Effect of PA-824 and of PA-824 Plus Moxifloxacin on the QTc Interval in Healthy Volunteers

NCT01674218 | Completed Phase 1

• 2 other identifiers: 10-0058N01AI80024C
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I, single-center, double-blinded, randomized, placebo-controlled, five-period cross-over clinical study of PA-824 to evaluate the effect of PA-824 and of PA-824 plus moxifloxacin on cardiac repolarization (QT/QTc interval duration) in a total of 75 healthy male and female participants, aged 18 to 45 years. Moxifloxacin will be used as an active control. Participants will be blinded to the treatments they will receive. The study consists of a screening period up to 26 days; enrollment, 1 day; five in-patient treatment periods consisting of an admission day (except in the first treatment period, when the pre-dose day is the baseline), dosing day and two post-dosing days; an out-patient period of at least three days and not more than 10 days between treatment periods; and a final visit 7 - 14 days after discharge from the last treatment period.

Conditions

Tuberculosis

Keywords

tuberculosis, safety, PA-824, QTc interval, moxifloxacin, healthy volunteers, crossover

Outcome Measures

Primary Outcomes (1)

• Effect of PA-824 on cardiac ventricular repolarization (CVR) as measured by QT interval corrected for heart rate using individual-specific formula (QTcI) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.

  24 hours after dosing of PA-824

Secondary Outcomes (8)

• Effect of PA-824 on CVR measured by QT interval corrected for heart rate by group-specific formula (QTcN), Fridericia (QTcF) and Bazett (QTcB) formulae during the first 24 hours following dosing in healthy volunteers compared to placebo.

  24 hours after dosing of PA-824

• Effect of PA-824 plus moxifloxacin on CVR as measured by QT and QT corrected for heart rate (QTcI, QTcN, QTcF, and QTcB) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.

  24 hours after dosing of PA-824

• The effect of Moxifloxacin on CVR as measured by QTcI, QTcN, QTcF, and QTcB, HR and non-QTc ECG intervals (HR, and PR, QRS, and RR intervals) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.

  24 hours after dosing of PA-824

• Safety and tolerability evaluated by ophthalmology exam.

  Screening , Day -2 and Day 45

• Analysis of the QTcI, QTcN, QTcF, QTcB, PR, QRS, and RR intervals and heart rate matched to PK sampling times to allow determination of any PK / pharmacodynamic effect of PA-824 alone and in combination with moxifloxacin.

  Day 1 of each treatment period at 0 h (pre-dose) and 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72(±4) and 96(±4) hrs (post-dose).

Study Arms (5)

Treatment E

EXPERIMENTAL

PA-824 400 mg plus moxifloxacin 400 mg

Drug: Moxifloxacin; Drug: PA-824

Treatment D

ACTIVE COMPARATOR

PA-824 placebo plus moxifloxacin 400 mg

Drug: Moxifloxacin; Other: Placebo

Treatment C

EXPERIMENTAL

PA-824 1000 mg plus moxifloxacin placebo

Drug: PA-824; Other: Placebo

Treatment B

EXPERIMENTAL

PA-824 400 mg plus moxifloxacin placebo

Drug: PA-824; Other: Placebo

Treatment A

PLACEBO COMPARATOR

PA-824 placebo and moxifloxacin placebo

Other: Placebo

Interventions

Moxifloxacin DRUG

Moxifloxacin will be given orally to the following treatment groups, in combination with either PA-824 or PA-824 placebo: Treatment D: 400 mg + PA-824 placebo; Treatment E: 400 mg + PA-824 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.

Treatment D; Treatment E

PA-824 DRUG

PA-824 will be given orally to the following treatment groups, together with either moxifloxacin or moxifloxacin placebo: Treatment B: 400 mg + moxifloxacin placebo; Treatment C: 1000 mg + moxifloxacin placebo; Treatment E: 400 mg + moxifloxacin 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.

Treatment B; Treatment C; Treatment E

Placebo OTHER

Placebo tablets to match Moxifloxacin or PA-824 will be given orally, in combination with either moxifloxacin or PA-824: Treatment A: PA-824 placebo + moxifloxacin placebo; Treatment B: PA-824 400 mg + moxifloxacin placebo; Treatment C: PA-824 1000 mg + moxifloxacin placebo Treatment D: PA-824 placebo + moxafloxacin 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.

