Clinical trial NCT00701077: DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
Official title: DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Brugada Syndrome
Keywords: Brugada syndrome
Electrophysiological study
Ion channel blockade
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2008-06-19
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Brugada syndrome is a rare disease potentially leading to severe arrhythmic events in otherwise healthy subjects.In many patients an Implantable cardiovertor defibrillator (ICD) is implanted to prevent sudden cardiac death. ICD are however associated with potential complications and are not available in all countries.Pharmacological blockade of specific ion channels (Ito) represents a promising therapeutic approach in this syndrome.The 3,4-diaminopyridine (3,4-DAP) is a pharmacological Ito blocker that can be used in humans.The aim of the study is to evaluate the effect of 3,4-DAP on ventricular arrhythmia inducibility in Brugada patients requiring an electrophysiological study for arrhythmic risk stratification.

Detailed description: Background:

The Brugada syndrome is a rare disease potentially leading to severe arrhythmic events in otherwise healthy subjects.In many patients an Implantable cardiovertor defibrillator (ICD) is implanted to prevent sudden cardiac death. ICD are however associated with potential complications and are not available in all countries.Pharmacological blockade of specific ion channels (Ito) represents a promising therapeutic approach in this syndrome. Experimental data show that increased Ito current may be associated with both the ECG feature and arrhythmogenic substrate observed in the syndrome. Moreover, Ito blockade reverse the ECG abnormalities and suppress arrhythmogenicity.The 3,4-diaminopyridine (3,4-DAP) is a pharmacological Ito blocker that is already used in humans for another indication.

Main objective:

The aim of the study is to evaluate the effect of 3,4-DAP on ventricular arrhythmia inducibility in Brugada patients requiring an electrophysiological study for arrhythmic risk stratification.

First end point:

Re-inducibility or non re-inducibility of sustained ventricular arrhythmia during electrophysiological study on treatment

Tested hypothesis:

The 3,4-DAP decreases the proportion of re-inducibility during the electrophysiological study with a re-inducibility rate of 80% in the placebo group and 25% in the 3,4-DAP group

Secondary objective:

* to assess the effect of 3,4-DAP on ST segment elevation in Brugada patients
* to describe the relationship between 3,4-DAP plasma concentration measured at 45 minutes and electrophysiological study result and ST segment elevation

Study design:

2 centres, randomised, double blind, parallel groups, placebo controlledA single dose of 20 mg of 3,4-DAP

Included patients and number of patients:

Included patients will all have a diagnosed Brugada type 1 ECG and will require an electrophysiological study for arrhythmic risk stratification purpose. Only inducible patients will be included in the study.Using a classical approach, the hypothesis would be that 80% of on placebo patients would be re-inducible when only 25% of on drug patients would. To test such an hypothesis, 32 patients (16 in each group) would have been necessary (a=5%, b=20%).Provided the essential binary response of the electrophysiological study we choose a sequential approach in order to get the opportunity stop for success or futility the inclusions before the end of the study. The maximum number of included patients will then be 42 (21 in each group).

Protocol duration:

Study duration is 48 hours for each patient.The protocol duration is planned for 5 years.

Per protocol procedures:

* Electrophysiological study with ventricular programmed stimulation performed twice
* Continuous ECG recording- Blood sampling for 3,4-DAP plasma concentration measurement Potential implications:If the study hypotheses are confirmed it would then be justified to design long term efficacy studies in Brugada patients implanted with an ICD.

Eligibility criteria: Inclusion Criteria:

* Man or woman ≥ 18 years old
* Brugada syndrome diagnosed with a type 1 ECG either spontaneous or drug-induced
* Electrophysiological study indicated for arrhythmic risk stratification purpose
* Inducibility of a sustained ventricular tachycardia (\> 30 seconds) or ventricular fibrillation requiring defibrillation
* Physical medical examination
* Signed written informed consent

Exclusion Criteria:

* Personal or familial history of epilepsy
* Pregnancy
* Body weight \> 100 kg
* the need of \>1 counter shock for defibrillation
* Alcohol or cocaine consumption during the protocol
* Class I (with the exception of local anaesthesia by lidocaine), II, III and IV antiarrhythmic drugs, antidepressant drugs, ATP dependent potassium channel activators, sultopride not stopped for \> 7 halve-lives
* No medical insurance

Primary outcomes:
measure: Electrophysiological study result (re-inducibility or not) 45 minutes after drug intake
timeFrame: 45 minutes after drug intake
Secondary outcomes:
measure: the effect of 3,4-DAP on ST segment elevation in Brugada patients (45 minutes)
timeFrame: at 45 minutes
measure: the relationship between 3,4-DAP plasma concentration measured at 45 minutes and electrophysiological study result and ST segment elevation
timeFrame: at 45 minutes
Other outcomes:
Locations:
city: Paris
country: France
facility: Lariboisière University Hospital - Cardiology department
Study officials:
affiliation: Lariboisière University Hospital - Cardiology Department
name: Fabrice EXTRAMIANA, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: