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

• Status: Recruiting
• Trial end date: 2022-03-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Michael Hoelscher
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP); German Federal Ministry of Education and Research; Radboud University
• Treatments: Dolutegravir; Ethambutol; Isoniazid; Pyrazinamide; Rifampin

Criteria

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)