PMID- 34606332
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20220518
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 65
IP  - 12
DP  - 2021 Nov 17
TI  - Thorough QT Study To Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for 
      Gonorrhea, on Cardiac Repolarization in Healthy Adults.
PG  - e0129221
LID - 10.1128/AAC.01292-21 [doi]
LID - e01292-21
AB  - Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as 
      single oral dose treatment to address the growing global threat of Neisseria 
      gonorrhoeae. To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc 
      (TQT) study was performed in healthy subjects. In this randomized, double-blind, 
      placebo-controlled, 4-period crossover study, 72 subjects in a fasted state 
      received a single dose of zoliflodacin at 2 g (therapeutic), zoliflodacin at 4 g 
      (supratherapeutic), placebo, and moxifloxacin at 400 mg as a positive comparator. 
      Cardiac repolarization was measured by duration of the corrected QT interval by 
      Fridericia's formula (QTcF). At each time point up to 24 h after zoliflodacin 
      administration, the upper limit of the one-sided 95% confidence interval (CI) for 
      the placebo-corrected change from the predose baseline in QTcF (DeltaDeltaQTcF) was less 
      than 10 ms, indicating an absence of a clinically meaningful increase in QT 
      prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of 
      DeltaDeltaQTcF for moxifloxacin was longer than 5 ms at four time points from 1 to 4 h 
      after dosing, demonstrating adequate sensitivity of the QTc measurement. There 
      were no clinically significant effects on heart rate, PR and QRS intervals, 
      electrocardiogram (ECG) morphology, or laboratory values. Treatment-emergent 
      adverse events (AEs) were mild or moderate in severity and transient. This was a 
      negative TQT study according to regulatory guidelines (E14) and confirms that a 
      single oral dose of zoliflodacin is safe and well tolerated. These findings 
      suggest that zoliflodacin is not proarrhythmic and contribute to the favorable 
      assessment of cardiac safety for a single oral dose of zoliflodacin. (This study 
      has been registered at ClinicalTrials.gov under registration no. NCT03613649.).
FAU - Newman, Lori M
AU  - Newman LM
AUID- ORCID: 0000-0001-5464-5208
AD  - National Institute of Allergy and Infectious Diseasesgrid.419681.3, Rockville, 
      Maryland, USA.
FAU - Kankam, Martin
AU  - Kankam M
AD  - Altasciences Clinical Kansas, Inc., Overland Park, Kansas, USA.
FAU - Nakamura, Aya
AU  - Nakamura A
AD  - Emmes Company, LLC, Rockville, Maryland, USA.
FAU - Conrad, Tom
AU  - Conrad T
AD  - Emmes Company, LLC, Rockville, Maryland, USA.
FAU - Mueller, John
AU  - Mueller J
AD  - Entasis Therapeutics, Waltham, Massachusetts, USA.
FAU - O'Donnell, John
AU  - O'Donnell J
AD  - Entasis Therapeutics, Waltham, Massachusetts, USA.
FAU - Osborn, Blaire L
AU  - Osborn BL
AD  - National Institute of Allergy and Infectious Diseasesgrid.419681.3, Rockville, 
      Maryland, USA.
FAU - Gu, Kenan
AU  - Gu K
AD  - National Institute of Allergy and Infectious Diseasesgrid.419681.3, Rockville, 
      Maryland, USA.
FAU - Saviolakis, George A
AU  - Saviolakis GA
AD  - DynPort Vaccine Company, Frederick, Maryland, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03613649
GR  - HHSN272201500005C/AI/NIAID NIH HHS/United States
GR  - HHSN272201500005I/HHS | National Institutes of Health (NIH)/
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
DEP - 20211004
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Barbiturates)
RN  - 0 (Fluoroquinolones)
RN  - 0 (Isoxazoles)
RN  - 0 (Morpholines)
RN  - 0 (Oxazolidinones)
RN  - 0 (Spiro Compounds)
RN  - FWL2263R77 (zoliflodacin)
SB  - IM
MH  - Adult
MH  - Barbiturates
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Electrocardiography
MH  - Fluoroquinolones
MH  - *Gonorrhea
MH  - Healthy Volunteers
MH  - Heart Rate
MH  - Humans
MH  - Isoxazoles
MH  - *Long QT Syndrome
MH  - Morpholines
MH  - Oxazolidinones
MH  - Spiro Compounds
PMC - PMC8597722
OTO - NOTNLM
OT  - Neisseria gonorrhoeae
OT  - cardiac safety
OT  - gonorrhea
OT  - thorough QT study
OT  - zoliflodacin
EDAT- 2021/10/05 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/05/17
CRDT- 2021/10/04 17:17
PHST- 2021/10/05 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/04 17:17 [entrez]
PHST- 2022/05/17 00:00 [pmc-release]
AID - 01292-21 [pii]
AID - aac.01292-21 [pii]
AID - 10.1128/AAC.01292-21 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0129221. doi: 
      10.1128/AAC.01292-21. Epub 2021 Oct 4.