZ-043

Patients receiving the investigational drug in cohorts 1 - 8 will take BTZ-043 in fasting state for 13 days and after a pre-defined high-fat, high-caloric meal on day 14.

After all patients of a current cohort have completed at least 7 days of dosing, the TSC, composed of the national principal investigator (PI), the trial statistician, the sponsor representative and two independent scientists, will review safety data, including clinical, lab and electrocardiography (ECG) data, to assess whether dose limiting toxicity of BTZ-043, as defined below, has been observed in any participant. Depending on the outcome, the TSC will then decide on dose escalation, or on enrolling more participants to the same or a lower dose in the following cohort, according to dose escalation and stopping rules.

After the end of stage 1, the TSC will decide which of the BTZ-043 doses, which are deemed to not exceed the acceptable toxicity level, are to be moved to stage 2.

Stage 2: after the highest possible dose of the investigational drug, that has proven to be safe within the 1st stage, is identified, all remaining patients will be recruited and randomised to receive one of three different doses of BTZ-043 or to control treatment with Rifafour e-275® at a ratio of 3:3:3:2 favouring the experimental treatment.

Stage 2 is focusing on adverse effects, early bactericidal activity (EBA), PK and an evaluation of PK drug-drug interaction potential.

Allocation of patients:

Arm 1: patients to receive BTZ-043 in a higher dose
Arm 2: patients to receive BTZ-043 in a medium dose
Arm 3: patients to receive BTZ-043 in a lower dose
Control Arm 4: patients to receive Rifafour e-275® as control treatment

Participants will take in BTZ-043 in either fasted or fed state, depending on which state has shown to lead to higher exposure during the 1st stage.

Additional measurements in the 2nd stage in BTZ-arms 1 to 3 only:

• Drug-drug interactions will be investigated: patients, who have been randomized to BTZ-043 arms, will additionally be randomized to receive either a probe drug cocktail, with drugs specifically metabolized by certain enzymes, or dolutegravir at a ratio of 2:1. Probe drugs or Dolutegravir (DTG) will be given pre-BTZ on day 0 and on day 14.

After the course of study drugs is completed (on day 14), all patients (in stage 1 and stage 2) will be referred to a government clinic to complete their course of tuberculosis (TB) according to national standards for a total of 6 months of first-line therapy.

Study Design

Study Type:

Interventional

Actual Enrollment :

77 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Stage 1: We will enrol patients sequentially in up to 8 cohorts of at least 3 patients to receive BTZ-043 in ascending doses. Patients in the first cohort will receive the lowest dose of 250mg of BTZ-043 for 14 days. After each patient in a cohort has completed at least 7 days, a dosing recommendation for the next cohort will be made using the continual reassessment method (CRM) algorithm. Stage 2: This will be a parallel group comparison of 4 treatment regimens. Patients will be randomized to receive either one of three doses of BTZ-043 within the therapeutic window defined in stage 1, or the control regimen of daily doses of Rifafour e-275®, adapted to body weight, for 14 days in the ratio 3:3:3:2.Stage 1: We will enrol patients sequentially in up to 8 cohorts of at least 3 patients to receive BTZ-043 in ascending doses. Patients in the first cohort will receive the lowest dose of 250mg of BTZ-043 for 14 days. After each patient in a cohort has completed at least 7 days, a dosing recommendation for the next cohort will be made using the continual reassessment method (CRM) algorithm. Stage 2: This will be a parallel group comparison of 4 treatment regimens. Patients will be randomized to receive either one of three doses of BTZ-043 within the therapeutic window defined in stage 1, or the control regimen of daily doses of Rifafour e-275®, adapted to body weight, for 14 days in the ratio 3:3:3:2.

Masking:

Single (Outcomes Assessor)

Masking Description:

Laboratory staff, analysing and evaluating the sputum and safety blood samples of the participants will be blinded to the treatment cohort/arm.

Primary Purpose:

Treatment

Official Title:

A Prospective Phase Ib/IIa, Active-controlled, Randomized, Open-label Study to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Multiple Oral Doses of BTZ-043 Tablets in Subjects With Newly Diagnosed, Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis

Actual Study Start Date :

Nov 15, 2019

Actual Primary Completion Date :

Mar 3, 2022

Actual Study Completion Date :

