Trial design, funding and approval

The RCT was a single-centre (multisite) individually randomised 2 × 2 factorial design comparing the effect of MODs with medication dispensed in usual packaging and of weekly compared with a monthly medication supply. The trial was conducted across six NHS Norfolk GP practices and 14 pharmacies which served the patients registered at these GP practices. Five of the GP practices and 13 of the pharmacies were situated in the Norwich area, including its suburbs, and one GP practice and pharmacy was based in a small, nearby market town.

The trial was funded by the NIHR HTA programme and started in August 2011 (ref. HTA 09/34/03). The trial was approved by the Cambridge South Research Ethics Committee (ref. 12/EE/0251), Norfolk Primary Care Trust (ref. 99999) and additionally by Norfolk County Council (in respect of social services usage data only). The trial is registered with the International Standard Randomised Controlled Trial Register (ref. ISRCTN 30626972) and the UK Clinical Research Network (ref. UKCRN 12739).

A number of changes to procedure were necessary as a result of the failure to obtain a suitable EAM system. Table 15 provides a summary of deviations from the protocol with reasons for the deviation. All deviations were appropriately notified as amendments to the protocol.

TABLE 15

Deviations from the trial protocol with rationale

Participant eligibility

The pilot had two phases. Phase 1 established patients’ adherence; only patients identified as unintentionally non-adherent progressed to phase 2, which was randomisation.

As described in Chapter 3, refinements to the eligibility criteria were necessary because of constraints of the proposed EAM system.

Eligibility criteria

The process for ensuring that all randomised participants fulfilled the inclusion and exclusion criteria was multistage and is summarised in Figure 7. Some eligibility criteria are repeated at the different stages where appropriate multiple information sources were used to confirm eligibility.

FIGURE 7

Process for determining participant eligibility.

Inclusion

Patients were included if they were:

• aged ≥ 75 years
• registered with one of six participating medical practices
• prescribed three or more SODF medications expected to be continued for 12 months (of which at least two were from a defined list in Table 16)
• capable of providing informed consent.

TABLE 16

Defined list of medications for eligible patients

Exclusion

Patients were excluded if they:

• were regularly prescribed medication not currently dispensed by a pharmacy recruited to the study
• had a life expectancy of less than 12 months
• were currently involved in a clinical trial
• were not self-administering their medication
• were currently receiving or had previously received medication in a MOD
• were diagnosed with Parkinson’s disease or a severe mental health disorder such as schizophrenia
• were deemed by the health-care team to be unsuitable for study inclusion for other reasons
• were using a medication organisation strategy incompatible with trial participation
• were intentionally non-adherent.

Identification

One member of each of the six recruited medical practices undertook a database search to identify potentially eligible patients. A GP subsequently screened the list to exclude any patients deemed unsuitable. The reasons for exclusion were recorded in order to further refine the exclusion criteria of a definitive study.

Recruitment

Two patient recruitment methods were tested, passive and active, to determine their acceptability and effectiveness. For consenting patients, responses to questionnaire 1 (see Appendix 5) were used to identify whether or not the patient should be excluded on the following criteria:

• were using a medication organisation strategy incompatible with trial participation
• were intentionally non-adherent.

Passive recruitment

Patients identified by GP database search, and subsequently GP screened for suitability, were sent recruitment packs. Recruitment packs comprised a letter of invitation on GP practice-headed paper (see Appendix 6), patient information leaflet (PIL; see Appendix 7), consent form (see Appendix 8), questionnaire 1 (see Appendix 5) and a pre-paid envelope. Participants were asked to return completed documents directly to researchers. Questionnaire 1 was not attached to the consent form and so patients were able to choose to return both, either or neither. Implicit consent was assumed for any questionnaires returned. One reminder was sent to each non-responding patient 3 weeks after initial posting.

A standard operating procedure (SOP) for passive recruitment was prepared (see Appendix 9). Three practices used only passive recruitment which commenced during August 2012 and was completed in February 2013.

Active recruitment

This process involved one of six researchers recruiting patients when they presented for routine appointments at the participating GP practices. Patients identified by GP database search, and subsequently GP screened for suitability, were highlighted on the GP system, which enabled practice reception staff to identify the potentially eligible patients who would be presenting at the medical practice on a recruitment day. Such patients were provided with a PIL and an explanation that there was a researcher present who would like to talk to them about the study if they were interested. Patients who chose to approach the researcher were informed about the study and given a recruitment pack which they could complete at the medical practice or take away. If patients volunteered information indicating that they were ineligible (e.g. they were already using a MOD), they were informed of their ineligibility and thanked for their time. The SOP for active recruitment is provided in Appendix 10.

Three practices used active recruitment for a 3-week period followed by passive recruitment, as previously described. Active recruitment was carried out in 3-week tranches during the period September to November 2012.

Intervention and comparator

Participants were randomised to one of the following arms for 8 weeks:

1. four MODs dispensed monthly either collected by the patient or delivered to the patient’s home, according to usual patient routine
2. one MOD delivered to the patient’s home weekly
3. usual medication packaging dispensed monthly and either collected by patient or delivered to the patient’s home, according to usual patient routine
4. usual-care medication packaging delivered to the patient’s home weekly.

Other prescribed medication that could not be dispensed in a MOD, for example inhalers, creams, liquids and when-required medication, was supplied in usual packaging with the MOD.

Medication organisation devices

Nomad Clear, Nomad Clear-XL and a Venalink device were used. MODs contained all SODFs prescribed to the patient unless they were unsuited to being dispensed in a MOD [e.g. because they are to be taken ‘when required’, their administration requires special processes, such as dissolving or chewing, or their dose is likely to change frequently or at short notice (e.g. warfarin)]. Monthly MODs were either collected from the pharmacy or delivered from the pharmacy to the patient according to the usual routine of the patient. Weekly MODs were delivered to the patient.

Usual care

Medication supplied in the manufacturer’s usual packaging or in accordance with usual dispensing procedures when this is inappropriate, for example prescription requests for a quantity other than the manufacturer’s pack size. Monthly packaging was either delivered to the participant or collected from the pharmacy according to the participant’s usual routine. Weekly packaging was delivered to the participant’s home.

Outcome measures and outcomes

Data collection

Questionnaire data were collected from patients by postal return or in their own homes if participants requested help to complete forms. Data on pharmacy activities and the empty packaging for pill counts were obtained from each participating pharmacy. Patient data on comorbidities and use of health-care services for the period 2 months prior to and 2 months after the start of the trial were obtained from participating GP practices. Data on use of social care services were obtained from Norfolk County Council Social Services Department.

Prevalence of intentional non-adherence

All consenting participants were screened for factors including intentional non-adherence, non-self-medication, current or previous use of a MOD and complex medication management strategies using questionnaire 1. Intentional non-adherence was investigated using eight statements in four pairs across three sections of the questionnaire and an arbitrary cut-off of extreme agreement (strongly agree or ‘yes’ response) with three or more of the eight statements on intentional non-adherence was used to indicate likely intentional non-adherence. Statements included widely accepted reasons for intentional non-adherence in a UK setting and addressed the need for treatment breaks, addiction concerns, cost–benefit, perceived toxicity, medication necessity and side effects.

Questionnaire 1 was also used to identify participants already using MODs or using methods of medication organisation which would either be incompatible with EAM or unethical to remove from a participant.

Participants not meeting the inclusion criteria because of intentional non-adherence, use of MOD or other trial-incompatible medication organisation strategy were thanked for their interest by letter and informed we would be making no further contact with them (see Appendix 11).

Participants identified as potentially eligible after completing questionnaire 1 were contacted by telephone to arrange a preliminary baseline visit in their own home, and their usual pharmacy was identified.

Prevalence and magnitude of unintentional non-adherence

The purpose of the baseline visit was multifold: to meet with patients (often for the first time); to confirm that all non-medical inclusion criteria had been identified (e.g. that there were no obvious unreported medication-taking strategies in place); to remove existing prescribed medication so as to ensure that the patient did not accidentally take medicines from a non-study pack; and to deliver a new 28-day medication supply to be taken over the following 4-week period, which would allow the study team to ascertain whether or not patients may be unintentionally non-adherent.

Prior to the baseline visit, participants were asked to collect all medicines together. At the baseline visit, researchers stressed that they would not reveal information to their GPs about how well participants took their medicine, as researchers were interested only in measuring the participants’ usual medication-taking habits. Researchers recorded name, form and quantity of all existing medicines and then removed them from use by placing them in one or more large clear bags secured with a cable tie. Details were recorded on administration form 1 (see Appendix 12) and participants were asked to endorse the record. Medications no longer required or expired were returned to the pharmacy for destruction with participant consent.

Each secure bag was labelled clearly with the participant’s name and instructions not to use the contents unless absolutely necessary. The sealed medicines were returned to the participant for safe keeping and participants were asked to inform researchers if they needed to open the bag during the study. A follow-up appointment was arranged for 3 weeks (± 2 days) after the initial visit.

