Clinical trial NCT04582409: A Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of HSY244 in Participants With Atrial Fibrillation
Official title: A Randomized, Placebo-controlled, Investigator- and Participant-blinded Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of HSY244 in Participants With Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Atrial Fibrillation
Keywords: atrial fibrillation
arrhythmia
pharmacological cardioversion
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-10-09
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a randomized, placebo-controlled, investigator- and participant-blinded study to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of HSY244 in participants with atrial fibrillation (AF), with and without heart failure (HF).

Detailed description: A screening period of up to 3 days (72 hours) was used to assess eligibility. After eligibility was confirmed, patients were randomized to either HSY244 or placebo. Prior to study drug administration, pre-dose assessments were completed. After the start of study drug administration, the participant was monitored for cardioversion to sinus rhythm. If a participant was still in AF at 90 minutes after the start of study drug administration, direct current cardioversion was planned to be applied at a time deemed appropriate by the investigator.

Eligibility criteria: Key Inclusion Criteria:

* At screening, written informed consent were required to be obtained before any assessment was performed and only participants able to provide written informed consent themselves were included in this study.
* Hemodynamically stable men and women (either of non-child-bearing potential or child bearing potential with highly effective contraception) between 18 and 80 years of age (inclusive) at screening with a clinical indication for direct current cardioversion of AF.
* At screening, current episode of AF had been ongoing for ≥6 hours and ≤60 days
* Successful initiation and achievement of therapeutic levels of national guideline and institution-specific anticoagulation therapy as appropriate for the duration of the AF episode and risk for the participant.
* Completion of national guideline and institution-specific imaging evaluation for left atrial thrombi as appropriate for the duration of AF episode and risk for the participant.
* At screening, participants were required to weigh at least 60 kg to participate in the study and were required to have a body mass index (BMI) within the range of 18 - 45 kg/m\^2. BMI = Body weight (kg) / \[Height (m)\]\^2
* At screening, vital signs (systolic blood pressure and pulse rate) were assessed in the sitting position. Sitting vital signs were required to be within the following ranges (exclusive):

  * systolic blood pressure between 100-160 mmHg and diastolic blood pressure 60-100 mmHg
  * pulse rate (ventricular rate) between 60-120 bpm.

Key Exclusion Criteria:

* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during dosing and for 4 days after stopping of investigational drug.
* Sexually active males unwilling to use a condom during intercourse while taking investigational drug and for 96 hours after study drug administration. A condom was required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of the investigational drug via seminal fluid to their partner. In addition, male participants could not donate sperm for the time period specified above.
* Use of any anti-arrhythmic class I or III drug (including Ranolazine \[Ranexa\]) within 5 half lives before randomization; including use of amiodarone within 3 months before randomization.
* At screening, history of current diagnosis of ECG abnormalities or cardiac rhythm disorders as determined by the Investigator's interpretation of the ECG findings indicating a significant risk for participating in the study, such as:

  * History of Torsades de Pointes (TdP), any other polymorphic ventricular tachycardia, sustained monomorphic ventricular tachycardia, long QT syndrome, or Brugada syndrome.
  * Wolfe-Parkinson-White (WPW) syndrome
  * In the absence of a complete bundle branch block a resting QTcF \>460 msec for men and \>470 msec for women (mean of ≥ 5 consecutive QT intervals)
  * In the presence of a complete bundle branch block, a prolonged QTcF or JTc that, in the opinion of the investigator, may pose a risk to patient safety
  * Third-degree (complete) heart block, or second-degree Mobitz type II heart block
* Attempted or unsuccessful cardioversion within 2 weeks prior to randomization.
* Presence of known severe mitral regurgitation and/or known severely dilated left atrium.
* Pre-existing or tachycardia-induced moderate to severe cardiac dysfunction (New York Heart Association Class III and IV).
* History within the preceding 3 months prior to randomization of: myocardial infarction, unstable angina, cardiac surgery, or a percutaneous coronary intervention.
* History of a confirmed stroke or transient ischemic attack (TIA).
* History or current diagnosis of any seizure disorder, epilepsy, significant head trauma, or other disorders increasing the risk for seizures.
* History or current diagnosis of a major neurologic or psychiatric disorder that, in the opinion of the investigator, poses a risk to patient safety to participate.

Primary outcomes:
measure: Number of Participants With Conversion to Sinus Rhythm for at Least 1 Minute Within 90 Minutes From the Start of Study Drug Administration.
timeFrame: 90 minutes from the start of study drug administration
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax)
timeFrame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
measure: Area Under the Plasma Concentration-time Curve (AUClast)
timeFrame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
Other outcomes:
Locations:
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Lansing
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Bad Oeynhausen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: