Persons with RMS (relapsing multiple sclerosis) treated with DMTs at Carmel Medical Center’s specialized MS clinic in Haifa, Israel: 186 at baseline (T0), 6 months later (Time 1) and 12 months (Time 2) since baseline. Recruitment is depicted at Fig. 2.
A prospective observational study design was used. Data were collected in a large single-center between February 2016 and August 2018. Inclusion criteria were: RMS diagnosis, being at baseline on DMT of Fingolimod, Dimethyl Fumarate, Interferon beta-1a and Glatiramer Acetate. Exclusion criteria at recruitment were: language literacy (n = 14), cognitive impairment (n = 3), and disinclination to participate (n = 2) and moving to another clinic (n = 8). The survey and neurological evaluation (see details below) were administered prospectively at baseline, 6 months (Time 1, median length of 6.9 months) and 12 months later (Time 2, median length of 6.8 months from Time 1). Medication possession data were retrieved retrospectively for the same periods.
The study was approved by an Internal Review Board of Carmel Medical Center (#0061-14-CMC) and registered (clinical trials registry #NCT02488343). All participants were provided written informed consent confirming that they were free to leave the study at any time.
Adherence and Persistence
Medication withdrawal records were retrieved from the computerized dataset of 'Clalit Health Services'; these were available for 136 PwMS in the prospective study who are members of this Health Maintenance Organization (HMO) and not for 50 PwMS treated at the clinic yet are members of other HMOs. Based on medication withdrawal data, Medication Possession Ratio (MPR) was computed for each PwMS based on her/his medication type and the initial prescription: it was estimated as the total days with index medication supply within the refill interval (six months between baseline and time 1 and six months between time 1 and time 2) divided by the number of days between the first prescription data and the last prescription date. Using the commonly accepted threshold of MPR ≥ 80% (10), PwMS were considered adherent if they were above the threshold and non-adherent when they were below this threshold.
Patient-reported outcomes measures - Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ; (25)) and Probabilistic Medication Adherence Scale (ProMAS; (26)). The items from MS-TAQ used in this analysis tapped whether the participant did not take a prescribed dose in the last four weeks and the reported number of these doses. In cases of reported non-adherence, the percentage was calculated per regiment. The ProMAS is an overall estimation 18-item questionnaire tapping adherence behaviors (e.g., "I have never changed my medicine use myself", "When I am away from home, I occasionally do not take my medicines") to which respondents indicate 'yes, true' (coded as 1) or 'no, not true' (coded as 0). Higher individual's adherence scores represent better adherence rates. Adherence categories are low (sum score 0–4), medium low (sum score 5–9), medium-high (sum score 10–14) and high (sum score 15–18). Internal reliabilities of the ProMas were baseline = 0.83, Time 1 = 0.82 and Time 2 = 0.83.
A score of adherence was constructed so that good adherence was defined as either = > 80% medication claims per regiment (medication possession ratio (MPR)), or = > 80% self-reported medication use by MS-TAQ or being at the medium-high and high categories of ProMAS. Full details are described in a methodological report (24). Low adherence was defined as the complement. Persistence was defined as staying with the same medication from baseline till Time 2.
Self Report Habit Index (SRHI; (27)) is a 12-item PRO assessing habit strength, specifically repetition, automaticity of medication taking behavior and the sense of identity the medication behavior reflects (in either administration route). The items were measured on a five-point bipolar scale, ranging from ‘I completely agree’ (4) to ‘I completely disagree’ (0). An overall score for habit strength was constructed (higher values denote less habit). Cronbach's internal reliabilities were α = 0.86, α = 0.88 and α = 0.86 for baseline and Time 1, respectively.
Belief about Medicine Questionnaire (BMQ; (28) is used to assess the cognitive represetations of medicines. The 18-item scale contains two five-item subscales measuring Necessity and Concerns about medication and two four-item subscales measuring Harm and Overuse. Scores on this measure were constructed so that higher scores indicate stronger beliefs in the concepts represented by the scale. Internal reliabilities were α = 0.81 for both baseline and Time 1; internal reliabilities of the subscales ranged from α = 0.71 to α = 0.83.
Illness perceptions (Brief Illness Perception Questionnaire; (29)). The B-IPQ includes eight items graded on a linear 0–10 response scale assessing cognitive and emotional representations of illness. Each item refers to one dimension of illness perception (consequences, timeline, identity, personal control, treatment control and coherence, and the (two-item) dimension of emotional representation). The scale was scored so that higher scores represent more negative illness perceptions. Cronbach's internal reliabilities were α = 0.71, 0.76 at baseline and Time 1, respectively.
Emotional states (Hospital Anxiety and Depression Scale (HADS;(30) is a self-report 14-items depression and anxiety questionnaire widely used in medical settings and has been used in the past among PwMS (31, 32). Respondents rate the degree to which they have been experienced depression and anxiety over the last week. Reliabilities were α = 0.84 and α = 0.85 at baseline for depression and anxiety, respectively.
Background and clinical variables examined for this study included age, gender, marital status, educational attainment and subjective social economic status, ethnicity, comorbidity, MS duration, time on current DMT and type of DMT. Physical disability was assessed by a neurologist using a widely used scale of disease progression and neurological impairment (Kurtzke Expanded Disability Status Scale, EDSS; (33)).
Descriptive analyses for background and clinical characteristics were conducted and reported for all participants. For categorical variables, counts and percentages are provided whereas means and standard deviations (SDs) are presented for continuous variables. Adherence was constructed such that non-adherence was defined as either detected/reported by one of the PRO or MPR (24); it is presented across Time 1 and Time 2 and also by DMT administration route. Persistence is reported as staying with the same medication between baseline and Time 2 and reasons for discontinuation are described.
Then, adherent and non-adherent PwMS were compared in their background and clinical characteristics as well as their perceptions. Categorical variables were analyzed using a chi-square test, and continuous variables were analyzed using the t-test or Mann-Whitney U test (depending on the normality of distribution, tested using Kolmogorov-Smirnov test). Statistical significance was set for p < 0.05. The relative contribution of variables found to be significantly different among the two groups were further evaluated using binary logistic regression analysis while adjusting also for age and gender. A similar analysis - comparing those who persisted with their medication to those who did not persist in their background and clinical characteristics as well as their perceptions - was conducted.