Treatment A; Treatment B; Treatment C; Treatment D

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject must be 18 to 45 years of age (inclusive).
• Subject must be a healthy male or female volunteer as determined by medical history, physical examination, 12-lead ECG and laboratory evaluations (hematology, clinical chemistries and urinalysis tests) within study-defined ranges at Screening. (See Appendix B for acceptable ranges of laboratory and vital signs assessments).
• Body Mass Index (BMI) must be between 18 and 30 kg/m\^2 inclusive.
• Subject must be non-tobacco/nicotine using (3-month minimum).
• Subject must be Tuberculin Skin Test/Purified Protein Derivative (TST/PPD) negative (within the previous 1 year) at Screening. The TST/PPD may be omitted if the subject presents written evidence of having a negative test during the previous 12 months.
• Subject must be able to give voluntary written informed consent before any study related procedure is performed.
• If female, has no childbearing potential (as defined below) or agrees to avoid becoming pregnant from the day of screening through one week after the last dose by using one of the following acceptable methods of birth control in addition to the use of a barrier method (condom) by the male partner (even if vasectomized):
• Hormonal contraceptives; or
• intrauterine contraceptive device; or
• diaphragm in combination with contraceptive jelly, cream, or foam; or
• spermicide; or
• abstinence. Non-childbearing potential is defined as being post-menopausal for at least 2 years, status after bilateral tubal ligation for at least 1 year, status after bilateral oophorectomy or status after hysterectomy.
• If male, agrees to avoid fathering a child from the day of screening to three months after the last dose.
• All female subjects must have a negative serum pregnancy test at Screening, Enrollment (Day-2) and at check-in for each treatment period.
• Subject agrees not to donate blood during the study and up to 14 days after the end of the last treatment period.

You may not qualify if:

• A history of clinically significant acute illness (resolved within 4 weeks of screening) or history of cardiac arrhythmias or unexplained syncope or presence of cardiac, vascular gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, or psychiatric disease or any other condition which, in the opinion of the Site Principal Investigator (PI), would jeopardize the safety of the subject or impact the validity of the study results.
• Subject has had major surgery within 4 weeks of screening.
• has an uncontrolled intercurrent illness (i.e., active infection) or fever (oral temperature \>/=100 degrees Fahrenheit or \>/= 37.7 degrees Celsius) at screening.
• History of lens opacity or evidence of lens opacity on screening ophthalmologic examination or any other clinically significant ophthalmic dysfunction or disease.
• Subject has been on an abnormal diet during the 4 weeks preceding screening. Abnormal diet is defined as a diet in which the subject has a significant change in eating habits (e.g., liquid diet only) and an unbalanced diet (e.g., protein only, high fat, low carbohydrate, etc.).
• Subject has engaged in strenuous physical activity or consumed alcohol, grapefruit, and caffeine- or methylxanthine-containing beverages from 48 hours before reporting to the clinic for enrollment until discharge from the clinical site in the last treatment period.
• Previous participation in any other study of PA-824.
• History of seizures (other than febrile seizures during childhood) or known or suspected Central Nervous System (CNS) disorders that may predispose to seizures.
• History of photosensitivity or phototoxicity reactions after use of quinolones or other drugs.
• History of allergy or severe side-effects with nitroimidazoles (e.g., Flagyl and related substances and azole antifungals or aromatase inhibitors).
• History of allergy to moxifloxacin or any fluoroquinolone antibiotic.
• History of tendinopathy associated with quinolones or other drugs, including glucocorticoids, or a condition that predisposes to tendon rupture.
• Subject has received an investigational drug in a clinical trial within 30 days prior to screening.
• Subject has used any over the counter (OTC) medication, including vitamins and herbal supplements, antacids, cough and cold medications, within 7 days prior to Day 1 of treatment with study drugs or during the study, unless in the opinion of the PI, the substance would not likely impact on the conduct of this study.
• Subject has used any prescription medication, except hormonal contraceptives, within 30 days prior to Day 1 of treatment with study drugs or during the study, unless in the opinion of the PI, the substance would not likely impact the conduct of this study.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Quintiles Phase I Services - Overland Park

Overland Park, Kansas, 66211-1553, United States

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Moxifloxacin; pretomanid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

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

Study Record Dates

• First Submitted: August 23, 2012
• First Posted: August 28, 2012
• Study Start: September 1, 2012
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: November 14, 2014

Record last verified: 2013-03

Locations

US (1)