History of congenital long QT syndrome or corrected QT interval (QTc) > 450 msec within 2 weeks of randomization
Participants may not have corrected QT (QTc) > 470 msec or family history of long QT syndrome
Participants may not have any of the following cardiac criteria:\r\n* Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs) using the screening clinic ECG machine-derived QTc value\r\n* No history of QT prolongation associated with other medications that required discontinuation of that medication\r\n* Patient must not be receiving any concomitant medications that are known to be associated with Torsades de Pointes\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval\r\n* Symptomatic heart failure – New York Heart Association (NYHA) grade II-IV
Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
Congenital long QT syndrome or corrected QT interval (QTc) > 500 msec
Patients with congenital long QT syndrome
Any of the following cardiac criteria:\r\n* Resting corrected QT interval (QTc) > 480 msec obtained from electrocardiogram (ECG)\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) eg, complete left bundle branch block, third degree heart block\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval\r\n* Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) grade >= 2\r\n* Uncontrolled hypotension – systolic blood pressure (BP) < 90 mmHg and/or diastolic BP < 50 mmHg\r\n* Left ventricular ejection fraction (LVEF) below lower limit of normal for site
Must not have a family history of long corrected QT interval (QTc) syndrome
QTc >480 msec, or family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
Uncorrectable electrolyte abnormalities, long QT syndrome or taking medications known to prolong the QT interval
History of long QT syndrome or clinically significant cardiac arrhythmias (except stable atrial fibrillation)
Significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to:\r\n* History of clinically significant (as determined by the treating physician) atrial arrhythmia; or any ventricular arrhythmia\r\n* History of congenital long QT syndrome\r\n* Abnormal QT corrected for heart rate using Bazett's formula (QTcB) (>= 450 msec in males and >= 470 msec in females)\r\n* Ejection fraction =< 50% as assessed by echocardiogram
Participants with a personal or family history of long QT syndrome
Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
Any factors that increase the risk of corrected QT interval (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to the prolong the QT interval that a patient is unable to stop
Congenital long QT syndrome
ENROLLMENT TO THE DOSE ESCALATION, EXPANSION AND PART II: History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or Torsades de Pointes
EXPANDED ACCESS COHORT: History of QT syndrome, Brugada syndrome, known history of clinically significant QTc prolongation, or Torsades de Pointes
History of cardiac failure, significant/symptomatic bradycardia, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following:\r\n* Known risk to prolong the QT interval or induce torsade’s de pointes\r\n* Uncorrected hypomagnesemia or hypokalemia\r\n* Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg\r\n* Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse\r\n* On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 450 (based on a mean of 3 ECGs)
Participants with a personal or family history of long QT syndrome
Clinically significant cardiovascular disease, active or within 3 months prior to enrollment. Ongoing cardiac dysrhythmias, uncontrolled atrial fibrillation, bradycardia or congenital long QT syndrome
History of congenital long QT syndrome or mean (average of triplicate measurements) corrected QT (QTc) measured using Fridericia's method >/=450 millisecond (ms) at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus) Vismodegib
No known history of prolonged QT syndrome
QTc prolongation >450 ms or other factors that increase the risk for QT interval prolongation (e.g., heart failure, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], family history of long QT interval syndrome, or concomitant use of medications that may prolong QT interval)
Participant has long QT Syndrome at screening.
Baseline QTc prolongation (e.g., repeated demonstration of QTc interval > 480 milliseconds or history of congenital long QT syndrome or torsades de pointes)
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
Participants with a personal or family history of long QT syndrome.
Any factors that increase the risk of QTc prolongation or risk of rrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
History of congenital long QT syndrome or torsades de pointes
Patients with a prior history of drug-induced serotonin syndrome, or a family history of long-QT syndrome
Patients with congenital long QT syndrome (for cohort 2a and 2b [belinostat cohorts] only, electrocardiogram [ECG] not required for cohort 1)
Any known cardiac abnormalities such as:\r\n* Congenital long QT syndrome\r\n* Corrected QT(QTc) interval >= 500 milliseconds
Congenital long QT syndrome
No congenital long QT syndrome or known 1st degree relative with unexplained sudden death under 40 years of age
Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome
Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
Corrected QT (QTc) interval (i.e., Friderica’s correction [QTcF]) >= 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening
Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
Any of the following cardiac abnormalities or history:\r\n* Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia.
Any of the following cardiac criteria: \r\n* Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec;\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250msec;\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
Resting ECG with corrected QT (QTc) > 470 msec on two or more time points within a 24 hour period, noted within 14 days of treatment, or family history of long QT syndrome
Any of the following cardiac criteria:\r\n* Mean resting corrected QT interval (QTc using Frederica’s formula [QTcF]) > 470 msec\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block)\r\n* Congenital long QT syndrome or family history of long QT syndrome
Baseline prolongation of the rate-corrected QT interval (QTc) > 480 milliseconds or history of congenital long QT syndrome or Torsades de pointes
Patients with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) that meets New York Heart Association (NYHA) class II or above
Family or personal history of long QT syndrome
Positive risk assessment for cardiovascular disease including prior anthracycline cumulative dose more than 50% above recommended non-cardiotoxic levels, left ventricular ejection fraction (LVEF) <50%, valvular heart disease, or severe hypertension, (see Table 1). Cardiac subjects with a New York Heart Association (NYHA) classification of 3 or 4 will be excluded. (Cardiology consultation should be requested if any question arises about cardiac function.) This also includes subjects with baseline QT/QTc interval >480 msec, a history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) and using concomitant medications that significantly prolong the QT/QTc interval.
Resting electrocardiogram (ECG) with corrected QT Interval (QTc) > 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome.
Has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT. syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives.
Participants with known congestive heart failure, symptomatic or Left ventricular (LV) ejection fraction <50% or shortening fraction <27% and participants with congenital long QT syndrome, bradyarrhythmias, or QT interval (QTc)>480 milliseconds on at least 2 separate electrocardiograms (ECG).
Subject has familial short QT syndrome, is receiving medications that are known to shorten the QT interval, or has a clinically significant abnormal electrocardiogram (ECG).
Patients with congestive heart failure, congenital long QT syndrome; bradyarrhythmias, drugs known to prolong the QT interval
Absence of history of congenital long QT syndrome
History of risk factors for TdP, including family history of long QT syndrome.
Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
Congenital long QT syndrome or family history of unexpected sudden cardiac death
Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
Patients with a documented history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes, or taking drugs that are known to prolong the QT
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age
Any history of congenital long QT syndrome
Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or of long QT syndrome
Known congenital long QT syndrome
Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following:\r\n* History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry\r\n* Documented cardiomyopathy\r\n* Patient has a known left ventricular fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)\r\n* Long QT syndrome or family history of long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:\r\n** Risk factors for torsades de pointe (TdP) including uncorrected hypokalemia or hypomagnesaemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia\r\n** Concomitant medications(s) with a known risk to prolong the QT interval and/or known to cause torsades de pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study drug)\r\n** Inability to determine the corrected QT (QTc) interval\r\n* Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)
History of congenital long QT syndrome or torsades de pointes
Congenital long QT syndrome
History of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome); concomitant use of medications with a low risk of QT/QTc prolongation (including, but not limited to diphenhydramine, famotidine, ondansetron) is permissible
Cardiovascular disorders such as:\r\n* Inability to monitor the QT interval on electrocardiogram (ECG)\r\n* Complete left bundle branch block\r\n* Right bundle branch block plus left anterior or posterior hemiblock\r\n* Use of a ventricular-paced pacemaker\r\n* Congenital long QT syndrome or a known family history of long QT syndrome\r\n* Clinically significant resting bradycardia (< 50 beats per minute)\r\n* Corrected QT interval (QTc) > 450 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc\r\n* Myocardial infarction within 6 months prior to starting study\r\n* History of unstable angina within 6 months prior to study entry\r\n* Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)\r\n* History of or presence of clinically significant ventricular or atrial tachyarrhythmias
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval
Known family or personal history of long corrected QT (QTc) syndrome or ventricular arrhythmias including ventricular bigeminy
History of serious ventricular arrhythmia (VT or VF, ? 3 beats in a row) and/or risk factors (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
QT prolongation and/or familiar history of QT prolongation and uncontrolled cardiac arrhythmias
History or family history of long QT syndrome.
Diagnosed congenital long QT syndrome
Clinically significant electrocardiogram (ECG) changes at enrollment which obscure the ability to assess the PR, QT, and QRS interval; congenital long QT syndrome.
Any of the following cardiac criteria\r\n* Resting corrected QT interval (QTc using Fridericia’s formula) > 480 msec\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiograph (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block)\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval \r\n** Symptomatic congestive heart failure or left ventricular ejection fraction (LVEF) < 50%
History of congenital long QT syndrome
Corrected QT interval (QTc) > 470 msec (as calculated per institutional standards) at study entry or congenital long QT syndrome
History of congenital long QT syndrome
History of serious ventricular arrhythmia (VT or VF, ? 3 beats in a row) and/or risk factors (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
PHASE I: Resting electrocardiogram (ECG) with corrected QT QTc) > 470msec on two or more time points within a 24h period, or a family history of long QT syndrome
PHASE II: Resting ECG with QTc > 470msec on two or more time points within a 24h period, or a family history of long QT syndrome
Mean corrected QT interval (QTc) > 480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in a next-of-kin relative.
Corrected QT (QTc) interval > 480 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes
Congenital long QT syndrome
Resting electrocardiogram (ECG) with QTc > 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome
A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome, etc.)
Known family history of congenital long QT syndrome.
Patients with congenital long QT syndrome
A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome)
Diagnosed congenital long QT syndrome
Congenital long QT syndrome
Corrected QT (QTc) prolongation > 480 msec (Bazett's formula) or congenitally long QT syndrome
Any of the following cardiac criteria:\r\n* Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived corrected QT (QTc) value\r\n* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
QTcF >470 msec on screening ECG or congenital long QT syndrome
Any factor increasing the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval.
Any of the following cardiac criteria: Mean resting QT interval corrected for heart rate (QTc) more than 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
Must not have a family history of long QTc syndrome
Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome.
Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
A history of additional risk factors for Torsade de Pointes (e.g., clinically significant heart failure, hypokalemia, family history of long QT syndrome)
Corrected QT (QTc) interval > 480 msec (based on the mean value of the triplicate electrocardiography [ECG]s), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
History of long-QT syndrome
History of congenital long QT syndrome or torsades de pointes
Resting electrocardiography (ECG) with correct QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
History of cardiac disease (arrhythmia, conduction abnormality, congenital prolonged QT syndrome, or prolonged corrected QT [QTc] rhythm noted during initial electrocardiogram [EKG] > 480 ms)
Impaired cardiac function including any one of the following:\r\n* Inability to monitor the QT interval on electrocardiogram (ECG)\r\n* Congenital long QT syndrome or a known family history of long QT syndrome\r\n* Clinically significant resting brachycardia (< 50 beats per minute)\r\n* QTc > 450 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc\r\n* Myocardial infarction within 12 months prior to starting study\r\n* Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)\r\n* History of or presence of clinically significant ventricular or atrial tachyarrhythmias
QT interval corrected using Fridericia's formula (QTcF) >470 msec or history of prolonged QT syndrome or Torsades de pointes, or familial history of prolonged QT syndrome.
