4-way Crossover QT Evaluation in Healthy Subjects

A Phase 1, Randomized, Blinded, Placebo and Moxifloxacin Controlled, 4-Period Crossover, Study Evaluating the Effect of ZTI-01 on 12-Lead Electrocardiogram Parameters in Healthy Adult Subject

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.

Study Overview

• Status: Completed
• Conditions: Cardiac Repolarization in Healthy Subjects
• Intervention / Treatment: Drug: ZTI-01; Drug: Moxifloxacin 400mg; Other: Placebo IV

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 Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Pharmaron

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapeutic ZTI-01 6 g IV; intravenous fosfomycin (only antibiotic in phosphonic acid derivative class) 6g	Drug: ZTI-01; 6g IV fosfomycin; Other Names: IV fosfomycin; fosfomycin disodium; fosfomycin for injection
Experimental: Supra-therapeutic ZTI-01 12 g IV; intravenous fosfomycin (only antibiotic in phosphonic acid derivative class) 12g	Drug: ZTI-01; 6g IV fosfomycin; Other Names: IV fosfomycin; fosfomycin disodium; fosfomycin for injection
Active Comparator: moxifloxacin 400 mg PO; oral moxifloxacin 400mg film coated tablets - Avelox(TM)	Drug: Moxifloxacin 400mg; oral moxifloxacin (Avelox 400 mg) + IV normal saline (Placebo); Other Names: Positive control; Other: Placebo IV; IV Placebo (0.9% Normal Saline); Other Names: Negative Control
Placebo Comparator: Placebo IV; IV 0.9% normal saline solution	Other: Placebo IV; IV Placebo (0.9% Normal Saline); Other Names: Negative Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of ZTI-01 at the therapeutic and supra-therapeutic plasma concentration on cardiac repolarization expressed by QT interval	Determine the change-from-baseline QTc (ΔQTc) when compared with placebo, and moxifloxacin (400 mg PO)	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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax after a single dose IV administration of ZTI-01 6g and 12g	Maximum plasma concentration Cmax (microg/mL) by dose (6g and 12g)	Cmax at end of 1-hour single dose infusion

Collaborators and Investigators

• Sponsor: Nabriva Therapeutics AG
• Investigators: Study Chair: Evelyn J Ellis-Grosse, PhD, Chief Scientific Officer

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2018
• Primary Completion (Actual): April 12, 2018
• Study Completion (Actual): August 21, 2018

Study Registration Dates

• First Submitted: May 8, 2018
• First Submitted That Met QC Criteria: October 15, 2018
• First Posted (Actual): October 17, 2018

Study Record Updates

• Last Update Posted (Actual): March 6, 2019
• Last Update Submitted That Met QC Criteria: March 5, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Moxifloxacin; Fosfomycin
• Other Study ID Numbers: ZTI-01-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: final report, publication

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No