The assessment of unintentional non-adherence was made by DUC. If a participant had taken fewer than expected SODFs, they were identified as unintentionally non-adherent. Researchers also confirmed the participant’s willingness to continue in the study and carried out randomisation. Participants were informed of their randomisation status. If participants were randomised to receive a MOD, they were shown the three study MODs (Nomad, Nomad XL and Venalink) and asked to select their preferred MOD. Their choice and confirmation that they were able to use it were recorded using administration form 2 (see Appendix 13).

Irrespective of adherence status or willingness to continue in the trial, participants were asked to continue to take the 1-week (approximately) medication supply remaining in the packs delivered at the baseline visit and then to continue to obtain their prescribed medications according to their usual supply routine. Pharmacists were informed of randomisation status for all participants.

Adherence monitoring

In the absence of a suitable EAM system, DUC was used to determine adherence to prescribed SODFs. Patients were provided with a number of large, clearly labelled, sealable plastic wallets in which to store used medication packaging. Wallets were returned to pharmacies by patients or delivery drivers coinciding with usual collection from the pharmacy. Researchers contacted patients for whom medicines had not been returned to the pharmacy. The number of doses returned for each medicine was counted and recorded.

Characterisation of the participant population

Cognitive function was assessed using the 11-item MMSE. It is scored out of 30, with scores of 23 and above indicative of cognitive function within the normal range.⁶⁵

Manual dexterity was assessed using the 9-HPT, which was scored by measuring the period of time, in seconds, taken to move pegs, similar in dimension to medication capsules, from a tray into a 3 × 3 array of holes which accommodate the pegs in a vertical orientation, and then to remove them and place them back into the tray.⁷⁶

Visual acuity was assessed using the smallest font size that could be read on the Bailey–Lovie Near Chart.⁷¹ Participants used their usual visual aids and held the chart at their normal reading distance (approximately 40 cm). The test took place under the lighting conditions that patients would usually be exposed to when taking their day-time medicines.

General practitioner records were accessed by a member of the research team in order to obtain participant comorbidities.

Participants also completed baseline health and quality-of-life measures as described in Chapter 7.

Randomisation

Randomisation was carried out at the participant’s home by researchers. Participants identified as unintentionally non-adherent were randomised to phase 2. Researchers used mobile internet to connect to the secure study database. The randomisation sequences were generated automatically using an online system developed and managed by Norwich Clinical Trials Unit. Allocation was automatically recorded in the study database. Randomisation was done on a permuted block basis. There were six strata, one per GP medical practice. There were four randomisation arms (usual supply weekly, usual supply monthly, MOD weekly, MOD weekly). The codes for each stratum were blocked randomly into groups of four or eight to try and even out the distribution across randomisation arms.

Blinding

Given the nature of the interventions under study (MOD and frequency of dispensing), blinding was not possible for patients, researchers or pharmacists involved in the study.

Administration and timings

At commencement of the intervention, researchers visited the participant and explained procedural details emphasising how and when medicines would be supplied and asking that all medication packaging was retained for researchers. It was again stressed that researchers would not feed information back to GPs about how well participants were taking their medicine and that they were only interested in measuring the participants’ usual medication-taking habits. At this visit, researchers delivered the first medicines of the intervention and follow-up questionnaires: EQ-5D-3L combined with the Investigating Choice Experiment CAPability measure for Older people (ICECAP-O, questionnaire 2), a patient satisfaction survey (questionnaire 3, see Appendix 14). A further questionnaire and letter of invitation for any person living with or caring for the participant (questionnaire 4, see Appendix 15) was also left with the participant. Researchers agreed to telephone participants 1 week prior to completion of the intervention to explain the procedure for returning to usual care.

General practice and pharmacy participation

General practice participation at this stage of the trial was limited to routine prescription preparation and required only minimal interaction between researchers and prescription managers.

Pharmacists were informed directly after randomisation of the randomisation status of their participant. They were asked to follow the instructions provided in the SOP for pharmacies (see Appendix 16). Briefly, pharmacists prepared medicines according to randomisation. In the case of medicines that were to be dispensed in MODs, after the first delivery (carried out by researcher), these were delivered to the participant by the pharmacist via their usual delivery service for weekly supply or were collected by participants. Medicines that were dispensed in usual packaging were delivered weekly to patients randomised to usual care and delivered or collected in accordance with usual practice for patients randomised to monthly supply.

