Safety, Tolerability and Pharmacokinetic Profile of PBTZ169 Formulated as Native Crystal Powder: Multiple Ascending Doses, Randomized, Placebo- Controlled, Parallel-group, Sequential Phase Ib Trial in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- PBTZ169
- Conditions
- Tuberculosis, Pulmonary
- Sponsor
- Innovative Medicines for Tuberculosis
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Safety and tolerability of increasing multiple oral doses of PBTZ169 in healthy male adult subjects evaluated by Treatment Emergent Adverse Events (TEAEs).
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a randomized, double-blind, placebo-controlled, multiple ascending dose study conducted at one study center in Switzerland.
Four (4) panels (A, B, C and D) of 8 male subjects (6 active and 2 placebo) each receiving multiple doses of PBTZ169 or a matching placebo, at increasing dose levels, once or twice daily.
Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment, 1 under placebo) will be investigated in parallel. Panels will start sequentially.
Safety will be assessed throughout the study; serial ECGs and serial blood samples will be collected for the safety and PK assessment of PBTZ169.
Dose escalation will be allowed once the Trial Safety Board has determined that adequate safety and tolerability after each panel completion has been demonstrated to permit proceeding to the next panel.
In addition, a preliminary assessment of the drug interaction potential of PBTZ169 will be done by the measurement of inhibition or induction of human cytochromes through the metabolism of microdoses of standard probe substrates
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy male subjects aged between 18 and 48 years
- •Body weight (BW) ranging between 55 and 95 kg, providing body mass index (BMI) is between 18 and 28 kg/m2
- •Absence of significant findings in the medical history and physical examination as judged by the Investigator, especially for cardiovascular, pulmonary, haematological and nervous systems
- •Absence of significant laboratory abnormalities as judged by the Investigator. Gilbert's syndrome (increased total and unconjugated bilirubin when fasting) will be accepted if mild. Moderate creatine kinase increases (up to 600 IU/L) without clinical abnormalities, commonly found in physically active young males.
- •Absence of clinically significant abnormalities on 12-lead ECG
- •Negative urine drug screen (amphetamines, benzodiazepines, cannabis, cocaine, opiates)
- •Commitment to refrain from travel outside Europe over the whole study duration
- •Ability to understand the procedures, agreement to participate and willingness to give written informed consent
- •Co-operative attitude and availability for scheduled visits over the entire study period
- •Commitment to refrain from alcohol and tobacco consumption over the whole study period.
Exclusion Criteria
- •History of major cardiovascular, pulmonary, hepatic, immunological, renal, haematological, gastrointestinal, genitourinary, neurological, or rheumatologic disorders
- •Active diseases of any type, including inflammatory disorders and infections. Mild acne is permissible providing no systemic or local treatment is provided or planned (except for cleaning lotions)
- •History of significant allergy or asthma. Allergic rhinitis or conjunctivitis is acceptable if non-symptomatic when starting the study and if symptoms are not anticipated to occur during the study to a point that would require corticosteroid therapy (e.g. in case of annual use)
- •History of cardiovascular dysfunction if considered as clinically relevant (conduction abnormality, arrhythmia, bradycardia, angina pectoris, cardiac hypertrophy unless elicited by training, pulmonary embolism)
- •Hypertension defined as supine blood pressure \>150/90 mmHg or recurrent hypotensive events considered as clinically relevant or documented orthostatic hypotension
- •Sick sinus syndrome, known long QT syndrome, reproducible observation of corrected QT interval QTc ≥440 msec or of pronounced sinus bradycardia (\<40 bpm/min)
- •Intense sport activities. Moderate sport is acceptable and activities should remain fairly constant throughout the study
- •Any clinically significant laboratory values on screening that are not within normal range on single repeat (Gilbert's syndrome or CK elevations usually acceptable if moderate)
- •Positive hepatitis B and C antigen screen
- •Positive HIV antibody screen or screen not performed
Arms & Interventions
Panel A - Active
N = 6, 150 mg twice daily of PBTZ169
Intervention: PBTZ169
Panel A - Placebo
N = 2, 150 mg twice daily of PBTZ169 matching placebo
Intervention: Placebo
Panel B - Active
N = 6, 300 mg twice daily of PBTZ169
Intervention: PBTZ169
Panel B - Placebo
N = 2, 300 mg twice daily of PBTZ169 matching placebo
Intervention: Placebo
Panel C - Active
N = 6, 600 mg once daily of PBTZ169
Intervention: PBTZ169
Panel C - Placebo
N = 2, 600 mg once daily of PBTZ169 matching placebo
Intervention: Placebo
Panel D - Active
N = 6, 600 mg twice daily of PBTZ169
Intervention: PBTZ169
Panel D - Placebo
N = 2, 600 mg twice daily of PBTZ169 matching placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Safety and tolerability of increasing multiple oral doses of PBTZ169 in healthy male adult subjects evaluated by Treatment Emergent Adverse Events (TEAEs).
Time Frame: Days 0-17
Evaluation by thorough monitoring of Treatment Emergent Adverse Events (TEAEs) following doses of PBTZ169 crystalline or placebo
Secondary Outcomes
- Relative oral bioavailability assessment of PBTZ169 in healthy male subjects after multiple dosing(Days 0-17)
- Metabolism interaction of multiple oral doses of PBTZ169 by measuring ratios of 7 probe substrates before the first and and after the last dose(Days -1 to 14)
- Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Cmax(Days 0-17)
- Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Tmax(Days 0-17)