Known history of QT/corrected QT (QTc) prolongation or torsades de pointes (TdP); patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drugs
A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
Any of the following cardiac criteria:\r\n* Mean resting corrected QT interval (QTc using Fridericia’s formula [QTcF]) > 470 msec obtained from 3 electrocardiograms \r\n* Congenital or family history of long or short QT syndrome, Brugada syndrome, known history of QTc prolongation or torsades de pointes within 12 months of entering the study\r\n* Abnormal echocardiogram at baseline (left ventricular ejection fraction [LVEF] < 40% and shortening fraction [SF] < 15%)
Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
Prolonged QT interval (corrected QT interval [QTc] > 480 milliseconds) on screening electrocardiogram (EKG) or congenital long QT syndrome
Congenital long QT syndrome or history of torsades de pointes
Personal or family history of long QT syndrome
Clinically significant cardiac arrhythmias, prolonged QT interval, congenital long QT syndrome
Patients must not have a mean resting corrected QT interval (QTc) > 450 msec obtained from 3 consecutive electrocardiograms (ECGs); performed within 28 days prior to sub-study registration; patients must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block); patients must not have any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age
Patients must not have a mean resting corrected QT interval (QTc) > 450 msec obtained from 3 consecutive electrocardiograms (ECGs); performed within 28 days prior to Step 2 re-registration; patients must not have any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block); patients must not have any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age
Patients must not have a screening corrected QT Fridericia’s formula (QTcF) interval > 480 msec based on the average of the triplicate electrocardiograms (EKGs) performed within 28 days prior to registration; NOTE: triplicate EKGs are required at other timepoints; patients must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or torsade de pointes
Patients must not have a screening QTcF interval > 480 msec based on the average of the triplicate EKGs performed within 28 days prior to step 2 re-registration; NOTE: triplicate EKGs are required at other timepoints; patients must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or torsade de pointes
Patients with congenital long QT syndrome, bradyarrhythmias, or QTc > 480 msec are not eligible
Congenital long QT syndrome
A history of additional risk factors for torsade de pointes (e.g., clinically significant heart failure, hypokalemia, family history of long QT syndrome)
At screening, patients must have no known history of congenital long QT syndrome and must have a corrected mean QTc interval =< 450 msec at baseline
Patients with congenital long QT syndrome are excluded
Subjects with Long QT Syndrome at Screening.
Any concomitant medications that are associated with a risk of corrected QT interval (QTc) prolongation and/or torsades de pointes should be discontinued or replaced with drugs that do not carry these risks, if possible; patients who must take medication with a risk of possible risk of torsades de pointes should be watched carefully for symptoms of QTc prolongation, such as syncope; patients with personal or family history of congenital long QTc syndrome are NOT eligible
Patients with QTc interval ?450 msec or with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome)
Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF) >450 msec obtained from 3 electrocardiograms (ECGs); family or personal history of long or short QT syndrome; Brugada syndrome or known history of QTc prolongation or torsade de pointes within 12 months of the subject entering the study.
Congenital long QT syndrome or a corrected QT interval (QTc) ?450 ms at Screening (unless secondary to pacemaker or bundle branch block).
Congenital long QT syndrome or family history of long QT syndrome
Patients who have a mean resting correct corrected QT (QTc) interval using the Fridericia formula (QTcF) > 470 msec (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome; AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
History of additional risk factors for torsade de pointes (e.g., family history of long QT syndrome).
Clinically significant cardiac abnormalities including QRS duration of >120 msec; QTcF >470 msec for women and >450 msec for men; Abnormal cardiac rhythm; Clinically significant cardiac valve abnormality; Documented history of left ventricular ejection fraction <0.30 within 6 months; Permanent pacemaker or automatic implantable cardioverter defibrillator; History of torsades de pointes, congenital long QT syndrome, or family history of long QT syndrome or sudden death
Patients considered at risk for life-threatening QTc prolongation (i.e., personal or family history of Long QT syndrome, presence of implantable pacemaker, or implantable cardioverter defibrillator, etc.)
History of long QT syndrome or a family member with this condition
Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, and etc.
Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
Congenital long QT syndrome.
Family history of long QT syndrome or other risk factors for torsades de pointes, and/or the use of concomitant medications that prolong the QT/QTc interval
Long QT Syndrome
Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Congenital long QT syndrome or taking drugs known to prolong the QT interval
That have a known risk to prolong the QT interval or induce Torsades de Pointes.
