A Randomized, Single-Dose, Comparative, Positive and Placebo Controlled, Four-Way, Four Period, Cross-Over Study to Evaluate the Effect of DIC075V on QTc Intervals in Healthy Subjects

NCT01812538 | Completed Phase 1

• 1 other identifier: DFC-011
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

This study is conducted to evaluate the effectiveness of DIC075V on ventricular repolarization in healthy subjects compared to placebo after a single dose of DIC075V administered intravenously (IV) and to evaluate ECG assay sensitivity by evaluating the baseline-adjusted effect of a single oral (PO) moxifloxacin 400 mg dose on ventricular repolarization in healthy subjects compared to placebo. Other secondary objectives are as follows:

• To evaluate the effect of DIC075V on ventricular repolarization in healthy subjects compared to placebo at the Tmax of diclofenac and hydroxypropyl-β-cyclodextrin (HPβCD).
• To determine if there is a pharmacokinetic/pharmacodynamic (PK/PD) relationship between the duration of the QTc intervals and diclofenac and HPβCD plasma concentrations.
• Obtain additional pharmacokinetic (PK) information on diclofenac and HPβCD in healthy subjects.
• Provide additional safety information.

Conditions

Ventricular Repolarization

Outcome Measures

Primary Outcomes (1)

• Time-matched active drug-placebo difference in baseline-adjusted QTc interval

  The primary ECG endpoint is the time-matched active drug-placebo difference in baseline-adjusted QTc interval using the Fridericia correction formula (QTcF). The QTcF is evaluated at the time point where the maximal baseline and placebo-adjusted value is observed. These measurements are consistent with ICH E14 guidance.

  At -1.5, -1.0, and -0.5 hours (pre-dose), and 5, 10, 15, and 30 minutes (2-min window) and 1, 2, 4, 6, 8, 12, and 23.5 hours (5-min window) on Study Days 1, 4, 7, and 10.

Secondary Outcomes (3)

• Time-matched active drug-placebo difference in baseline-adjusted QTc interval using the Bazett's correction formula (QTcB) evaluated at the timepoint where the maximum mean baseline- and placebo-adjusted QTcB is observed for each active treatment arm

  At -1.5, -1.0, and -0.5 hours (pre-dose), and 5, 10, 15, and 30 minutes (2-min window) and 1, 2, 4, 6, 8, 12, and 23.5 hours (5-min window) on Study Days 1, 4, 7, and 10.

• Time matched active drug-placebo difference in baseline adjusted QTcF at the subject-specific Tmax or the next available ECG timepoint

  At -1.5, -1.0, and -0.5 hours (pre-dose), and 5, 10, 15, and 30 minutes (2-min window) and 1, 2, 4, 6, 8, 12, and 23.5 hours (5-min window) on Study Days 1, 4, 7, and 10.

• Time-matched active drug-placebo difference in the maximum baseline-adjusted QTcF of each subject at each active treatment period.

  At -1.5, -1.0, and -0.5 hours (pre-dose), and 5, 10, 15, and 30 minutes (2-min window) and 1, 2, 4, 6, 8, 12, and 23.5 hours (5-min window) on Study Days 1, 4, 7, and 10.

Other Outcomes (8)

• Maximum plasma concentration (Cmax) for diclofenac and HPβCD

  At Time 0 (pre-dose), and 5, 10, 15, 20, and 30 minutes and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 23.5 hours after dosing on Study Days 1, 4, 7 and 10.

• Time to Cmax (Tmax) for diclofenac and HPβCD

  At Time 0 (pre-dose), and 5, 10, 15, 20, and 30 minutes and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 23.5 hours after dosing on Study Days 1, 4, 7 and 10.

• Areas under the curve to the last sample with a measurable concentration [AUC(0-t)] for diclofenac and HPβCD

  At Time 0 (pre-dose), and 5, 10, 15, 20, and 30 minutes and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 23.5 hours after dosing on Study Days 1, 4, 7 and 10.

