Protocol CHRC2012- QT003 version dated December 13,

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1 Protocol Title: Longitudinal Registry of QT monitoring Protocol Number: CHRC2012-QT003 Author: Anatoly Langer, MD Coordinating Centre: Canadian Heart Research Centre Number of pages: 11 Protocol CHRC2012- QT003 version dated December 13,

2 Background: The majority of out-of-hospital sudden cardiac arrests occur among either those patients in whom cardiac arrest is the first clinical expression of the underlying disease, or those in whom disease is previously identified but classified as low risk. The incidence of SCD is age-related and may range from 1 per 1000 in a 50 year old man to 8 per 1000 in a 75 year old man. Screening for higher risk features in the general population has not been widely adopted though a variety of relatively inexpensive strategies have been proposed. ECG represents a particularly useful tool given that a variety of easily obtainable measures, such as conduction abnormalities (e.g. QRS duration, heart block), QT prolongation, early repolarization, and arrhythmia can be obtained as indicators of potentially modifiable risk. Prolonged QTc interval and the risk of sudden cardiac death was studied as part of the Rotterdam Study in a prospective population-based cohort of 3,105 men and 4,878 women aged 55 years and older. After follow-up period of 6.7 years, abnormally prolonged QTc interval (450 ms in men, 470 ms in women) was associated with a three-fold increased risk of sudden cardiac death (hazard ratio, 2.5; 95% confidence interval, 1.3 to 4.7), after adjustment for age, gender, body mass index, hypertension, cholesterol/high-density lipoprotein ratio, diabetes mellitus, myocardial infarction, heart failure, and heart rate. In patients with an age below the median of 68 years, the corresponding relative risk was 8.0 (95% confidence interval 2.1 to 31.3). The authors concluded that QTc prolongation on the electrocardiogram should be viewed as an independent risk factor for sudden cardiac death (2). The association between QT interval and cardiovascular morbidity and mortality is well established (3-6). QT prolongation has been shown to be predictive of sudden death and has therefore been advocated as an important screening measure in adults and children. Other ECG derived variables such as the duration of QRS have also been related to the occurrence of sudden death; however, there is no evidence that commonly used medications impact on the QRS duration. Thus the safety of medications and the Protocol CHRC2012- QT003 version dated December 13,

3 potential increase in the risk of sudden death has only been raised for QT prolongation and forms the basis of this longitudinal monitoring study. QT and its measurement 1. The QT interval represents the duration of ventricular depolarization and subsequent repolarization, and is measured from the beginning of the QRS complex to the end of the T wave. 2. Normal range for QT has been well established and is frequently corrected for the heart rate: QTc. Normal limits for the QTc are well established and provide a convenient way to follow individuals: QTc (msec) Male Female Normal <430 <450 Borderline Prolonged >450 >470 While the precision of QT measurement is likely better when 12 lead ECG is used, the single lead QT measurement is more optimal to the monitoring of prolongation of QT given its simplicity of use. FDA: Why measure and follow QT/QTc (7) An undesirable property of some drugs is their ability to prolong the QT interval which favors the development of cardiac arrhythmias, most clearly Torsades de pointes (TdP), but possibly other ventricular tachyarrhythmias as well. TdP is a polymorphic ventricular tachyarrhythmia that can degenerate into ventricular fibrillation, leading to sudden death. While the degree of QT prolongation is recognized as an imperfect biomarker for proarrhythmic risk, in general there is a qualitative relationship between QT prolongation and the risk of TdP, especially for drugs that cause substantial prolongation of the QT interval. Because of its inverse relationship to heart rate, the measured QT interval is routinely corrected by means of various formulae to a less heart rate dependent value known as the QTc interval. It is not clear, however, whether arrhythmia development is more closely related to an increase in the absolute QT interval or QTc. Most drugs that have caused TdP clearly increase both the absolute QT and the QTc (hereafter called QT/QTc). FDA has recommended that changes as small as 5 msec maybe of significance. This is because even a small drug-induced increase in the QT interval in a population indicates some risk of torsade de pointes if large numbers of patients are exposed. Indeed, some non-cardiovascular drugs that have been withdrawn from the market because they cause torsade de pointes result in a mean increase in the QT interval as small as 5 to 10 msec in populations of patients (8, 9). FDA mandates that all new drugs undergo testing to ensure that there is no QT prolongation, however, the QT testing is normally done in healthy volunteers and never for prolonged periods of time. Since new drugs are tested in only a few thousand patients for approval, the fact that no cases of TdP have been observed before a drug is approved is not very informative; even if no cases are recorded in a data base including 5000 patients, the 95 percent confidence interval for the risk of TdP would be 0 to 1 in 1600 with the upper limit reflecting the potential for a very high incidence after marketing (10). Thus the true effect of any drug or combination of drugs in any one individual over a period of time is unknown and has never been addressed. Protocol CHRC2012- QT003 version dated December 13,

