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

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

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.

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:

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.

General inclusion criteria:

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.

2. Understand and willing to comply with the study procedures.

3. Male or female adults, aged 18 up to and including 64 years.

4. Body weight ≥ 40 kg.

5. 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:

6. Newly diagnosed, previously untreated, drug-susceptible pulmonary TB

7. Chest X-ray which is consistent with TB

8. Ability to produce an adequate volume of sputum (at least 10ml estimated overnight production)

9. ≥ 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:

1. Poor general condition, where delay in treatment cannot be tolerated or death within three months is likely, as assessed by the investigator.

2. The patient is pregnant or breast-feeding.

   Disease-specific exclusion criteria:

3. The patient is infected with HIV.

4. 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.

5. Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.

6. 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:

   1. Clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis, excluding limited lymph node involvement)
   2. Serious lung conditions other than TB or significant respiratory impairment in the discretion of the investigator
   3. Neuropathy, epilepsy or significant psychiatric disorder
   4. Any diabetes mellitus
   5. Cardiovascular disease, such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
   6. Current or history of hypertension (systolic blood pressure >135 mmHg and/or diastolic blood pressure of >85 mmHg) AND/OR ever received antihypertensive treatment)
   7. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
   8. 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:

7. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity >2x the upper limit of normal (ULN)

8. serum alkaline phosphatase (ALP) or y-glutamyl transferase (GGT) > 2x the ULN

9. serum total bilirubin level >1.5 times the ULN

10. estimated creatinine clearance (eCrCl) using the Cockcroft and Gault formula level lower than 60 mls/min

11. haemoglobin level <8.0 g/dL

12. platelet count <100,000/mm3

13. serum potassium below the lower level of normal (LLN) for the laboratory

    ECG-specific exclusion criteria:

14. corrected QT interval (QTc)F of > 450 milliseconds (ms)

15. Atrioventricular (AV) block with PR interval > 200 ms

16. QRS complex > 120 ms

17. any other changes in the ECG that are clinically relevant as per discretion of the investigator

    Restricted medication:

18. Treatment with drugs active against Mycobacterium Tuberculosis (MTB) within the last 3 months prior to screening

19. 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)