Abstract
Objectives
Adherence to multiple sclerosis (MS) treatment is essential to optimize the likelihood of full treatment effect. This prospective, observational, single-center cohort study investigated adherence to fingolimod over the 2 years following treatment initiation. Two facets of adherence – implementation and persistence – were examined and compared between new and experienced users of disease-modifying treatments (DMTs).
Materials and methods
Implementation rates were based on the proportion of days covered and calculated as percentages per half-yearly visits and over 2 years, captured through refill data, pill count, and self-report. Nonadherence was defined as taking less than 85.8% of prescribed pills. Implementation rates were classified as nonadherent (<85.8%), suboptimally adherent (≥85.8% but <96.2%), and optimally adherent (≥96.2%), including perfectly adherent (100%). Persistence, ie, time until discontinuation, was analyzed by Kaplan–Meier analysis. Reasons for discontinuation were recorded.
Results
The cohort included 98 patients with relapsing MS, all of whom received a dedicated education session about their medication. Of these 80% were women, 31.6% had fingolimod as first DMT, and 68.4% had switched from other DMTs. The mean implementation rate over 2 years was 98.6% (IQR1–3 98.51%–98.7%) and did not change significantly over time; 89% of measurements were in the optimally adherent category, 45.6% in the perfectly adherent category. There was one single occurrence of nonadherence. New users of DMTs were 1.29 times more likely to be adherent than experienced users (OR 1.29, 95% CI 1.11–1.51; P<0.001), but not more persistent. Nineteen of 98 patients discontinued fingolimod.
Conclusion
The very high implementation rates displayed in this sample of MS patients suggest that facilitation by health care professionals in preserving adherence behavior may be sufficient for the majority of patients. Targeted interventions should focus on patients who are nonadherent or who stop treatment without intention to reinitiate.
Supplementary materials
Materials and methods
Outcome measures
Implementation rates
In addition to the calculation method, capsules lost or destroyed were subtracted from the number of pills possessed. Capsules stored at other places were added to the number of pills left. Medication intake on the day of the study visit, ie, before or after the study visit, was accounted for. Prescription alterations, eg, intake only every second day, were reflected by adapting the denominator to the actual number of days prescribed. The denominator had variable value, because study visits did not take place exactly every 183 days. A visit window of ±3 weeks was allowed.
If participants forgot to bring their package, or if the regular consultation had to be planned outside the study-visit window, participants were asked to send a photo of the package by SMS or email. The rest of the visit was done by phone or email. Exceptionally, information by telephone was accepted, but everything was done to get an “objective” image of the number of capsules left in the package.
No gaps between the first prescription and the first intake had to be considered, as the study started with the first dose taken under observation. Timing of implementation was of no relevance. In the patient-education program at treatment initiation, patients were taught to take the capsule at the same time of the day as much as possible. If they forgot to do so, they might either take it later the same day or omit it until the next day.
As an example of calculating the implementation rate, between the study visits of January 1 and July 1, 2014 (181 days), a patient refills two packages of 98 capsules. In the previous measurement period, 20 capsules had been left in the package. On July 1, the patient has already taken the capsule in the morning and has 33 capsules left in his current package. He keeps two capsules in his work office. One capsule has been squeezed, and he has thrown it away. Therefore, the implementation rate is:
and as such, two capsules were missed.
The study’s simple and easy-to-perform method was chosen because electronic measurement was not feasible at the time the study was designed: electronic smart packages were not available yet, and a MEMS was not affordable. Comparing medication intake with plasma concentration levels was not feasible, due to the lack of a clear correlation (personal communication from the manufacturer).
Dropout
Other reasons than discontinuing fingolimod could lead to study dropout, eg, changing neurologist or if the primary end point – implementation – could not be measured despite the patient continuing to take fingolimod.
Results
Implementation rates
For all patients missing more than 14 capsules (n=10) per 6 months, refill patterns and self-report did not indicate a treatment interruption of more than 14 days, which would have required reinitiation under first-dose observation.
Fidelity to the protocol and performance integrity
Among all intended implementation measurements of persistent participants, three data sets of the month-6 visit could not be retrieved: one patient was traveling abroad, and two patients did not deliver the information on the number of capsules left in the package. Among 329 visits performed, 90.9% of pill counts were done as intended, ie, with the package present at the visit; 26 were done by photo, one was done by email, and four by telephone. Twelve visits were performed outside the visit window, but were still included into the analysis. Time deviations ranged between 5 days too late and 10 days too early.
Six patients were prescribed dose reductions during one or more measurement periods. The alternative prescribing pattern was either pausing every second or every third day. In five cases, the change was due to lymphocyte counts lower than 0.2×109/L, and in one case due to a degenerative problem of the macula.
Some aspects should be mentioned about fidelity to the minimal-adherence intervention by the nurses performing the study. It is possible that some unintended behavior may have influenced or increased adherence: the nurses acknowledged participants’ implementation achievements a lot. Also, patients often expressed feelings of guilt or shame if they had not taken all pills, and the nurses alleviated these expressions by explaining that missing some pills, eg, “was normal” or “that it would not reduce efficacy”. For ethical reasons, because the adherence study was part of clinical care, addressing adherence was not omitted when deemed appropriate.
Acknowledgments
We are very grateful to the people with MS who participated in the study. We thank Ludwig Kappos for enabling the study at the MS Center Basel. Special thanks are due to the MS nurses and study investigators Suzana Miteva and Karin Wild, who performed the study visits and data-collection procedures. We thank Nancy Wochnik for data control. We also thank all nurses and physicians of the center for supporting the study. A special thanks to Kayal Kündig and her colleagues (SVK) for providing the refill data. We appreciate the help of Nicholas Sanderson in editing the manuscript from the English-language perspective. This investigator-initiated trial was funded by Novartis Pharma Schweiz, who had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript. Novartis had the option to review the final version of the article to protect confidential or patentable information. We would like to thank Novartis Pharma Schweiz for funding the study.
Author contributions
AZ designed the study, coordinated its implementation, interpreted the study results, and drafted the manuscript. MC analyzed the statistics and contributed substantially to the interpretation of results. IA and BFD contributed substantially to interpretation of the data and reviewed and revised the manuscript. BFD was involved in the medical care of the patients in the study. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.
Disclosure
AZ has received travel grants for participation in investigator meetings of clinical studies and nurse meetings, and her institution has received consultancy fees for nurse-advisory activities by Actelion, Biogen, Genzyme, Merck Serono, Novartis, Roche, and Sanofi. She has no conflicts of interest relative to the study reported here. MC has no conflicts of interest to declare relative to the study reported here. IA is an equity-holding partner in Matrix45. Matrix45 provides scientific services to pharmaceutical companies on a nonexclusive basis. Employees may not hold equity in sponsor organizations, and may not accept direct payments or other benefits from sponsor organizations. As a faculty member of the University of Arizona, IA has no conflicts of interest to declare relative to the study reported here. BFD received for the institution (University Hospital Basel) advisory board or speaker fees from Biogen, Teva and Novartis, which were used exclusively for research support. BFD received travel support from Novartis, Biogen, and Genzyme. BFD has no conflicts of interests in this work.