Moshkovska 2011.

Methods	Randomized controlled trial
Participants	The study location was a gastroenterology outpatient clinic at Leicester General Hospital, UK 43 participants were randomized to the intervention group and 41 participants were randomized to the control group The inclusion criteria were patients aged 18 to 80 years, with ulcerative colitis, and on maintenance oral 5‐ASA therapy The exclusion criteria were those who were unwilling or unable to provide informed consent
Interventions	Intervention: PERCEPTUAL (MOTIVATIONAL) INTERVENTIONS Participants who were assigned to the intervention group attended a one‐on‐one education and motivation session conducted by the researcher. First, this session aimed to identify perceptual and practical barriers to 5‐ASA medication adherence and, second, to motivate, convince, and educate. The session was designed as a structured dialog allowing the patient to comment and ask questions. Educational topics included ulcerative colitis, 5‐ASA medication, and adherence. Participants were also encouraged to identify practical barriers to 5‐ASA medication use, as well as perceived barriers to adherence. Strategies for overcoming these barriers were also discussed. Sessions lasted for 20 to 30 minutes and were intended to deliver individualized support to each patient. At the end of the session patients were offered an educational leaflet to take away. Patients had the option of being accompanied to these educational sessions by a relative or friend and any accompanying person was also offered a leaflet specifically written for relatives and friends. During the session patients were offered a free choice of up to 3 practical adherence enhancing interventions; simplifying of dosing regime, medication reminder charts, visual medication reminders for refrigerators and bedside cabinets, daily electronic pill box organizers with alarms, weekly electronic pill box organizers, weekly non‐electronic pill box organizers, mobile telephone alarm set‐up, taking into consideration that practical problems and adherence may change over time. Participants had the option of changing these interventions at any time during the study and at weeks 4 and 24 they were formally asked whether they wished to change the interventions. One brief follow‐up telephone call was made to patients in the intervention group at week 4. During the mid‐study visit a 10‐minute reinforcement session was held during which the importance of adherence to prescribed 5‐ASA medication was reiterated, beliefs regarding medicine‐taking were reassessed, and any practical problems were discussed. All intervention group patients were given a telephone number which enabled them to obtain advice at specified times or leave a message for a return call Control: USUAL CARE Patients in the control group received standard prescribed care from their clinical team. The treatment regime for these patients was not changed in any way as a result of involvement in the study and no reminders or other additional adherence support was offered by the research team. Participants in the control group provided 3 urine samples at 0, 24, and 48 weeks and completed questionnaires during baseline and end‐of‐study visits. At the end of the study, control group participants were given the educational leaflets that intervention group participants received at the beginning of study
Outcomes	The measures of adherence were the concentration of the drug in the urine of participants, which involves the use of high performance liquid chromatography (HPLC) for determination of 5‐ASA and its metabolites in the urine. Samples were collected at baseline, mid‐study (24 weeks), and at the end of the study (48 weeks) The patient outcomes were disease activity (flare ups), for which data were collected from medical records during the study period. A flare‐up was defined as an unscheduled hospital admissions or appointment related to ulcerative colitis
Notes	―
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer‐generated randomization schedule was used to assign each subject to an intervention or control arm. Preparation of the randomization sequence involved blocking to ensure comparable final numbers in the intervention and control groups and also stratification by gender, duration of disease, and ethnicity to ensure comparable participant characteristics in the 2 groups (pg 1875)
Allocation concealment (selection bias)	Low risk	Sequentially numbered, opaque, sealed envelopes containing a computer‐generated randomization sequence were prepared by a member of the research team (M.A.S.) not involved in any way in patient recruitment or delivery of the intervention
Selective reporting (reporting bias)	Unclear risk	No protocol available; although it appears that everything was reported it is difficult to determine this without a protocol
