| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with an established diagnosis of LQT3. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with LQT3 syndrome. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10024803 |
| E.1.2 | Term | Long QT syndrome |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate, in subjects with LQT3, the effect of oral eleclazine on mean daytime QTcF interval (in msec) after 24 weeks of treatment with eleclazine (based on standard 12-lead ECG data). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate in subjects with LQT3:
• The effect of oral eleclazine on mean daytime QTcF interval (in msec) after 12 weeks of treatment with eleclazine (based on standard 12-lead ECG data)
• The effect of oral eleclazine on mean daily (daytime and nocturnal) QTcF interval (in msec) after 24 weeks of treatment with eleclazine (based on Holter data)
• The effect of oral eleclazine on mean nocturnal QTcF interval (in msec) after 24 weeks of treatment with eleclazine (based on Holter data) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
2) Males and females 18 to 70 years old, inclusive, at time of Screening.
3) Subjects with an established diagnosis of LQT3 (by genotype testing).
4) Mean (of triplicate) QTc interval ≥ 480 msec (or ≥ 460 msec, for subjects who are currently taking ranolazine or Class I antiarrhythmic drugs such as mexiletine) at 3 or more time points, determined by standard 12-lead ECG, at Screening.
5) Subjects with an implanted cardiac device (eg, pacemaker, implantable cardioverter-defibrillator [ICD], implantable loop monitor) may participate in the study, provided that they are not predominantly ventricular-paced, in the judgment of the investigator.
6) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to utilize protocol-specified method(s) of contraception.
7) Willing and able to comply with the requirements of the protocol and directions from the clinic staff. |
|
| E.4 | Principal exclusion criteria |
1) Known pathogenic mutations associated with LQT1 or LQT2.
2) Known or suspected history of seizures or epilepsy.
3) History of heart failure defined as New York Heart Association (NYHA) Class IV and/or known left ventricular ejection fraction (EF) ≤ 45%.
4) Known severe obstructive sleep apnea that is not treated. Known untreated moderate sleep apnea may be included after discussion with the medical monitor.
5) Body mass index (BMI) ≥ 40 kg/m2 at Screening.
6) Any abnormal laboratory value or physical examination (PE) finding at Screening, judged by the investigator to preclude enrollment in the study.
7) Severe renal impairment at Screening (defined as an estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2, using the 4 Variable Modification of Diet in Renal Disease [MDRD] equation), as determined by the study center.
8) Abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN, or total bilirubin > 1.5x ULN.
9) Current treatment with drugs known to prolong the QT interval (not including beta-blockers).
10) Current use of Class I and Class III antiarrhythmic drugs other than amiodarone. Such medications should be discontinued for at least 5 half-lives prior to Day 1.
11) Current use of amiodarone. Chronic use of amiodarone should be discontinued for at least 3 months prior to Day 1.
12) Current use of ranolazine. Ranolazine should be discontinued for at least 3 days prior to Day 1.
13) Current use of drugs or products that are strong inhibitors or inducers of CYP3A. Such medications should be discontinued 5 half-lives prior to Day 1.
14) Participation in prior clinical studies of eleclazine is not exclusionary, however subjects must have completed dosing of eleclazine in the prior study at least 60 days prior to Screening into this study.
15) Known hypersensitivity to eleclazine, its metabolites, or formulation excipients.
16) Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before study drug is administered. A negative serum pregnancy test at Screening and a negative urine pregnancy test at Day 1 are required for female subjects of childbearing potential.
17) Any clinically significant planned elective invasive surgery or procedure (including, but not limited to, pacemaker and/or ICD implantation and cervico-thoracic sympathectomy) during the projected single blind treatment period. Note that history of cervico-thoracic sympathetic ganglionectomy is not exclusionary. Recent or planned device generator changes are not exclusionary in this context.
18) An aborted cardiac arrest (ACA), ICD implantation, syncopal episode, or appropriate ICD therapy within 3 months prior to Screening. Recent or planned device generator changes are not exclusionary in this context.
19) Unless otherwise specified, participation in another investigational drug or investigational device study within the 30 days prior to Screening. Subjects participating in registries or observational studies are eligible for study participation.
20) Psychosocial or addictive disorders (including drug or alcohol abuse) that would interfere with the subject's ability to give informed consent or could compromise compliance with the protocol.
21) In the judgment of the investigator, any clinically-significant ongoing medical or surgical condition that might jeopardize the subject's safety or interfere with the conduct of the study.
22) Any other condition or circumstance that in the opinion of the investigator would preclude compliance with the study protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the difference between mean daytime QTcF interval (in msec) (AUC0-6/6) at baseline and at Week 24 (based on standard 12-lead ECG data). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint will be taken at baseline (Day 1) and at Week 24. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include:
• The difference between the mean daytime QTcF interval (in msec) (AUC0-6/6) at baseline and at Week 12 (based on standard 12-lead ECG data).
• The difference between the mean daily (daytime and nocturnal) QTcF interval (in msec) at baseline and at Week 24 (based on Holter data).
• The difference between the mean nocturnal QTcF interval (in msec) (midnight to 6:00 AM study center local time) at baseline and at Week 24 (based on Holter data). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For the secondary endpoints, data will be acquired at baseline, Week 12 and Week 24. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Finland |
| France |
| Germany |
| Israel |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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