Impaired cardiac function including any of the following:\r\n* Congenital long QT syndrome or a known family history of long QT syndrome;\r\n* Corrected QT (QTc) > 450 msec;\r\n* History or presence of clinically significant ventricular or atrial tachyarrhythmias;\r\n* Clinically significant resting bradycardia (< 50 beats per minute); \r\n* Myocardial infarction within 1 year of starting study drug;\r\n* Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
Diagnosed or suspected congenital long QT syndrome
Impaired cardiac function including any of the following:\r\n* Congenital long QT syndrome or a known family history of long QT syndrome\r\n* History or presence of clinically significant ventricular or atrial tachyarrhythmias\r\n* Clinically significant resting bradycardia (< 50 beats per minute)\r\n* Inability to monitor the QT interval by electrocardiogram (ECG)\r\n* Corrected QT (QTc) > 450 msec on baseline ECG; if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc\r\n* Myocardial infarction within 1 year of starting study drug\r\n* Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
Subject with a history of Long QT Syndrome at screening.
QTcF >470 msec on screening ECG or congenital long QT syndrome
Mean resting corrected QT interval (QTc), calculated using Fridericia’s formula, > 470 msec obtained from 3 electrocardiograms (ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of the patient entering in the study
Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age)
Impaired cardiac function including any of the following:\r\n* Inability to monitor the QT interval on electrocardiogram (ECG)\r\n* Congenital long QT syndrome or a known family history of long QT syndrome\r\n* Clinically significant resting brachycardia (< 50 beats per minute)\r\n* Corrected QT (QTc) > 450 msec on baseline ECG; NOTE: if the ECG shows a QTc interval greater than 450 msecs at screening triplicates should be performed, one minute apart to confirm the finding (after replacement of any electrolyte imbalance); if 2/3 or 3/3 of the ECGs confirm the QT prolongation (i.e. QTc interval > 450 msecs) the patient must not be included into the trial\r\n* Myocardial infarction =< 3 months prior to starting study\r\n* Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) \r\n* History of or presence of clinically significant ventricular, atrial tachyarrhythmias or ejection fraction cutoff\r\n* Left ventricle ejection fraction < 45%\r\n* History of congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Diagnosed or suspected congenital long QT syndrome
Have Fridericia-corrected QT interval (QTcF) > 470 msec (female) or > 450 (male), or history of congenital long QT syndrome.
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion if the arrhythmias are stable, asymptomatic, and unlikely to affect patient safety; patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade >= 3, corrected QT interval (QTc) prolongation > 450 ms, or other factors that increase the risk for QT interval prolongation (eg, heart failure, hypokalemia [defined as serum potassium < 3.0 mEq/L that is persistent and refractory to correction], or family history of long QT interval syndrome)
Congenital long QT syndrome
Diagnosed or suspected congenital long QT syndrome.
QTc greater than 480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or know history of QTc prolongation, or Torsade de Pointes (TdP).
Resting heart rate <50 bpm or > 90 bpm Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Patients with congenital long QT syndrome are excluded from this study
Corrected QT (QTc) interval >= 450 msec at baseline or history of congenital long QT syndrome or uncorrectable electrolyte abnormalities
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital or familial long QT syndrome or family history of unexplained sudden death under 40 years of age or any concomitant medications known to prolong QT interval.
At increased risk for developing prolonged QT interval, including hypokalemia or hypomagnesemia, unless corrected to within normal limits prior to first dose of SNX-5422; congenital long QT syndrome or a history of torsade de pointes; currently receiving anti-arrhythmics or other medications that may be associated with QT prolongation.
Diagnosed or suspected congenital long QT syndrome
History of risk factors for TdP, including family history of long QT syndrome
History of congenital long QT syndrome or corrected QT interval (QTc) greater than (>) 450 milliseconds at screening
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
That have a known risk to prolong the QT interval or induce Torsades de Pointes.
Resting electrocardiogram (ECG) with corrected QT (QTc) > 470 msec on 2 or more time points within a 24 hour period or a documented family history of long QT syndrome.
Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia
Subjects with heart-rate corrected QT (QTc) interval ?450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening.