4 Drug-induced QT prolongation All medications have good (therapeutic) effects and all medications have side effects. The side effects can vary from nuisance type of side effects like stomach upset to very serious side effects that threaten our lives. One of the most serious side effects is prolongation of the QT interval which may lead to a lethal arrhythmia, called Torsades de Pointes (TdP). QT prolongation has been established as a cause of sudden death in infants and young children as well as in adults as a result of QT prolongation. QT prolongation can occur as a congenital abnormality or be acquired, most commonly, as a result of medications including but not limited to antihistamines, antiinfectives (Azithromycin (11-18), Erythromycin (19-27), psychotherapeutic (e.g. antidepressant, antianxiety, antipsychotic, ADHD medications)(28), Ciprofloxacin (isolated reports of TdP: 29,30), Levofloxacin (18), hormones, cardiac drugs, neurological drugs (e.g. migraine), respiratory and sedatives. QT prolongation may also occur in conditions associated with autonomic neuropathy, such as diabetes mellitus (31). The website of the International Registry for Drug-induced Arrhythmias maintained by the Georgetown University ( ) provides an up-to-date list of drugs that prolong the QTc interval and/or induce TdP or ventricular arrhythmia (32). Importantly there is a disclaimer on the site: Drugs not listed here may have an, as yet, undetected potential to prolong the QT interval or induce Torsades de pointes. Not all drugs have been adequately tested for this potential. Therefore, the absence of a drug from these lists should not be considered an indication that they are free of risk of QT prolongation or Torsades de pointes. The risk of QT prolongation maybe further enhanced by bradycardia, hypokalemia, female gender, metabolic inhibitors, other QT prolonging drugs, underlying heart disease (CHF, LVH, AF), and genetic polymorphism (IKr or IKs). QT prolongation is an individual response which is a result of genetic predisposition, response to a particular drug, and the combination of other drugs that may have direct effects on the QT prolongation or effect changes in the metabolism of other drugs. A variety of genetic variations have now been identified as being associated with drug-induced QT prolongation (33). QT Prolongation is individual Genetic Predisposition QT prolongation Medications Heart Disease Diabetes Hypertension Protocol CHRC2012- QT003 version dated December 13,

5 There are also medical conditions that can prolong QT and there has been evidence linking QT prolongation with stroke in patients with diabetes (34). Protocol CHRC2012- QT003 version dated December 13,