Pharmacy data collection

Pharmacists were asked to record participant details, medicines supplied, time taken to dispense medicines and any near-miss dispensing or prescribing errors identified on administration form 3 (see Appendix 17), with further details, if necessary, on pro-forma follow-on sheets. They were also asked to record any other comments about the trial.

Adverse events

This pilot trial was not a clinical trial of an investigational medicinal product, and thus no formal process for recording adverse events (AEs) was implemented. Any potential AEs identified were defined in accordance with European Clinical Trial Directive 2001/20/EC as new or the worsening of pre-existing symptoms.

Serious adverse events

Serious adverse events (SAEs) are defined by European legislation as the development of an undesirable medical condition or the deterioration of an existing medical condition following or during exposure to an investigational medicinal product, whether or not it is considered causally related to that product, which results in hospitalisation or prolongation of hospitalisation; immediately life-threatening illness; persistent or significant disability; and incapacity or death.

Descriptions of all AEs were recorded using UEA SOP 206 with associated SAE form (see Appendices 19 and 20). Reports were made to the UEA research sponsor and local research and governance representative within stipulated time limits. Governance committees assessed the reports. All AEs identified were also reported to management and steering committees. The participant’s usual GP was contacted for an opinion on probable causality, that is whether the GP considered it unlikely, possible or likely that events occurred as a result of trial participation.

Sample size

The sample size was determined as follows. A total of 120 participants were required for the RCT. With four groups of 30 participants, the coefficient of variation of the SE estimates for any continuous outcome measure for each group was expected to be about 13% using a linear approximation and assumption of normality. These SE estimates, would have been used to inform the power calculation of a definitive trial and would have been within about 25% of their true values based on the expected half-width of a 95% CI. It was estimated that, in order to obtain 120 participants who are primarily unintentionally non-adherent, 720 potential participants needed to be screened using a self-report questionnaire. This estimate was based on the assumption that approximately 20% of participants would be intentionally non-adherent^17,18,77,78 and thus excluded. The remaining 576 participants would be monitored for non-adherence using DUC. This stage was expected to result in 30% attrition, and thus 403 participants would remain, of whom 160 (40%) were expected to be non-adherent. These participants would then be randomised and monitored for 3 months, during which process a further 25% attrition was expected, leaving 120 participants. (See Figure 8 for the flow diagram summarising participant pathway through trial.) Participants suspected of intentional non-adherence were advised to consult their pharmacist for a medicines use review or their GP.

FIGURE 8

Flow of participants.

The primary outcome measure was the mean difference in per cent adherence (measured by pill count) between participants in receipt of a MOD and participants who received their medication in usual-care packaging. This should provide an estimate of the effect of the factor packaging. As there are no reported trials with a similar population, that is pre-screened to remove participants likely to be adherent or demonstrate intentional non-adherence, data were not available to estimate the variance of adherence measured in this population. However, an upper estimate of the precision was determined by considering the dichotomisation of this outcome to the binary measure adherent versus non-adherent. Making the conservative assumption that 50% of participants would be adherent and with 60 participants receiving a MOD and 60 receiving usual-care packaging, the half-width of a 95% CI around the difference between these groups should be less than 18%.

No interim analyses or stopping guidelines were included in the study design.

Statistical methods

A dedicated study database was designed, built and maintained by Norwich Clinical Trials Unit, data were analysed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA) and PASW statistics version 18 (SPSS Inc., Chicago, IL, USA). Descriptive analyses were used to report recruitment and consent rates, social and health (comorbidities) status, participant functional abilities in addition to prevalence of intentional and unintentional non-adherence. Unintentional non-adherence during a 3-week screening period was calculated as follows:

The magnitude of unintentional non-adherence was determined from median and interquartile divergence for all unintentionally non-adherent participants.

Unintentional non-adherence during the 8-week trial period was identified and magnitude calculated as described above for the 3-week screening. Percentage medication adherence was reported for participants randomised to MODs or usual care and weekly or monthly delivery for each medication. This approach took into account that there were varied individual daily dose regimes and that not all participants returned all packs. Analyses were undertaken for any medicines returned by participants for whom at least 1 week’s medication packaging was returned. Previous research indicated that the data may be negatively skewed with minimal deviation from 100% adherence.¹⁵ Secondary analysis was, therefore, undertaken using a dichotomisation of 100% versus less than 100% adherence.

Analyses were carried out with respect to incidence of reported AEs. Fisher’s exact (two-tailed) test was used to determine the statistical significance of the events with respect to type of packaging and frequency of supply.