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Placebo

Drug: DIC075V

Experimental 1

EXPERIMENTAL

DIC075V 37.5 mg

Drug: DIC075V

Experimental 2

EXPERIMENTAL

DIC075V 75 mg

Drug: DIC075V

Active control

ACTIVE COMPARATOR

Moxifloxacin hydrochloride 400 mg

Drug: DIC075V

Interventions

DIC075V DRUG

Four single dose treatments: * Placebo (normal saline) * Moxifloxacin (positive control) * DIC075V 37.5 mg * DIC075V 75 mg All subjects receive each of the 4 treatments.

Also known as: Voltaren, Voltarol, Cataflam, Zipsor

Active control; Experimental 1; Experimental 2; Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Willing and able to provide signed informed consent, including Health Insurance Portability and Accountability Act (HIPAA) Authorization.
• Healthy adult male and/or female subjects, 18-50 years of age.
• Body mass index (BMI) between 18-30, inclusive.
• Medically healthy with no clinically significant screening results (laboratory profiles, medical histories, ECGs, physical exam).
• Normal blood pressure (\<140 mmHg systolic and \<90 mmHg diastolic).
• Normal 12-lead ECG (QTc interval \<450 millisecond (ms) for males and \<470 ms for females):
• Consistent sinus rhythm
• No clinically significant conduction disorders
• PR interval between 120 and 230 ms
• HR ≤100 bpm and ≥40 bpm
• QRS interval ≤110 ms
• QT intervals that can be consistently analyzed.
• No medical history of cardiac disease or a family history of QT prolongation.
• No clinically significant electrolyte abnormality.
• Subjects with a calculated creatinine clearance greater than \>80 ml/min.

You may not qualify if:

• History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease.
• History of invasive cancer within the past 5 years (excluding non-melanoma skin cancers).
• History of hypersensitivity or allergy to the quinolone class of antibiotics; to diclofenac or other NSAIDs; or to HPβCD or other excipients in DIC075V (monothioglycerol, sodium hydroxide, hydrochloric acid, and water for injection).
• History or presence of alcoholism or drug abuse within the past 2 years.
• Use of tobacco products within the previous 6 months.
• Donation of blood within 45 days prior to Study Day -2.
• Plasma donation within 30 days prior to Study Day -2.
• Participation in a study of an investigational drug within 90 days prior to Study Day -2.
• Participation in another clinical trial within 45 days prior to Study Day -2.
• Female subjects who are pregnant or lactating.
• Hemoglobin below the reference range for the testing laboratory.
• Clinically significant abnormal laboratory values.
• Abnormal ECG. The abnormality of the ECG could be a QRS duration of \>110 ms, a first degree heart block defined as a PR duration \>230 ms, second or third degree heart block, or a complete heart block.
• Male subjects with a screening QTc interval ≥450 ms and female subjects with a QTc interval ≥470 ms.
• Presence of untreated or uncontrolled blood pressure, i.e., systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg.

Sponsors & Collaborators

• Hospira, now a wholly owned subsidiary of Pfizer: lead

Study Sites (1)

Cetero Research

Fargo, North Dakota, 58104, United States

Location

Related Publications (1)

• Carr DB, McDonnell Moorehead T, Bouchard A, Sprenger CR, Hamilton DA, Lang E, Madden D, Lacouture PG, Wright C 4th. Effects of injectable HPbetaCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo. Clin Ther. 2013 May;35(5):646-58. doi: 10.1016/j.clinthera.2013.03.014. Epub 2013 Apr 8.

  PMID: 23578606 DERIVED

MeSH Terms

Interventions

Diclofenac

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2013
• First Posted: March 18, 2013
• Study Start: May 1, 2009
• Primary Completion: July 1, 2009
• Study Completion: July 1, 2009
• Last Updated: July 24, 2015

Record last verified: 2015-07

Locations

US (1)