Other bias	Unclear risk	Many limitations of the study noted in the discussion. "It is acknowledged that there are a number of potential limitations to our study. Only 42% of those approached agreed to take part in the study. For ethical reasons, we are unable to provide data about baseline adherence levels in those who declined, and age and gender were not shown to influence outcomes in our sample. Anecdotally, the main reasons given for not participating were reluctance to provide urine samples, make additional visits to the hospital, or complete questionnaires. We have no reason to believe that differences between those who agreed or did not agree to take part resulted in recruitment bias due to patient characteristics. This was an exploratory study for which the sample size was not powered to detect a clinical difference relating to flare‐ups. We acknowledge that our definition of a flareup is based on the unscheduled hospital appointment or admission, which is open to challenge. In addition, the sample recruited contained a low proportion of people assessed as nonadherent at baseline. However, our findings suggest a useful area for future research involving a larger sample size of people with lower baseline adherence levels and collection of more detailed data relating to flare‐ups in order to further investigate the question of clinical impact. Additionally, a general problem with evaluating complex interventions is that it is difficult to accurately assess the contribution made by the various components. Nevertheless, our findings suggested that combining adherence enhancing interventions tailored to individual patients was an effective way of improving persistence with 5‐ASA medication. The difficulty of accurately measuring adherence to 5‐ASA medication has been previously confirmed in our program of work; however, the objective measure used was probably the most appropriate method available for evaluating the intervention. We are unable to confirm whether the positive trend, but lack of significance, for results relating to changes in health beliefs was due to the small sample size or to the limited effectiveness of those aspects of the intervention aimed at addressing patient perceptions; further studies exploring methods of modifying health beliefs are therefore required. It could be suggested that our study does not take account of the potential impact of once‐daily dosing regimes for patients with UC. Simplification of treatment can lead to improved patient adherence in a variety of disorders, and similar results have been reported in the treatment of UC. While we acknowledge that once‐daily regimes were not available to patients in our study, we do not believe that this reduces the validity of our findings. A range of factors influence the prescribing decisions made by clinicians, including national and local guidelines, cost, and availability. Moreover, a survey of 100 Canadian patients with UC revealed that factors such as medication efficacy and safety were rated as being more important than those related to the dosing regime or cost. In this survey, speed of symptom relief and infrequency of side effects were rated as the most important factors when considering UC medication. 37 It may also be pertinent to note that changing to a once‐daily dosing schedule could potentially lead to an actual decrease in adherence, as a single missed dose would equate to a full 24 hours of missed therapy. Finally, the need to consider cost‐effectiveness in the evaluation of adherence interventions has been suggested. 13 While formal assessment of cost‐effectiveness was not within the scope of the present study, the actual costs could be described as relatively low since the intervention involved only a brief educational session and provision of inexpensive leaflets and practical reminders. It would therefore seem reasonable to suggest that the intervention could be implemented in routine clinical care at relatively low cost". (pg 1880)
Blinding of outcome assessment (detection bias) Adherence measure	Low risk	(PRIMARY) HIGH ‐ PERFORMANCE LIQUID CHROMATOGRAPHY ‐ This is an objective measure of outcome
Blinding of outcome assessment (detection bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY ‐ No blinding; as a secondary outcome measure, disease activity (flare‐up) data were collected from medical records during the study period
Blinding of participants (performance bias) Adherence measure	Low risk	(PRIMARY) HIGH ‐ PERFORMANCE LIQUID CHROMATOGRAPHY ‐ This is an objective measure of outcome
Blinding of participants (performance bias) Patient outcome	Low risk	(PRIMARY) DISEASE ACTIVITY ‐ Patient lack of blinding unlikely to affect this outcome
Blinding of personnel (performance bias) Adherence measure	Low risk	(PRIMARY) HIGH ‐ PERFORMANCE LIQUID CHROMATOGRAPHY ‐ This is an objective measure of outcome
Blinding of personnel (performance bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY ‐ No information on blinding given. There is insufficient information to permit judgment of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) Adherence measure	Unclear risk	(PRIMARY) HIGH ‐ PERFORMANCE LIQUID CHROMATOGRAPHY ‐ Reasons for withdrawals were not noted
Incomplete outcome data (attrition bias) Patient outcome	Unclear risk	(PRIMARY) DISEASE ACTIVITY ‐ Reasons for withdrawals were not noted