History of congenital long QT syndrome or a corrected QTc interval >= 450 msec at baseline
A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome)
Impaired cardiac function including any one of the following:\r\n* Inability to monitor the QT interval on electrocardiogram (ECG)\r\n* Congenital long QT syndrome or a known family history of long QT syndrome\r\n* Clinically significant resting brachycardia (< 50 beats per minute)\r\n* Corrected QT (QTc) > 450 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc\r\n* Myocardial infarction =< 12 months prior to starting study\r\n* Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)\r\n* History of or presence of clinically significant ventricular, atrial tachyarrhythmias or ejection fraction cutoff\r\n* Left ventricle ejection fraction < 45%\r\n* History of, congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Patients with a family history of congenital long QT syndrome
Prolonged corrected QT (QTc) interval (>= 450 msec) as calculated by Bazett’s formula, or patients with a history of congenital long QT syndrome or uncorrectable electrolyte abnormalities
Concomitant use of drugs with a risk of causing prolonged QTc and/or torsades de pointes, or patients with a history of risk factors for torsades de pointes (e.g., familial long QT syndrome, heart failure, left ventricular hypertrophy, slow heart rate [< 45 beats per minute])
Long QT syndrome or a known family history of long QT syndrome
Impaired cardiac function including any of the following:\r\n* Congenital long QT syndrome or a known family history of long QT syndrome;\r\n* History or presence of clinically significant ventricular or atrial tachyarrhythmias\r\n* Clinically significant resting bradycardia (< 50 beats per minute) \r\n* Inability to monitor the QT interval by electrocardiogram (ECG)\r\n* Corrected QT interval (QTc) > 450 msec on baseline ECG; if QTc > 450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc\r\n* Myocardial infarction within 1 year of starting study drug\r\n* Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
No clinical evidence of heart failure or history of untreated ejection fraction below the lower limit of normal per institutional standards, or significant QT prolongation (> grade 1, 480 msec) no history of congenital long QT syndrome, and no use of drugs known to increase the risk of torsades de point - patients may be eligible for study if the drug can be changed to another agent with less risk
Congenital long QT syndrome or a known family history of long QT syndrome
QT related exclusion criteria:\r\n* QT interval corrected using Fridericia’s formula (QTcF) at screening > 470 msec\r\n* History of syncope or family history of idiopathic sudden death\r\n* Sustained or clinically significant cardiac arrhythmias\r\n* Risk factors for torsades de pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade atrioventricular (AV) block\r\n* Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis, uncontrolled hypothyroidism or cardiac failure\r\n* Concomitant medication(s) known to increase the QT interval
Patients with congenital long QT syndrome
History of significant cardiovascular disease, defined as:\r\n* Congestive heart failure greater than New York Heart Association (NYHA) class III according to the NYHA functional classification \r\n* Unstable angina or myocardial infarction within 6 months of enrollment\r\n* Serious cardiac arrhythmia\r\n* A prolonged QT/corrected QT (QTc) interval (QTc > 500 ms) demonstrated on electrocardiogram (ECG) at screening or baseline; a history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or the use of concomitant medications that prolonged the QT/QTc interval
Mean QTc > 500 msec (with Bazett’s correction) in screening electrocardiogram or history of familial long QT syndrome
Diagnosed congenital long QT syndrome
Congenital long QT syndrome
History of congenital long QT syndrome, or a baseline >470 msec QTcF abnormality (average of the triplicate reading).
Personal or family history of long QT syndrome
Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix F) or who have a history of long QT syndrome
Patients with QTcF >470 msec at screening ECG or congenital long QT syndrome
Congenital long QT syndrome or subjects taking concomitant medications known to prolong the QT interval (e.g., tricyclics, azithromycin, methadone).
Subject is known to have long QT syndrome.
Impaired cardiac function including ongoing cardiac dysrhythmias of grade > 2, ejection fraction < 50%, atrial fibrillation of any grade, or corrected QT (QTc) prolongation > 450 ms, or other factors that increase the risk of QT prolongation (i.e. family history of long QT interval syndrome, hypokalemia defined as serum potassium < 3.0 mEq/L)
Family history of long QTc syndrome
Family history of long QTc syndrome
Impaired cardiac function including any one of the following: a. inability to monitor the QT interval on electrocardiogram (ECG), b. congenital long QT syndrome or a known family history of long QT syndrome, c. clinically significant resting brachycardia (< 45 beats per minute), d. QTc > 480 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc, e. impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to screening, symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
QTcF >480 msec on screening ECG or congenital long QT syndrome
Corrected QT interval (QTc) >470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome.
