Status and phase
Conditions
Treatments
About
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.
Full description
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:
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:
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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
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:
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:
Primary purpose
Allocation
Interventional model
Masking
77 participants in 12 patient groups
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal