Primary: To assess the efficacy of Ranexa® (ranolazine) compared to placebo on reducing average weekly angina frequency in patients with Type 2 diabetes mellitus, coronary artery disease and chronic stable angina who remain symptomatic despite treatment with one or two antianginal agents.
Secondary: To evaluate the efficacy of Ranexa compared to placebo on average weekly frequency of sublingual nitroglycerin use.
Eligible patients entered a four-week, single-blind placebo run‑in period and were provided an eCOA Handheld with built-in prompts for entry of daily angina episodes, daily number of sublingual nitroglycerine used and a daily dyspnea score (on a scale from 1 to 5). Data collected on the ERT eCOA Handheld were used in support of the primary endpoint for the trial and to assess efficacy.
Eight million people in the U.S. alone suffer from chronic stable angina, the chest pain and tightness associated with myocardial ischemia caused by coronary artery disease (CAD), yet many patients remain undertreated.2,3,4 Those with Type 2 diabetes mellitus and CAD present an especially challenging group because their disease is often more extensive and difficult to manage.5 Gilead Sciences utilized ERT eCOA Handhelds to electronically collect patient reported outcomes (PRO) in a study to evaluate the antianginal efficacy of Ranexa in this patient population.
In previous trials, Ranexa had been proven as an effective antianginal treatment in patients with clinically manifest CAD, both as monotherapy and in combination with other commonly prescribed medications as add-on therapy. This study aimed to extend these findings in a specific subpopulation by demonstrating a reduction in weekly angina frequency and a decrease in sublingual nitroglycerin use in Type 2 diabetes patients who also suffered from CAD and chronic angina, and who remained symptomatic despite treatment with one or two other therapies.
SELECTING ELECTRONIC PRO (ePRO) OR PAPER PRO
Previous Ranexa studies used exercise treadmill parameters as the primary endpoint. While effective and easily verifiable, attaining the data was costly, provided numerous logistical challenges and bore questionable clinical relevance, especially at the level of the individual patient. Other possible endpoints such as number of angina episodes and sublingual nitroglycerin use imparted concerns about using patient diaries to collect endpoint data.
Regardless of the methodology chosen, diaries would have to be translated into numerous local dialects and languages, as it included 104 different sites across 14 countries in North America, Europe and Asia. Diaries would also need to be shipped globally, raising concerns about logistics costs and management.
Paper diaries have proven to be inaccurate although it is difficult to measure actual protocol compliance without time stamps. One study showed paper compliance to be as little as 11% when reported compliance was 90%.7 There also is the potential, known colloquially as the “Parking Lot Syndrome,” for a patient to complete multiple entries in a paper diary just before their appointment, rather than daily for a stretch of time. Paper diaries can also be observed and analyzed only after collection and data are extracted, offering little chance to assess a study while it is still ongoing.
Alternatively, using an eDiary also prompted concerns. Many chronic angina sufferers are well above 50 years old. It was unclear if they would be able to operate an eCOA Handheld or read the prompts on an electronic screen. eDiaries could also raise issues if software or trial updates were needed, or support issues if a device malfunctioned.
745 eCOA HANDHELDS USED IN 14 COUNTRIES, BY 104 SITES AND 16 LANGUAGES
Devices designed to collect three daily questions about angina episodes and symptoms from subjects
ERT eCOA Handhelds were chosen because they eliminated diary, data and logistics concerns. Observing the patient-reported number of angina episodes and sublingual nitroglycerin use over a period of time follows the increasing regulatory emphasis on PROs.8,9,10 It also provides a significantly more cost-effective trial design than using an exercise treadmill endpoint. By using eCOA Handhelds, an electronic PRO (ePRO) diary could be designed and customized to fit the exact trial needs.
ERT eCOA Handhelds were advantageous versus other ePRO providers because ERT had significant experience in the angina indication, having run previous global Phase III angina studies in similar regions around the world. Additionally, ERT provided a capability to integrate data from the eCOA Handheld directly into Medidata Rave, streamlining data management and reducing discrepant data across the two systems.
ERT eCOA Handhelds eliminate concerns created by a paper diary around data quality. eDiary completion times are logged and verified, enabling accurate data collection and contemporaneous compliance. The ERT eCOA Handheld used in this trial resulted in 98% compliance of all 927 trial participants. There was 97% compliance among the 101 trial participants who were 75 years of age or older.
The eDiary was designed to include daily reminders to encourage patient completion. And, the eDiary design also featured retroactive “look-back” entries for patients to complete the previous day if it had been missed, but only for the past 24 hours — a feature not feasible in paper designs.
The electronic design of the ERT eCOA Handheld allowed for mid‑study parameter changes to be implemented without any impact on data collection or accuracy. ERT’s expertise in conducting over 2,000 trials allowed for easy trial integration in 14 countries on three continents. Devices were translated into local languages, and ERT successfully handled distribution logistics. Frequent and reliable data transmission allowed for real-time upload to ERT Portal and seamless integration and transmission to Medidata Rave eCRF database. This reduced data clarification forms and increased the speed of the time from last patient, last visit (LPLV) to final data transfer.
FREQUENCY DISTRIBUTION OF ANGINA EPISODES
The frequency distribution of angina episodes collected electronically on handheld devices showed a normal (Gaussian) distribution with an R2 of 0.999. An important aspect of this finding is the bell shaped symmetrical frequency distribution curve is characteristic of many real world physical and biological phenomena and is known to describe random data variation.
- Compliance: Of the 77,968 possible entries, 76,418 (or 98%) of available diaries were completed. Despite concerns about elderly populations, in this study and others, this population demonstrates high and stable compliance.11,12 Further, high eDiary compliance can also be attributed to the study design which included randomization criteria of at least 85% compliance over a three-week screening and the ability to enter episodes which occurred over the previous 24 hours. Lastly, to ensure compliance, if an assessment had not been transmitted since the previous evening, email alerts were sent to sites and monitors.
- Increased Event Rate: Prompting a patient to respond daily can generally lead to more accurate data, since the data is captured in real-time. Studies in oncology have shown that capturing patient symptoms on a daily basis provides a more complete and accurate representation of the patient symptom profile than the intervallic collection of data.13,14
- Retroactive Diary Design: This element enabled additional data collection with a limited window of recall to the past 24 hours. Data showed 0.02% duplicated data entries. Future designs would prevent this possibility.
- ERT eCOA Handheld Software Update Timing: In some instances, sites obtained automatic downloads for software upgrades prior to IRB approval. Due to a protocol amendment affecting eligibility criteria, ERT had to carefully manage the timing manually so that sites received updated study software only after IRB was approved for the protocol amendment.
Gilead Sciences successfully completed the trial and collected the needed regulatory-compliant patient-driven primary endpoint data. The ERT eCOA Handheld was customized to fit the trial’s needs to provide accurate and verified data, accommodating mid-trial changes. The result:
- An efficacious trial to support Gilead Sciences’ work to benefit angina sufferers
- Confirmation that eDiaries are an effective and economical way to capture angina endpoints such as episodes and dyspnea in angina patients vs. treadmill or paper diaries
- Evidence that global patients, including elderly patients demonstrate high and stable compliance with eDiary completion at 98%
- Retrospective entry of up to 24 hours can increase compliance
- Upgrades and mid-study changes need to be timed carefully with IRB approvals
- Kosiborod M, Arnold SV, Spertus JA, et. al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). JACC. 2013 May 21;61(20):2038-45.
- The Task Force on the Management of stable angina pectoris of the European Society of Cardiology, European Society of Cardiology (ESC) (2006) Guidelines on the management of stable angina pectoris. http://eurheartj.oxfordjournals.org/ content/27/11/1341. Accessed June 2, 2016.
- Gibbons R, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). www.acc.org/clinical/ guidelines/stable/stable.pdf. Accessed June 2, 2016.
- The Task Force on the Management of stable angina pectoris of the European Society of Cardiology, European Society of Cardiology (ESC) (2006) Guidelines on the management of stable angina pectoris. http://eurheartj.oxfordjournals.org/content/27/11/1341. Accessed June 2, 2016.
- Lopez-Séndon J, Purcell H, Camici P, et al. Chronic stable angina guidelines – is there an emerging international consensus? Br J Cardiol 2012; 19: S2–S11. 8 Zamorano JL, Garcia-Moll X, Ferrari R, et al. Demographic and clinical characteristics of patients with stable coronary artery disease: results from the CLARIFY registry in Spain. Rev Esp Cardiol 2014; 67: 538–544.
- Management of Coronary Artery Disease and Chronic Stable Angina. U.S. Pharmacist website. https://www.uspharmacist.com/article/management-of-coronary-artery-disease-andchronic-stable-angina. Published February 16, 2017. Accessed May 11, 2017.
- Stone, et al. Patient non Compliance with Paper Diaries British Medical Journal, 2002; 324: 1193.
- FDA Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. FDA website. http://www.fda.gov/downloads/ Drugs/.../Guidances/UCM193282.pdf. Published December 2009. Accessed June 2, 2016.
- EMA Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_ guidline/2010/08/WC500095754.pdf. Published June 2010. Accessed June 2, 2016.
- Guideline on the Clinical Investigation of Anti-Anginal Medicinal Products in Stable Angina Pectoris. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2009/09/WC500003316.pdf. Published June 1, 2006. Accessed June 2, 2016.
- Basch, E., M. McCabe, A. Iasonos, D. Schrag, H. I. Scher, R. Farquhar, J. Speakman, P. Fearn, D. Artz, M. G. Kris, A. Culkin, and A. Barz. Long-Term Toxicity Monitoring Via Electronic Patient-Reported Outcomes In Patients Receiving Chemotherapy. Journal of Clinical Oncology 2007; 25(34): 5374-5380.
- Gary ST, Otero AV, Dallabrida SM. Effective Use of Electronic Patient Reported Outcomes (ePRO) in Breast Cancer. PHT Corporation, March 2013. In press.
- Basch, Ethan, Alexia Iasonos, Tiffani McDonough, et al. Patient Versus Clinician Symptom Reporting Using The National Cancer Institute Common Terminology Criteria For Adverse Events: Results Of A Questionnaire-based Study. The Lancet Oncology 2006; 7(11): 903-909.
- Basch, E., M. G. Kris, G. Heller, et al. Adverse Symptom Event Reporting By Patients Vs Clinicians: Relationships with Clinical Outcomes. JNCI Journal of the National Cancer Institute 2009; 101(23): 1624-1632.
ERT is a global data and technology company that minimizes uncertainty and risk in clinical trials so that customers can move ahead with confidence. With more than 40 years of clinical and therapeutic experience, ERT balances knowledge of what works with a vision for what’s next, so we can adapt without compromising standards.
Powered by the company’s EXPERT® technology platform, ERT’s solutions enhance trial oversight, enable site optimization, increase patient engagement and measure the efficacy of new clinical treatments while ensuring patient safety. Since 2014, more than half of all FDA drug approvals came from ERT-supported studies. Pharma companies, biotech and CROs have relied on ERT solutions in 9500+ studies spanning three million patients to date. By identifying trial risks before they become problems, ERT enables customers to bring clinical treatments to patients quickly — and with confidence