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 electrocardiogram [ECG] data)The…
ID
Source
Brief title
Condition
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be assessed by the incidence of treatment-emergent AEs (including
new from baseline PE findings and medical history), clinically significant
abnormalities in vital signs, laboratory parameters, ECG variables, ACAs, CV
deaths, SCDs, CV hospitalizations, seizures, and other relevant events to be
described in detail in the CEC charter.
The primary efficacy 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).
Secondary outcome
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 (midnight to 6:00 AM study center
local time) QTcF interval (in msec) at baseline and at Week 24 (based on Holter
data)
The additional endpoints include:
* The difference between the mean daily (daytime and nocturnal) QTcF interval
(in msec) at baseline and at Week 12 (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 12 (based on Holter
data)
* The maximal reduction of QTcF interval between predose (T = 0) and any time
within 24 hours post loading dose of eleclazine on Day 2 (based on standard
12-lead ECG)
* The maximal reduction in time-matched QTcF interval (in msec) from baseline
to Day 2, Week 12, and Week 24 (based on standard 12 lead ECG or Holter data).
Baseline for each time point is the value at the nominal time point on Day 1
corresponding to the postdose nominal time point
* Proportion of subjects who have a mean daytime QTcF interval (in msec)
(AUC0-6/6) of * 500 msec vs < 500 msec at baseline vs Week 12 and at baseline
vs Week 24 (based on standard 12 lead ECG data)
* Changes in other markers of ventricular repolarization from baseline to Week
12 and baseline to Week 24 (based on Holter* data)
Background summary
The congenital long QT syndrome (LQTS) represents a group of diverse genetic
disorders characterized by a prolonged QT interval on a 12-lead
electrocardiogram (ECG). The common pathogenesis of LQTS involves prolongation
of the ventricular action potential, caused either by
decreases in the outward potassium current or increases in the late inward
sodium or calcium current, leading to QT prolongation, increased susceptibility
to early afterdepolarizations (EADs), and sustained polymorphic ventricular
tachycardia (VT) (torsade de pointes). The disease clinically manifests as
syncope and cardiac arrest. While LQTS is relatively rare, with an estimated
prevalence of 1 in 2000-5000 individuals, it is highly lethal, with greatly
increased mortality rates relative to the general population. It has been well
established that the risk of sudden cardiac death (SCD) is directly related to
the QTc interval, and preliminary data suggest that shortening of the QTc
interval reduces this risk.
Depending on the molecular and genotypic basis of the action potential
prolongation, 13 subtypes of LQTS have been identified to date. Among them,
long QT types 1, 2, and 3 are the most common, with 30-35%, 25-40%, and 5-10%
of cases, respectively. Types 1 and 2 LQTS (LQT1 and LQT2) are both
characterized by loss-of-function mutations involving potassium channels; the
affected genes are KCNQ1 and KCNH2, respectively. These mutations result in
decreases in either the slowly activating (IKs; LQT1) or the rapidly activating
(IKr; LQT2) component of the outward-rectifying potassium current. Type 3 LQTS
(LQT3) is caused by mutations in the gene encoding the cardiac sodium channel
Nav1.5 (SCN5A), which results in impaired inactivation of the channel and a
consequent increase in the late inward sodium current (late INa). LQT3 is
distinguished by greater lethality, even within the broader context of LQTS.
While the overall frequency of cardiac events in LQT1 and LQT2 is typically
greater than that of LQT3, the events that occur in LQT3 are often more
malignant, with an approximately 5-fold risk of mortality relative to both LQT1
and LQT2.
As with the clinical course and prognosis, the relative efficacy of available
treatment options is dependent on genotype. Because cardiac events in LQT1 are
typically triggered by exercise, beta-blockers are considered the mainstay of
prophylactic pharmacotherapy in these patients.
However, in contrast to LQT1, cardiac events in LQT3 occur more frequently at
rest in the absence of adrenergic stimulation. Moreover, patients with LQT3
shorten their QT intervals with tachycardia. These data therefore suggest that
beta-blockers would have diminished utility in LQT3. Indeed, observational data
have borne this out, with consistently lower efficacy rates of beta-blockers in
patients with LQT3.
Moreover, the well-described association between LQT3 and sinus node
dysfunction presents an additional potential limitation to the use of
beta-blockers in patients with this genotype.