History of congenital long QT syndrome or mean corrected QTc interval > 450 msec at baseline
Patients with a history of long-QT syndrome or documented family history of long-QT syndrome; patients who must remain on drugs that prolong the QT interval
Baseline prolongation of the rate-corrected QT interval (QTc) > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes
Congenital long QT syndrome.
Patients with congenital long QT syndrome
History of congenital long QT syndrome or QTc > 470 msec
Have Fridericia-corrected QT interval > 470 milliseconds (msec) (female) or > 450 msec (male), or history of congenital long QT syndrome
Patients with a known history or predisposition to cardiac conduction interval abnormalities, including QT Syndrome, or known family history of long QT Syndrome or taking medications that are known to prolong the QT interval.
Personal or family history of long QT syndrome
Corrected QT (QTc) interval ? 450 msec at baseline or history of congenital long QT syndrome or uncorrectable electrolyte abnormalities. (Patients with well controlled atrial fibrillation are exempt from this criteria.)
Congenital long QT syndrome, congestive heart failure, or bradyarrhythmia
Patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion if the arrhythmias are stable, asymptomatic, and unlikely to affect patient safety; patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade >= 3, corrected QT interval (QTc) prolongation > 450 ms, or other factors that increase the risk for QT interval prolongation (eg, heart failure, hypokalemia [defined as serum potassium < 3.0 mEq/L that is persistent and refractory to correction], or family history of long QT interval syndrome)
Patients with unexplained syncope, history of or known risk factors for torsade des pointes, including congenital long QT syndrome, or family history of LQTS.
Patients must have corrected QT (QTC) interval =< 480 msec on electrocardiogram (EKG) at baseline; patient with congenital long QT syndrome are not eligible
Patients with congenital prolonged QT syndrome
Congenital long QT syndrome
Congenital long QT syndrome
History of congenital long QT syndrome or congenital short QT syndrome
At increased risk for developing prolonged QT interval, including hypokalemia or hypomagnesemia, unless corrected to within normal limits prior to first dose of SNX-5422; congenital long QT syndrome or a history of torsade de pointes; currently receiving anti-arrhythmics or other medications that may be associated with QT prolongation
Congenital long QT syndrome
Patients with a corrected QT interval (QTc) at baseline of > 450 milliseconds or other factors that increase the risk of QT prolongation or arrhythmic events (i.e., heart failure, hypokalemia with potassium < 3.5 despite supplementation, family history of long QT syndrome) should be excluded
Congenital long QT syndrome or family history of unexpected sudden cardiac death.