6 Primary Objective: To provide a long term assessment of changes in QT/QTc in patients exposed to medications as a result of medical management of their condition(s). Secondary Objectives: a. To study the impact of specific medications on QT/QTc such as but not limited to: i. Mental Health e.g. medications for attention-deficit/hyperactivity disorder (ADHD) ii. Cardiovascular e.g. anti-arrhythmic, anti-hypertensive iii. Anti-infective and anti-allergic b. To study the impact of specific medical conditions on QT/QTc such as, but not limited to: i. Diabetes ii. Hypertension c. To study the long term variability of heart rate and QRS duration in relation to the long term variability of the QT. d. To study the feasibility of self monitoring in the community e. To establish the optimal frequency of monitoring Inclusion Criteria: 1. Access to the HeartCheck device 2. Concern about QT prolongation because of the medication or combination of medications or a medical condition Exclusion Criteria: 1. Inability to record ECG 2. Inability to transmit ECG 3. Inability to measure QT Reason for study design: Relatively high incidence of sudden cardiac death in population treated with high risk medications of almost one per 1000 person-years and calculated population at risk of non-cardiac QTc-prolonging medication 2% (1). Protocol CHRC2012- QT003 version dated December 13,

7 Monitoring for QT prolongation can now be accomplished safely and if detected, can be used to alert physicians and patients that safety may be compromised and therefore a change in medication or additional testing may be needed. Registry Logistics 1. Canadian Heart Research Centre ( an academic, non-profit research organization will coordinate all aspects of study deployment. 2. CardioComm Solutions ( ) will sell the FDA and Health Canada approved handheld ECG devices, HeartCheck : to interested participants. 3. Only those individuals who have purchased the device will be invited to participate. This will ensure compliance with long term follow-up. Since the study aims to monitor QT over two years, the purchase of the device identifies a committed and therefore likely compliant participant. 4. The registry will be reviewed by a Central Ethics Committee. 5. Physicians, pharmacists and their patients, or patients directly will be invited to participate. 6. Participants will be asked to complete a brief personal health record on the CHRC website directly or with the help of their physician or pharmacists (Appendix A). 7. Participants will have access to their health record so that the QT results can be accessed by them individually. 8. Participants will be asked to record an ECG monthly and submit the ECG along with the following if available: a. Date b. Blood pressure (BP) c. List of current Medications 9. The QTc measures obtained in individuals will be posted inside the individual health record along with the date to facilitate follow-up. 10. Participants and their physicians will be alerted if QT/QTc prolongation is detected based on FDA suggestion: QT/QTc to > 500 ms or of >50 ms over baseline are commonly used as thresholds for potential discontinuation consideration (FDA, 2005). Sample Size It is anticipated that 1,000 patients will be enrolled to establish parameters for proper sample size calculation. Interim analysis will be performed at that time. Protocol CHRC2012- QT003 version dated December 13,

8 Appendix A: ecrf variables a. Patient name b. Date of birth c. Gender d. Patient s address and phone number e. address where the alert in case of QT prolongation is to be sent (could be MD, pharmacist or the patient themselves) f. Inclusion criteria g. Exclusion criteria h. Date the ecrf is completed (this will be used for reminders for monthly QT monitoring) i. Medical condition j. Which of the following medications are you taking (include all) k. Have you experienced in the last 3 month (yes/no for all): a. Shortness of breath b. Chest pain c. Palpitations d. Syncope/ Pre-syncope Appendix B: Prior Medical History 1. Neurology/Psychiatry a. Epilepsy b. MS c. Depression d. ADHD e. Parkinson s disease f. schizophrenia 2. Chest/Pulmonary a. Asthma b. COPD c. Bronchiectasis 3. Endocrine a. Diabetes Mellitus b. Thyroid c. Addison s disease d. Diabetes insipidus e. Hyperlipidemia 4. Cardiac a. AF or other arrhythmia b. CVA/TIA c. CHF / cardiomyopathy d. Pacemaker/ICD e. CAD: MI, CABG, PCI f. HT g. Heart failure Protocol CHRC2012- QT003 version dated December 13,

9 5. Cancer a. Breast b. Prostate c. other 6. Smoking 7. Immune 8. Liver a. Arthritis b. SLE c. Crohn s disease d. Ulcerative colitis e. psoriasis f. allergies 9. Chronic renal disease 10. Hemophylia 11. Glaucoma 12. HIV 13. Infection requiring antibiotic Protocol CHRC2012- QT003 version dated December 13,

