Standardized Educational Plan for Epilepsy Patients With Comorbidities

OBJECTIVES OF THE STUDY The primary objective of the study is to verify whether or not a comprehensive and standardized educational plan is followed by a significant reduction of the number of adult patients with epilepsy and comorbidity presenting clinically relevant adverse treatment effects.

Secondary objectives include the effects of the following comprehensive and standardized educational plan:

• Reduction of the total number of adverse treatment events
• Reduction of the number of medical contacts
• Improvement of the health-related quality of the patient's life (HRQOL)
• Reduction of the direct costs of the health care assistance
• Improvement of the patient's compliance

The hypothesis to be tested is that a comprehensive and standardized educational plan is superior to the present modalities adopted to manage treatment safety in clinical practice for the following reasons:

• It raises the level of attention towards the putative adverse effects of the drugs currently taken and the possible drug interactions
• It helps identifying any clinically relevant event at onset to prevent the occurrence of symptoms or signs leading to medical contact and hospital admission
• It educates the patient to live with the treatment schedule representing the best compromise in terms of safety

METHODS Study design. This is a randomized, controlled, open-label, pragmatic trial. Study population. Patients eligible for inclusion are identified among those consecutively seen in the outpatient services of the participating units.

Intervention. Patients fulfilling the inclusion/exclusion criteria will be randomized to receive a comprehensive and standardized educational plan (experimental arm) or to usual care, ie the management of the adverse event/drug interaction as usually done in clinical practice and in keeping with each unit's modalities (control arm).

The comprehensive and standardized educational plan consists in the discussion with the patient and, if available, the caregiver of each of the following points (of which a written summary will be made available:

• The cause and nature of the adverse event and/or drug interaction
• The tolerability profile of each drug present in the schedule, illustrated as a simple list including the commonest adverse events presented in decreasing order of frequency
• The clinical manifestations (if any) associated with the current drug interaction(s)
• Any contraindication to the use of over-the-counter drugs potentially interfering with the current treatment schedule
• The reasons for and the potential benefits of the suggested treatment change
• An encouragement to withdraw any potentially interfering or contraindicated drug or compounds not unequivocally found to be efficacious for that specific case

Study conduction. After signing the informed consent form, eligible patients will be immediately randomized to receive the comprehensive and standardized educational plan or to usual care. Patients assigned to the experimental arm will be given an appointment for a one-hour private meeting to discuss all the items included in the comprehensive educational plan. The patients assigned to the control arm will be managed as done in the context of usual care in that same ambulatory visit. All patients will be seen at one, three and six months after admission and whenever indicated for the management of the individual case.

Outcomes. These include one primary and a number of secondary outcomes. The primary outcome is defined by the number of patients free from clinically relevant adverse treatment events and/or the number of drug interactions in each treatment arm at end of study.

Secondary outcomes include the following:

• The number of patients free from clinically relevant adverse treatment events and/or drug interactions in each treatment arm at each intermediate visit
• The mean and median number of adverse treatment events in each treatment arm, at each intermediate visit and at end of study
• The monetary costs of medical contacts, hospital admissions, and drugs; the one-hour meetings with patients assigned to the experimental arm will be included in the costs. Costs will be calculated by the healthcare economy service of Mario Negri Institute according to current national values.
• Total HRQOL summary score changes (comparing last follow-up to admission visit)
• Number of patients with at least weekly omissions of the assigned treatment schedules

Randomization. A centralized randomization procedure will be adopted. Randomization will be performed by accessing to a user-friendly, protected centralized database, which will proceed to the assignment to the experimental or control arm after verification of the appropriateness of the inclusion/exclusion criteria. To control for center-related confounding, a separate randomization list will be made available for each center.

Blinding (masking). For the purposes of the study, treating and evaluating physicians will be represented by different persons. Given the diversity between the two management policies, neither the patients nor the caring physicians involved in administering interventions will be blind to the assigned arm. An attempt will be made to blind physicians assessing outcomes.

Statistical analysis. The data will be analyzed using the SPSS-13 package for PC. The statistical analysis plan will include descriptive statistics to compare the baseline characteristics of the two populations and the distribution of the treatment schedules, the number and type of adverse events (present at baseline or occurring during follow-up), and the proposed changes, along with the cost items (medical contacts, hospitalizations, drug costs) and the HRQOL scores. For descriptive statistics, the chi-square test, the Student's t test, the analysis of variance (ANOVA) or equivalent non parametric tests will be used as appropriate. The chi-square test will be also used to test the number of patients free from relevant adverse events at end of study (primary end-point) and at each intermediate visit. The analysis of the primary end-point is based on the intention-to-treat analysis and includes all randomized patients. Repeated measures ANOVA will be used to compare the difference between the two treatment arms in the mean change in the number of adverse events, the number of omitted drug doses, the total monetary costs, and the total HRQOL scores at each follow-up visit (where applicable) and at study end.

Timing. The duration of the entire study is 24 months with the following distribution:

• Months 1-3: Protocol approval by the local units' ethics committees and preparation of the electronic database
• Months 4-15: Patients' enrolment
• Months 16-21: Completion of follow-up
• Months 22-24: Data analysis and scientific report An interim assessment of the recruitment rate will be performed at the end of month 12 to decide whether or not the enrolment can be completed as expected. If needed, a request will be made to postpone patients' enrolment to the end of month 21 and the study completion of the end of month 30.

Ethical aspects. Each eligible patient will be properly informed about the study aims, the use of the diaries, and the requirements to be met at each visit. A summary sheet outlining the study objectives and conduct will be given to the patient and will be part of the written informed consent form. The patient will be also instructed about the possibility to withdraw from the study for any plausible reason without any interference with the management of his/her disease as done in clinical practice. The confidentiality of the data collected for the study purposes will be granted by giving access (through nominal username and password) only to persons officially involved in the study conduction. The data will be managed without disclosing the patients' identity.