Known history of QT prolongation or is taking any medication known to lead to QT prolongation
History of familial long QT syndrome, or use of medications that may cause QTc interval prolongation
Clinically significant ECG changes which obscure the ability to assess the PR, QT, and QRS interval; congenital long QT syndrome
Diagnosed or suspected congenital long QT syndrome
History of clinically significant cardiac disease, including but not limited to a history (personal or family) of congenital long QT syndrome
Patients with risk factors for torsades de pointes, including uncorrected hypokalemia, uncorrected hypomagnesemia, family history of long QT syndrome, clinically significant/symptomatic bradycardia, high-grade atrio-ventricular (AV) block, autonomic neuropathy (including that caused by diabetes or Parkinson’s disease, uncontrolled hypothyroidism, cirrhosis, or the use of concomitant medications known to prolong the QT interval)
Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age
Congenital long QT syndrome or family history of unexpected sudden cardiac death
Any of the following cardiac abnormalities or history:\r\n* Clinically significant abnormal 12-lead electrocardiograph (ECG), QT interval corrected using Fridericia's method (QTcF) > 450 msec\r\n* Inability to measure QT interval on ECG\r\n* Personal or family history of long QT syndrome\r\n* Implantable pacemaker or implantable cardioverter defibrillator\r\n* Resting bradycardia < 55 beats/min
Any concomitant medications that are associated with a risk of corrected QT (QTc) prolongation and/or Torsades de Pointes should be discontinued or replaced with drugs that do not carry these risks, if possible; patients who must take medication with a possible risk of Torsades de Pointes should be watched carefully for symptoms of QTc prolongation, such as syncope; patients with personal or family history of congenital long QTc syndrome are NOT eligible
History of congenital long QT syndrome or QTc > 450 ms
Diagnosed or suspected congenital long QT syndrome;
Risk factors for torsades de pointes such as:\r\n* Uncontrolled hypokalemia\r\n* Uncontrolled hypomagnesemia or hypermagnesemia\r\n* Cardiac failure (New York Heart Association class II or higher)\r\n* Clinically significant/symptomatic bradycardia (hear rate [HR] < 50), or high-grade atrioventricular (AV) block\r\n* Known diagnosis of QT prolongation (QTc >= 470) or family history of long QT syndrome\r\n* Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes, or Parkinson's disease), human immunodeficiency virus [HIV], cirrhosis, uncontrolled hypothyroidism or cardiac failure\r\n* Concomitant medications known to prolong the QT interval during the same time as pasireotide is to be administered (unless approved by principal investigator [PI] and QTc < 470; standard transplant medications that are known to prolong the QT (e.g. azoles, ondansetron, etc.) are permitted but caution is advised and patients should be closely monitored)
Congenital long QT syndrome, prolonged QT interval, or family history of sudden unexplained death or long QT syndrome
Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome);
History of long QT syndrome.
Patients with congenital long QT syndrome
Familial short QT syndrome
Grade 3 or higher recent (within the past 6 months) or ongoing cardiac dysrhythmias, family history of long QT syndrome, or serum potassium < 3.0 mEq/L that is persistent and refractory to correction
Congenital long QT syndrome, or 1st degree relative with unexplained sudden death under 40 years of age;
QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval
Subject has a history (or family history) of long QT syndrome.
Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following:\r\n* History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft (CABG) or myocardial infarction within 6 months prior to study entry\r\n* Documented cardiomyopathy\r\n* Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) detected during screening\r\n* History of cardiac failure, significant/symptomatic bradycardia, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following:\r\n** Known risk to prolong the QT interval or induce torsade’s de pointes\r\n** Uncorrected hypomagnesemia or hypokalemia\r\n** Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg\r\n** Bradycardia (heart rate < 50 at rest), by electrocardiogram (ECG) or pulse\r\n** On screening, inability to determine the corrected QT using Fridericia's formula (QTcF) interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 450 screening ECG (based on a mean of 3 ECGs)
Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age
Has a known history of QT prolongation or is taking any medication that is known to lead to QT prolongation
A history of clinically significant electrocardiography (EKG) abnormalities, including QT prolongation, a family history of prolonged QT interval syndrome, or myocardial infarction (MI) within 6 months of study entry; patients with rate-controlled atrial fibrillation/flutter will be allowed on study
Has any factors that increase the risk of corrected QT (QTc) interval prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
History of, or at risk for, cardiac disease (e.g., long QT syndrome [> 450 msec] or concurrent treatment with any medication that prolongs QT interval).
Mean resting corrected QT interval (QTc), calculated using Fridericia’s formula, > 470 msec obtained from 3 electrocardiograms (ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or torsade de pointes within 12 months of the patient entering in the study
Concomitant medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age)
Subject with Long QT Syndrome.
A history of clinically significant electrocardiogram (EKG) abnormalities, including QT prolongation, a family history of prolonged QT interval syndrome, or myocardial infarction (MI) less than 1 year ago with ensuing unstable EKG
Corrected QT interval (QTc) > 470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome
Patients with history of long QT syndrome, uncorrectable electrolyte abnormalities, or corrected QT (QTc) > 500 msec
Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
Congenital long QT syndrome or a known family history of long QT syndrome