10 References: 1. Straus SMJM, Sturkenboom MCJM, Bleumink GS, et al. Non-cardiac QTc prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005;26: Straus S.M., Kors J.A., De Bruin M.L.; et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults, J Am Coll Cardiol Montanez A., Ruskin J.N., Hebert P.R., Lamas G.A., Hennekens C.H.; Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies, Arch Intern Med Zhang Y., Post W.S., Blasco-Colmenares E., Dalal D., Tomaselli G.F., Guallar E.; Electrocardiographic QT interval and mortality: a meta-analysis, Epidemiology Dekker J.M., Crow R.S., Hannan P.J., Schouten E.G., Folsom A.R.; Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study, J Am Coll Cardiol Deo R, Albert CM; Epidemiology and Genetics of Sudden Cardiac Death. Circulation. 2012;125: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non- Antiarrhythmic Drugs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER). October Khongphatthanayothin A, Lane J, Thomas D, Yen L, Chang D, Bubolz B. Effects of cisapride on QT interval in children. J Pediatr 1998;133: Pratt CM, Ruberg S, Morganroth J, et al. Dose-response relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996;131: CrossRef Web of Science Medline 10. Roden, DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004; 350: Matsunaga N, Oki Y, Prigollini A. A case of QT-interval prolongation precipitated by azithromycin. N Z Med J 2003; 116:U Samarendra P, Kumari S, Evans SJ, Sacchi TJ, Navarro V. QT prolongation associated with azithromycin/amiodarone combination. Pacing Clin Electrophysiol 2001;24: Russo V, Puzio G, Siniscalchi N. Azithromycin-induced QT prolongation in elderly patient. Acta Biomed 2006;77: Arellano-Rodrigo E, García A, Mont L, Roqué M. Torsades de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome. Med Clin (Barc) 2001;117: (In Spanish.) 15. Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and Torsades de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol 2007;18: Protocol CHRC2012- QT003 version dated December 13,

11 16. Huang BH, Wu CH, Hsia CP, Chen CY. Azithromycin-induced Torsadess de pointes. Pacing Clin Electrophysiol 2007;30: Kim MH, Berkowitz C, Trohman RG. Polymorphic ventricular tachycardia with a normal QT interval following azithromycin. Pacing Clin Electrophysiol 2005; 28: Poluzzi E, Raschke R, Moretti U, De Ponti F. Drug-induced Torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf 2009;18: Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006; 43: Vogt AW, Zollo RA. Long Q-T syndrome associated with oral erythromycin used in preoperative bowel preparation. Anesth Analg 1997;85: Tschida SJ, Guay DRP, Straka RJ, Hoey LL, Johanning R, Vance-Bryan K. QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature. Pharmacotherapy 1996;16: De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000; 56: Drici MD, Knollmann BC, Wang WX, Woosley RL. Cardiac actions of erythromycin: influence of female sex. JAMA 1998;280: Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of Torsadesss de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis 2002;35: Koh TW. Risk of Torsades de pointes from oral erythromycin with concomitant carbimazole (methimazole) administration. Pacing Clin Electrophysiol 2001;24: Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin use and the risk of sudden cardiac death. N Engl J Med 2004;351: Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006;43: Simkó J, Csilek A, Karászi J, Lorincz I. Proarrhythmic potential of antimicrobial agents. Infection 2008;36: Veglio M, Chinaglia A, Cavallo-Perin P. QT interval, cardiovascular risk factors and risk of death in diabetes. J Endocrinol Invest Feb;27(2): Woosley RL. Drugs that prolong the QTc interval and/or induce Torsades de Pointes Jamshidi et al. Common Variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. J Am Coll Cardiol 2012;60: Cardoso R.L., Salles GF, Deccache W. Interval Prolongation Is a Predictor of Future Strokes in Patients With Type 2 Diabetes Mellitus. Stroke. 2003;34: Protocol CHRC2012- QT003 version dated December 13,