May 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stage 1 - Cohort 1 (BTZ 250) Patients will receive 1 tablet of BTZ-043 orally once daily, containing 250mg BTZ-043 from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 2 (BTZ 500) Patients will receive 2 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (500 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 3 (BTZ 750) Patients will receive 3 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (750 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 4 (BTZ 1000) Patients will receive 4 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1000 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 5 (BTZ 1250) Patients will receive 5 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1250 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 6 (BTZ 1500) Patients will receive 6 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1500 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 7 (BTZ 1750) Patients will receive 7 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1750 mg in total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 1 - Cohort 8 (BTZ 2000) Patients will receive 8 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (2000 total) from Day 1 through to Day 14	Drug: BTZ-043 BTZ-043 (250mg per tablet)
Experimental: Stage 2 - Arm 1 (BTZ high) Patients will receive a higher dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.	Drug: BTZ-043 BTZ-043 (250mg per tablet) Drug: Probe Drug Cocktail A probe drug cocktail will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. The probe drug cocktail consists of Caffeine: 1 tablet à 150mg Tolbutamide: 1/4 tablet à 500mg Dextromethorphan: 10 ml syrup à 15mg/5ml Midazolam:2 ml solution à 5mg/5ml Digoxin: 2 tablets à 0.25mg Drug: Dolutegravir 50mg Tab 1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. Other Names: Tivicay®
Experimental: Stage 2 - Arm 2 (BTZ medium) Patients will receive a medium dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.	Drug: BTZ-043 BTZ-043 (250mg per tablet) Drug: Probe Drug Cocktail A probe drug cocktail will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. The probe drug cocktail consists of Caffeine: 1 tablet à 150mg Tolbutamide: 1/4 tablet à 500mg Dextromethorphan: 10 ml syrup à 15mg/5ml Midazolam:2 ml solution à 5mg/5ml Digoxin: 2 tablets à 0.25mg Drug: Dolutegravir 50mg Tab 1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. Other Names: Tivicay®
Experimental: Stage 2 - Arm 3 (BTZ low) Patients will receive a lower dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.	Drug: BTZ-043 BTZ-043 (250mg per tablet) Drug: Probe Drug Cocktail A probe drug cocktail will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. The probe drug cocktail consists of Caffeine: 1 tablet à 150mg Tolbutamide: 1/4 tablet à 500mg Dextromethorphan: 10 ml syrup à 15mg/5ml Midazolam:2 ml solution à 5mg/5ml Digoxin: 2 tablets à 0.25mg Drug: Dolutegravir 50mg Tab 1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. Other Names: Tivicay®
Active Comparator: Stage 2 - Arm 4 (control) Patients will receive a standard dose of Rifafour e-275® orally once daily according to body weight from Day 1 through to Day 14. Each tablet of Rifafour e-275® contains 150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide and 275mg ethambutol. The daily doses will be given to fasting patients, in accordance with South African Guidelines for treatment of TB. The total number of tablets will be based on the body weight at screening: participants weighing 38 - 54 kg: 3 tablets participants weighing 55 - 70 kg: 4 tablets participants weighing >70 kg: 5 tablets	Drug: Rifafour e-275® Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet) Other Names: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)

Outcome Measures

Primary Outcome Measures

Safety and tolerability of BTZ-043 [Day 1 to Day 22]
Safety and tolerability of BTZ-043 will be assessed by evaluation of Adverse Events (AEs) during treatment- and follow-up phase

Secondary Outcome Measures

Bactericidal Activity Endpoint - MGIT [Day -1 to Day 14]
• changes in time to detection in the Mycobacteria Growth Indicator Tube (MGIT™) liquid media culture system from baseline
Bactericidal Activity Endpoint - CFU [Day -1 to Day 14]
• changes in solid media colony forming units (CFU) from baseline
Bactericidal Activity Endpoint - LAM [Day -1 to Day 14]
• changes in sputum lipoarabinomannan (LAM) concentration from baseline
Bactericidal Activity Endpoint - MBLA [Day -1 to Day 14]
• changes in sputum molecular bacterial load assay (MBLA) from baseline
Pharmacokinetic Endpoint - BTZ-043 - AUC [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the area under the plasma concentration curve (AUC)
Pharmacokinetic Endpoint - BTZ-043 - Cmax [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the observed maximum concentration (Cmax)
Pharmacokinetic Endpoint - BTZ-043 - Tmax [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the time to reach Cmax (Tmax)
Pharmacokinetic Endpoint - BTZ-043 - Cmin [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the minimum observed plasma concentration 24 hours following the last dose (Cmin)
Pharmacokinetic Endpoint - BTZ-043 - Cl [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Clearance (Cl)
Pharmacokinetic Endpoint - BTZ-043 - Vd [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Volume of distribution (Vd)
Pharmacokinetic Endpoint - BTZ-043 - T1/2 [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Elimination half-life (T1/2)
Pharmacokinetic Endpoint - BTZ-043 - pharmacodynamics (PD) [Day 1, 12 and 14]
The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Relation of efficacy measurements to pharmacokinetic indices of BTZ-043 and its metabolites (AUC, Cmax)
Pharmacokinetic Endpoint - Population PK AUC [Day 1, 12 and 14]
A population PK-analysis of BTZ-043 and its two major metabolites will be carried out by measuring the AUC and describing PK differences of BTZ-043 and its main metabolites between subjects to quantify inter-individual variability, suitable for evaluation of alternative dosing regimens
Pharmacokinetic Endpoint - Population PK Cmax [Day 1, 12 and 14]
A population PK-analysis of BTZ-043 and its two major metabolites will be carried out by measuring the Cmax and describing PK differences of BTZ-043 and its main metabolites between subjects to quantify inter-individual variability, suitable for evaluation of alternative dosing regimens
Pharmacokinetic Endpoint - Food Effect PK AUC [Day 14]
The effect of food on the exposure of the BTZ-043 and its two major metabolites will be determined by measuring the AUC of BTZ-043 and its main metabolites and by evaluating the change after a high fat high calorie meal in comparison to the AUC under fasting conditions during the 1st stage.
Pharmacokinetic Endpoint - Food Effect PK Cmax [Day 14]
The effect of food on the exposure of the BTZ-043 and its two major metabolites will be determined by measuring the Cmax of BTZ-043 and its main metabolites and by evaluating the change after a high fat high calorie meal in comparison to the Cmax under fasting conditions during the 1st stage.
Pharmacokinetic Endpoint - Probe Drugs PK AUC [Day 0 and 14]
The effect on BTZ-043 at steady state on hepatic enzyme and P-glycoprotein activity (induction vs. inhibition) will be evaluated by measuring changes in AUC of the probe drugs administered on day 0, and day 14 during the 2nd stage.
Pharmacokinetic Endpoint - Probe Drugs PK Cmax [Day 0 and 14]
The effect on BTZ-043 at steady state on hepatic enzyme and P-glycoprotein activity (induction vs. inhibition) will be evaluated by measuring changes in Cmax of the probe drugs administered on day 0, and day 14 during the 2nd stage.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

