Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Ex-vivo Antitubercular Activity of PBTZ169 Formulation

NCT03423030 | Completed Phase 1 DMC

• 1 other identifier: IM-006-11
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomized, double-blind, placebo-controlled, single 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 undergoing 2 investigation periods and receiving either single doses of PBTZ169 at increasing dose levels or a matching placebo. Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment, 1 under placebo) will be investigated in parallel. Panels A and B are interleaved. 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 panel B and panel C completion has been demonstrated to permit proceeding to the next panel.

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of increasing single oral doses of PBTZ169 Formulation in healthy male adult subjects evaluated by Treatment Emergent Adverse Events (TEAEs).

  Evaluation by thorough monitoring of Treatment Emergent Adverse Events (TEAEs) following doses of PBTZ169 Formulation, PBTZ169 NCP or placebo

  Days 0-17

Secondary Outcomes (5)

• Relative oral bioavailability assessment of the PBTZ169 Formulation in comparison to NCP in healthy male subjects

  Days 0-2

• Pharmacokinetics (PK) of single oral doses of PBTZ169 using Cmax

  Days 0-2

• Pharmacokinetics (PK) of single oral doses of PBTZ169 using Tmax

  Days 0-2

• Pharmacodynamics (PD) exploration after single oral doses of PBTZ169 Formulation and NCP

  Days 0-1

• Broncho-alveolar passage exploration after single oral doses of PBTZ169 Formulation and NCP (tentative)

  Days 0-1

Study Arms (8)

Panel A - Active

EXPERIMENTAL

N = 6, 10 mg then 40 mg of PBTZ169 Formulation

Drug: PBTZ169 Formulation

Panel A - Placebo

PLACEBO COMPARATOR

N = 2, 10 mg then 40 mg of matching placebo

Drug: Placebo

Panel B - Active

EXPERIMENTAL

N = 6, 20 mg then 80 mg of PBTZ169 Formulation

Drug: PBTZ169 Formulation

Panel B - Placebo

PLACEBO COMPARATOR

N = 2, 20 mg then 80 mg of matching placebo

Drug: Placebo

Panel C - Active

EXPERIMENTAL

N = 6, First dosing of Panel C with 160 mg PBTZ169 Formulation then Second dosing of Panel C with 160 mg PBTZ169 Native Crystalline Powder (NCP)

Drug: PBTZ169 Formulation; Drug: PBTZ169 NCP

Panel C - Placebo

ACTIVE COMPARATOR

N = 2, 160 mg of matching placebo for the two interventions

Drug: Placebo

Panel D - Active

EXPERIMENTAL

N = 6, First dosing of Panel D with 320 mg PBTZ169 Formulation then Second dosing of Panel D with 320 mg PBTZ169 Native Crystalline Powder (NCP)

Drug: PBTZ169 Formulation; Drug: PBTZ169 NCP

Panel D - Placebo

ACTIVE COMPARATOR

N = 2, 320 mg of matching placebo for the two interventions

Drug: Placebo

Interventions

PBTZ169 Formulation DRUG

PBTZ169 Formulation supplied as powder for oral solution

Panel A - Active; Panel B - Active; Panel C - Active; Panel D - Active

Placebo DRUG

matching placebo supplied as powder for oral solution

Panel A - Placebo; Panel B - Placebo; Panel C - Placebo; Panel D - Placebo

PBTZ169 NCP DRUG

PBTZ169 NCP supplied as powder for oral solution

Panel C - Active; Panel D - Active

Eligibility Criteria

• Age: 18 Years - 48 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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 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 acceptable if mild)
• Positive hepatitis B and C antigen screen
• Positive HIV antibody screen or screen not performed
• Any recent acute illness or sequelae thereof which could expose the subject to a higher risk or might confound the results of the study
• Treatment in the previous three months with any drug known to have well-defined potential for toxicity to a major organ
• History of hypersensitivity to any drug if considered as serious
• Use of any medication the week prior to study or as based on the 5 plasma half-life rule and throughout study, including aspirin or other over-the-counter (OTC) preparations. Paracetamol is permissible before and during the study as a rescue medication but only with Investigator's permission
• Participation in a clinical investigation or blood donation of 500 ml within the past 3 months

Sponsors & Collaborators

• Innovative Medicines for Tuberculosis: lead
• Bill and Melinda Gates Foundation: collaborator

Study Sites (1)

Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, 1011, Switzerland

Location

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2018
• First Posted: February 6, 2018
• Study Start: December 5, 2017
• Primary Completion: March 28, 2018
• Study Completion: March 28, 2018
• Last Updated: July 13, 2018

Record last verified: 2018-07

Locations

CH (1)