4-way Crossover QT Evaluation in Healthy Subjects

Phase 1

Completed

• Conditions: Cardiac Repolarization in Healthy Subjects
• Interventions: Drug: Moxifloxacin 400mg; Drug: ZTI-01; Other: Placebo IV

• Registration Number: NCT03709927
• Lead Sponsor: Nabriva Therapeutics AG

Brief Summary

The purpose of this study is to evaluate if ZTI-01 (fosfomycin for injection), an investigational drug being developed to treat people with complicated urinary tract and kidney infections, has any effect on the electrical activity of the heart.

Detailed Description

This is a single-center, randomized, placebo-controlled, four-period, cross-over study to assess the effect of single-doses of ZTI-01 at therapeutic (T) and supratherapeutic (ST) plasma concentrations on the QTc interval versus placebo (P) and an open-label moxifloxacin (M) control (400 mg PO).

Assessment of safety data will include changes from baseline in vital signs and laboratory parameters, infusion site reactions, adverse events and clinically significant changes from baseline in 12-lead ECG parameters.

Study Timeline

• Study Start: 2018-01-11
• Primary Completion: 2018-04-12
• Study First Submitted: 2018-05-08
• Study Completion: 2018-08-21
• Study First Submitted QC: 2018-10-15
• Study First Posted: 2018-10-17
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-05
• Last Update Posted: 2019-03-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 41

Inclusion Criteria

• physically and mentally healthy volunteer
• a man or woman, 18 to 55 years of age
• a woman of childbearing potential using birth control / negative pregnancy test or a woman of non-childbearing potential
• males with female partners of childbearing potential agree to use contraception
• body mass index 19.0 to 32.0 kg/m2; weight of at least 60.0 kg at Screening
• willing to complete the required 4 study periods

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Exclusion Criteria

• History or evidence of cerebrovascular or cardiac disease
• Uncontrolled hypertension
• Electrographically significant abnormalities on ECG
• Clinically significant medical history (PI assessment)
• Clinically relevant lab abnormalities (PI assessment)
• Calculated eGFR < 60.0 mL/min/1.73m2 based on CKD-EPI 2009 equation
• Abnormal liver tests
• Positive serology HIV, HBsAg, or Hep C virus
• Hemoglobin, hematocrit, electrolytes below lower limit of normal
• Received any hepatic or renal clearance altering agents within 30 days
• History of allergy or hypersensitivity to drugs with clinically significant reaction
• Unwilling to refrain from strenuous exercise from 7 days prior to admission until discharge
• Uses any prescription drug / OTC, within 7 days prior to admission, or 14 days prior to Admission if the drug is a potential inducer or inhibitor of cP450, or 5 half-lives (if longer), or subject continued use of a prescription drug / OTC medication (except contraceptives)
• Scheduled to have surgical procedure during study
• Acute illness that has resolved in less than 14 days, or has had a major illness, or hospitalization within 1 month
• Unwilling to abstain from ingestion of caffeine or xanthine-containing products 96 hours prior and throughout study
• Unwilling to abstain from alcohol beginning 72 hours prior and throughout study
• History of high alcohol consumption within 6 months
• History of drug abuse (in the previous 3 years) or positive urine drug screen
• Used tobacco-containing products within 6 months or has a positive cotinine
• Consumed grapefruit and/or grapefruit juice within 14 days and throughout study
• Consumed other fruit juices within 72 hours and throughout study
• Consumed cruciferous vegetables or charbroiled meats within 7 days and throughout study
• Donated plasma or blood within 30 days or has a history of blood donation of > 450 mL within 3 months
• Used any investigational drug within 30 days
• Previously received fosfomycin
• Deemed by the Investigator to be inappropriate for this study
• Participated in another clinical study within 30 days (or 5 half-lives)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
moxifloxacin 400 mg PO	Moxifloxacin 400mg	oral moxifloxacin 400mg film coated tablets - Avelox(TM)
Therapeutic ZTI-01 6 g IV	ZTI-01	intravenous fosfomycin (only antibiotic in phosphonic acid derivative class) 6g
Supra-therapeutic ZTI-01 12 g IV	ZTI-01	intravenous fosfomycin (only antibiotic in phosphonic acid derivative class) 12g
Placebo IV	Placebo IV	IV 0.9% normal saline solution
moxifloxacin 400 mg PO	Placebo IV	oral moxifloxacin 400mg film coated tablets - Avelox(TM)

Primary Outcome Measures

Name	Time	Method
Effect of ZTI-01 at the therapeutic and supra-therapeutic plasma concentration on cardiac repolarization expressed by QT interval	24 hour Holter ECG at Baseline (Day -1) & day of dosing (Day 1) in each of 4 periods. 10 replicates per time point at 13 timepoints: pre-dose: 60, 45 and 30 minutes; after the start of infusion: 0.5, 1 (end infusion), 1.25, 1.5, 2, 3, 4, 8, 12, & 24 hrs	Determine the change-from-baseline QTc (ΔQTc) when compared with placebo, and moxifloxacin (400 mg PO)

Secondary Outcome Measures

Name	Time	Method
Treatment emergent adverse events (TEAEs)	From Day 1 start of dosing up to Day 36-38 (final follow up visit)	Number and percentage of subjects reporting a TEAE overall and by treatment

Trial Locations

Locations (1)

Pharmaron; 🇺🇸 Baltimore, Maryland, United States