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Trial registered on ANZCTR


Registration number
ACTRN12619000730101p
Ethics application status
Submitted, not yet approved
Date submitted
3/05/2019
Date registered
14/05/2019
Date last updated
14/05/2019
Date data sharing statement initially provided
14/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Antiarrhythmic effects of phenytoin or dantrolene in patients with cardiomyopathy.
Scientific title
Antiarrhythmic properties and safety of phenytoin or dantrolene in patients with cardiomyopathy; a randomised, double blinded, placebo controlled trial
Secondary ID [1] 298053 0
None
Universal Trial Number (UTN)
U1111-1232-2730
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart failure with reduced ejection fraction (HFrEF) 312537 0
Arrhythmia 312538 0
Cardiomyopathy 312713 0
Condition category
Condition code
Cardiovascular 311067 311067 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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).

Intervention code [1] 314287 0
Treatment: Drugs
Comparator / control treatment
Placebo comparator: matching capsules containing no active ingredients
Control group
Placebo

Outcomes
Primary outcome [1] 319847 0
• To determine the safety, tolerability and dosing of long term use of phenytoin and dantrolene in patients with heart failure.

Safety and tolerability will be assessed by:
• Discontinuation of subject due to a serious adverse event (SAE) or discontinuation of subject due to an extreme laboratory parameter
• Dose adjustment during the treatment period; and/or non-adherence to randomised treatment
• Number of SAEs
• Time to first appearance of AEs
• Time to dose adjustment
Participants will be questioned and monitored at all the visit times with regard to any AEs they may have experienced. Participants are required to contact the study investigators if there are any symptoms of possible AEs. The investigators then will decide if they need to organise another visit.

Common adverse effects of phenytoin (> 1%):
• Nausea and vomiting,
• insomnia,
• agitation,
• sedation,
• confusion,
• ataxia,
• nystagmus, diplopia, blurred vision,
• vertigo,
• behavioural disturbances,
• impaired learning (dose-related),
• gingival hypertrophy,
• skin eruption,
• coarse facies,
• hirsutism (long-term use),
• Increased liver enzymes (usually not clinically important): phenytoin is mainly metabolised in liver. Increase in transaminases more than three folds will be considered significant.

Common adverse effects of dantrolene include (have been experienced by approximately 20 % of patients):
• drowsiness,
• dizziness,
• weakness,
• general malaise,
• fatigue,
• Diarrhoea. If severe, it will require a temporary withdrawal of dantrolene therapy. If diarrhoea recurs upon readministration, it should be stopped permanently.


Timepoint [1] 319847 0
Safety and tolerability will be assessed on each follow up visit (2 months intervals), for a total of 12 months post-enrolment,
Secondary outcome [1] 369693 0
• To determine if phenytoin or dantrolene reduce the recurrence of ventricular arrhythmia in patients with cardiomyopathy compared to placebo.

The occurrence of Ventricular arrhythmias (VT or NSVT of at least three beats duration, > 120 bpm) will be assessed by the device interrogation.

Timepoint [1] 369693 0
The occurrence of ventricular arrhythmias will be assessed on each follow up visit ( 2 months intervals) for a total of 12 months post-enrolment.
Secondary outcome [2] 369982 0
• To determine the effects of dantrolene and phenytoin on heart failure symptoms.

The effect of dantrolene and phenytoin on heart failure symptoms will be assessed by using New York Heart Association (NYHA) functional class,
Timepoint [2] 369982 0
Heart failure symptoms will be assessed on each follow up visit ( 2 months intervals) for a total of 12 months post-enrolment.
Secondary outcome [3] 370294 0
• To determine the effects of dantrolene and phenytoin on quality of life in patients with heart failure.

The quality of life will be assessed by Minnesota Living with Heart Failure Questionnaire.
Timepoint [3] 370294 0
Minnesota Living with Heart Failure Questionnaire will be completed on each follow up visit (every 2 months), for a total of 12 months post-enrolment.
Secondary outcome [4] 370398 0
• To determine the effects of dantrolene and phenytoin on functional capacity in patients with heart failure.

The effects of dantrolene and phenytoin on functional capacity will be assessed by 6-Minute Walk Test.
Timepoint [4] 370398 0
The 6-Minute Walk Test will be performed three times during the study: once at the screening visit, once at the 6 months visit and once at the end of the trial (12 months visit).

Eligibility
Key inclusion criteria
Patients:
• with cardiomyopathy, Ejection Fraction<35%
• with Implantable Cardioverter Defibrillator (ICD) or Cardiac Resynchronisation Therapy (CRT)
• Aged 18 to 85

Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 302581 0
Hospital
Name [1] 302581 0
John Hunter Hospital
Address [1] 302581 0
Lookout Rd, New Lambton Heights NSW 2305
Country [1] 302581 0
Australia
Primary sponsor type
University
Name
University of Newcastle
Address
University Dr, Callaghan NSW 2308
Country
Australia
Secondary sponsor category [1] 302491 0
None
Name [1] 302491 0
Address [1] 302491 0
Country [1] 302491 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303222 0
The Hunter New England Human Research Ethics Committee
Ethics committee address [1] 303222 0
Research Ethics and Governance Office
Locked bag 1, New Lambton, NSW, 2305

Ethics committee country [1] 303222 0
Australia
Date submitted for ethics approval [1] 303222 0
30/04/2019
Approval date [1] 303222 0
Ethics approval number [1] 303222 0

Summary
Brief 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92906 0
Dr Nicholas Jackson
Address 92906 0
John Hunter Hospital, Lookout Rd, New Lambton Heights NSW 2305
Country 92906 0
Australia
Phone 92906 0
+61 2 4921 3000
Fax 92906 0
Email 92906 0
Njackson193@gmail.com
Contact person for public queries
Name 92907 0
Dr Ehsan Mahmoodi
Address 92907 0
John Hunter Hospital, Lookout Rd, New Lambton Heights NSW 2305
Country 92907 0
Australia
Phone 92907 0
+61 2 4921 3000
Fax 92907 0
Email 92907 0
ehsan.mahmoodi@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 92908 0
Dr Ehsan Mahmoodi
Address 92908 0
John Hunter Hospital, Lookout Rd, New Lambton Heights NSW 2305
Country 92908 0
Australia
Phone 92908 0
+61 2 4921 3000
Fax 92908 0
Email 92908 0
ehsan.mahmoodi@hnehealth.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The trial data will be stored in a computer database, maintaining confidentiality in accordance with national data legislation. This database will identify participants only with ID number. Only the study investigators, study staff and Research Project Manager will have access to completed data and other research documents. Any written documents will use ID numbers and computer databases will be password protected. Principles of confidentiality in the therapist-patient relationship stand for all participants in the study throughout the intervention.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 1938 0
Study protocol
Citation [1] 1938 0
Link [1] 1938 0
Email [1] 1938 0
Other [1] 1938 0
Summary results
No Results