General inclusion criteria:

Provide written, informed consent prior to all trial-related procedures including HIV testing.
Understand and willing to comply with the study procedures.
Male or female adults, aged 18 up to and including 64 years.
Body weight ≥ 40 kg.
Participants are either unable to conceive/father children AND/OR they will be using two effective methods of contraception, including methods used by the patient's sexual partner(s). At least one to be a barrier method.

Disease-specific inclusion criteria:

Newly diagnosed, previously untreated, drug-susceptible pulmonary TB
Chest X-ray which is consistent with TB
Ability to produce an adequate volume of sputum (at least 10ml estimated overnight production)
≥ 1 sputum sample from concentrated sputum positive for acid-fast bacilli on microscopy (at least 1+ on the International Union Against Tuberculosis and Lung Disease/World Health Organization (IUATLD/WHO) scale) from either a spot sputum or overnight sputum sample.

General exclusion criteria:

Poor general condition, where delay in treatment cannot be tolerated or death within three months is likely, as assessed by the investigator.
The patient is pregnant or breast-feeding.

Disease-specific exclusion criteria:

The patient is infected with HIV.
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.
Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
The patient has a history of or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, 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 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
Neuropathy, epilepsy or significant psychiatric disorder
Any diabetes mellitus
Cardiovascular disease, such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
Current or history of hypertension (systolic blood pressure >135 mmHg and/or diastolic blood pressure of >85 mmHg) AND/OR ever received antihypertensive treatment)
Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
Alcohol or other drug abuse, that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage, at the discretion of the investigator

Laboratory exclusion criteria at screening:

Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity

2x the upper limit of normal (ULN)

serum alkaline phosphatase (ALP) or y-glutamyl transferase (GGT) > 2x the ULN
serum total bilirubin level >1.5 times the ULN
estimated creatinine clearance (eCrCl) using the Cockcroft and Gault formula level lower than 60 mls/min
haemoglobin level <8.0 g/dL
platelet count <100,000/mm3
serum potassium below the lower level of normal (LLN) for the laboratory

ECG-specific exclusion criteria:

corrected QT interval (QTc)F of > 450 milliseconds (ms)
Atrioventricular (AV) block with PR interval > 200 ms
QRS complex > 120 ms
any other changes in the ECG that are clinically relevant as per discretion of the investigator

Restricted medication:

Treatment with drugs active against Mycobacterium Tuberculosis (MTB) within the last 3 months prior to screening
Requires medication as included in the following drug classes within 2 weeks prior to the first dose of study treatment:

medication that prolongs the QTc interval
Cytochrome P450 (CYP450) inhibitors or inducers, including grapefruit containing foods / beverages and St. John's Wort
Antacids or antipeptic drugs (antacids, H2 blockers, proton pump inhibitors)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	TASK Applied Sciences Clinical Research Centre	Cape Town		South Africa	7530
2	University of Cape Town Lung Institute (UCTLI)	Cape Town		South Africa	7700

Sponsors and Collaborators

Michael Hoelscher
European and Developing Countries Clinical Trials Partnership (EDCTP)
Radboud University Medical Center
German Federal Ministry of Education and Research

Investigators

Study Director: Michael Hoelscher, Prof, University Hospital, LMU Munich, Division of Infectious Diseases and Tropical Medicine
Principal Investigator: Andreas Diacon, Prof, TASK Applied Science Clinical Research Centre