Antiarrhythmic effects of phenytoin or dantrolene in patients with cardiomyopathy.
Antiarrhythmic properties and safety of phenytoin or dantrolene in patients with cardiomyopathy; a randomised, double blinded, placebo controlled trial
University of Newcastle
105 participants
Feb 1, 2020
Interventional
Conditions
Summary
This is a randomised, double blinded, placebo controlled trial to assess antiarrhythmic properties of phenytoin and dantrolene, their efficacy and safety for treating arrhythmias and heart failure. The study will compare all the 3 arms together: phenytoin versus dantrolene, phenytoin versus placebo and dantrolene versus placebo. Randomisation will occur after consent is obtained and on enrolment into the study, 105 participants will be randomised in a 1:1:1 ratio to one of 3 arms: • 35 will receive phenytoin • 35 will receive dantrolene • 35 will receive placebo The participants then will be followed in a 2 month interval visits. The visit numbers can increase if there are any concerns regarding the procedure or medication adverse effects (AEs). Repeat blood tests (liver function test and biochemistry profile, medications serum level) and device data collection will be performed prior to office visits. At these office visits, blood test results, occurrence of ventricular arrhythmia, heart failure symptoms (assessed by New York Heart Association (NYHA) functional class and Minnesota Living with Heart Failure Questionnaire) and medications adverse effects will be reviewed. Participants will also have Six-Minute Walk Test (6MWT) at the screening visit, 6 months visit and the last visit of the study.
Eligibility
Inclusion Criteria4
- Patients:
- with cardiomyopathy, Ejection Fraction<35%
- with Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronisation Therapy (CRT)
- Aged 18 to 85
Exclusion Criteria8
- Pregnant or breastfeeding females
- Childbearing age women (not on 2 contraceptive methods including non-oestrogen based OCP)
- Childbearing age women on oestrogen based OCP
- Inability to provide informed consent
- Patients with end stage kidney disease (eGFR<30) and patients on Dialysis
- Liver cirrhosis
- Patients with Aspartate transaminase (AST), and alanine transaminase (ALT) > 3 times upper limit of institutional normal value (ULN) on 2 measurements separated by at least 5 days
- Being prescribed the drug verapamil
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Interventions
105 participants will be enrolled and randomised in a 1:1:1 ratio to one of 3 arms: • 35 will receive phenytoin • 35 will receive dantrolene • 35 will receive placebo The trial medications will be provided by pharmacy at John Hunter Hospital. The total duration of the trial is 12 months with 2 monthly follow up visits. The participants will receive their medications at each follow up visit at John Hunter Hospital. Our recommended starting dosage for phenytoin is 5mg/kg/day, oral, in three divided doses. A period of 7 to 10 days is required to achieve therapeutic blood levels. In 2 weeks intervals, the medication serum level will be checked and the dose will be adjusted (Increase in 1mg/kg/day increments with maximum dose of 8 mg/kg/day if the level is too low or reduce the dose if the level is too high) until the targeted therapeutic level of 10-20 µg/ml is achieved. For dantrolene, our starting dose is 25 mg, three times a day, oral. The patients will have dantrolene serum concentration on a two-weekly basis and the dose will be adjusted until the targeted concentration of 1-10 micromole/L is achieved (The dose will be reduced if the level is too high and will be increased if the level is too low). ADHERENCE Face-to-face adherence reminder sessions will take place at the initial product dispensing and each study visit thereafter. This session will include: 1. Instructions about taking study pills including dose, timing, storage, and importance of taking pills regularly, and what to do in the event of a missed dose 2. Notification that there will be a pill count at every study visit 3. Importance of contacting the investigators if experiencing problems possibly related to study product such as symptoms of AEs or should they have any queries regarding the study progression. Participants are required to contact the study investigators immediately if they experience any of the following symptoms, which could indicate high serum concentration of the medications. These symptoms include: Nystagmus, dizziness, dysarthria, ataxia, tremor, drowsiness, involuntary movements, and seizure. Subsequent sessions will occur at the follow-up visits. Participants will be asked about any problems they are having taking their study pills. There will be brief discussion of reasons for missed doses and simple strategies for enhancing adherence, e.g., linking pill taking to meals or other daily activities. Participants will have an opportunity to ask questions and key messages from the initial session will be reviewed as needed. Participants will return the unused tablets and bottle at each follow-up visit. Unused tablets will be counted and recorded on the appropriate CRF (Case Report Form).
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ACTRN12619000730101