As the mechanism of QT lengthening in LQT3 involves an increase in late INa, it
has been postulated that medications that target the sodium channel would be
particularly effective in such patients. To this end, several Class I
antiarrhythmic medications, including mexiletine and
flecainide, have been observed to shorten the QTc interval in patients with
LQT3.
Additionally, more selective inhibition of late INa by the piperazine
derivative ranolazine was demonstrated to reduce QTc in a
concentration-dependent manner in patients with LQT3. Despite the
attractiveness of this mechanistically-based strategy, however, full adoption
of this approach is limited by concerns over IKr inhibition and tolerability in
currently available agents.
Study objective
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
electrocardiogram [ECG] data)
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)
The additional objectives of this study are to evaluate:
- The effect of oral eleclazine on the mean daily (daytime and nocturnal) QTcF
interval (in msec) after 12 weeks of treatment with eleclazine (based on Holter
data)
- The effect of oral eleclazine on the mean nocturnal QTcF interval (in msec)
after 12 weeks of treatment with eleclazine (based on Holter data)
- The effect of oral eleclazine on the maximal reduction in QTcF interval (in
msec) (based on standard 12 lead ECG and Holter data)
- The effect of oral eleclazine on changes in other markers of ventricular
repolarization from baseline to Week 12 and baseline to Week 24 (based on
Holter data)
- The safety and tolerability of oral eleclazine in subjects with LQT3
- The pharmacokinetic (PK) profile of oral eleclazine in subjects with LQT3
Study design
A single-arm, single-blind, multi-center study.
Intervention
Single-Blind Treatment Period: Oral single loading dose of 48 mg of eleclazine
(8 x 6 mg eleclazine tablets) on Day 2, followed by a daily maintenance dose of
3 mg of eleclazine (1 x 3 mg eleclazine tablet) from Day 3 through the Week 12
Visit, followed by a daily maintenance dose of 6 mg of eleclazine (1 x 6 mg
eleclazine tablet) from the day after the Week 12 Visit through Week 24
Open-Label Extension: Oral daily maintenance dose of 6 mg of GS 6615 (1 x 6 mg
eleclazine tablet) through the end of the OLE
Reference Therapy, Dose, and Mode of Administration:
Single-Blind Treatment Period: Oral single loading dose of placebo to match
eleclazine loading dose (8 x 6 mg matching placebo tablets) on Day 1
Study burden and risks
De patients will undergo the following procedures:
* Physical exam and vital signs * each visit, except week 2
* ECG * each visit, except week 2
* Holter-ECG * during 48 hours after each visit
* Placement of ZIO® XT Patch * 2x
* Blood- en urine sample * each visit, except week 2
* Pregnancy test (only womenthat can get pregnant) - each visit, except week 2
* Blood sample for pharmacokinetic - each visit, except screening and week 2
* Blood sample for pharmacogenomic research * 1x
As of 15 September 2014, 95 healthy subjects and 10 subjects with Long QT-3
syndrome have taken single doses and multiple doses of GS-6615 ranging from 3
mg to 60 mg in 5 different research studies.
This study can have the following side-effects: abnormal dreams, drowsiness,
increased urination at night, feeling tense, headache, fatigue (tiredness),
sweats, nausea (feeling sick to the stomach), vomiting, diarrhea, dizziness,
increased libido, upper respiratory tract infection, and temporary increase in
liver enzymes (blood tests related to the liver functions). There have been no
reports of serious or severe side effects related to taking eleclazine.
Furthemore the study procedures, like blood draws, ECGs and ZIO® XT Patch, may
cause discomfort.
Lakeside Drive 333
Foster City CA 94404
US
Lakeside Drive 333
Foster City CA 94404
US
Listed location countries
Age
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 as described in Appendix 3
7) Willing and able to comply with the requirements of the protocol and directions from the clinic staff
Exclusion criteria
1) Known pathogenic mutations associated with Long QT 1 syndrome (LQT1) or Long QT 2 syndrome (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 [see Appendix 6 and {8057}]), as determined by the study center
8) Abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x upper limit of normal (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 (see Appendix 5). 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 (see Appendix 4). 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-000042-30-NL |
| ClinicalTrials.gov | NCT02300558 |
| CCMO | NL49681.018.14 |