Although the study was not powered to detect differences of a particular size, and accepting the limitations of a feasibility study, the observed differences between the study groups were presented. Exploratory analyses were also undertaken to identify any indications that variables such as cognitive function, number of prescribed medicines and manual dexterity affect the primary outcome (adherence). This was to identify whether or not any subgroups of participants might benefit from MODs.

Results

The inability to obtain a suitable objective EAM solution also delayed a number of trial timelines. The initial intent was to carry out the 3-week assessment of unintentional non-adherence with immediate randomisation of eligible participants. As a result of difficulties identifying a suitable adherence monitoring device, there was a delay of 2–3 months between randomisation and the start of the RCT.

Recruitment

Figure 8 [Consolidated Standards of Reporting Trials (CONSORT) diagram] illustrates the flow of patients through the study. The most significant attrition during recruitment was at the stages of determining eligibility for EAM, followed by ineligibility as a result of medication-taking strategies that were inconsistent with MODs or electronic monitoring. A completed questionnaire 1 was received from 288 participants, of whom 11 (3.8%) were excluded because of current participation in a medication trial.

Participants using a medication organisation device or medication organisation strategy incompatible with trial participation

One hundred and two participants (35.4%) reported in questionnaire 1 using a MOD and were thus excluded. A further 27 (9.4%) participants reported use of strategies to aid correct medication taking which were incompatible with the study design. Six reported that they were not self-medicating, one reported using an alarm, three reported popping out their pills in advance into other containers, for example bottles or cups, which would have been incompatible with EAM. The remaining 17 participants reported using other equipment to organise their medicines. For example, some used a series of shot glasses and others ice cube trays.

Intentional non-adherence

Screening of questionnaire 1 responses identified 71 (24.7%) participants indicating extreme agreement with one of eight statements exploring intentional non-adherence. Eighteen (6.3%) indicated extreme agreement with two of eight statements and two (0.7%) participants indicated extreme agreement with three statements and were thus excluded from the study.

Unintentional non-adherence

All 80 eligible participants presented their medicines to the researchers during visit 1. Some medications were neatly presented with the correct blisters in their original packaging in an organised fashion and others appeared to have been randomly tossed into buckets, bags and boxes. One participant, who was subsequently withdrawn from the study, had very poor eyesight and used the colours and sizes of his medicine boxes to distinguish one from another. This participant had incorrect blisters inside boxes.

Many patients had medicines surplus to reasonable requirement in their possession, as summarised in Table 17. As an extreme example, one participant presented 17 unused tubes of Ovestin cream and seven unopened boxes of codeine phosphate. Many participants had excessive numbers of surplus prescribed painkillers. No patients reported any discomfort with or declined the removal from use of their old medicine stocks.

TABLE 17

Patient held medication stock in excess of requirement

Dosage unit count data were available for 76 subjects, of whom 41 (53.9%) were ‘fully adherent’ and thus excluded from further study participation. The remaining 35 participants (46.1%, 95% CI 34.8% to 57.3%) were unintentionally non-adherent. Five of these participants withdrew prior to randomisation and one was excluded after visit 2 because of concerns about his mental health on discussion with his health-care team.

Of the 29 randomised participants, three subsequently withdrew prior to receiving the intervention: one participant citing problems with delivery (n = 1 MOD weekly) and two participants stating that they preferred not to take part (n = 1 MOD weekly; n = 1 usual supply monthly). A further patient was withdrawn after randomisation to the usual supply monthly group because his eyesight was extremely poor and there were concerns that he was unable to manage his medicines safely; his health-care team were informed.

Twenty-five participants commenced the intervention, but primary outcome data were not received from three of these participants and thus they were excluded from analysis: one participant was admitted to hospital during the trial (n = 1 MOD monthly), while the other two participants (n = 1, usual care weekly; n = 1, usual care monthly) did not return any medication blister strips to enable the primary outcome measure to be calculated.

Table 18 summarises the baseline characteristics of participants randomised to each of the four groups. It can be seen that the participants were relatively evenly matched across the four groups.

TABLE 18

Participant characteristics

Table 19 illustrates the cognitive function, manual dexterity and visual acuity of participants. No randomised participant had significant cognitive impairment. There was substantial variation in manual dexterity and 12 (41.4%) participants had manual dexterity that was poorer than the normative value for the population aged over 71 years.⁷⁹

TABLE 19

Participant functional ability

Relationship of adherence to cognitive and physical function

The relationships between adherence and MMSE scores, dexterity scores and visual acuity were explored for possible factors predicting adherence among the 22 subjects in whom adherence was measured in the trial. Spearman’s rank correlation (r_s) was used to quantify the relationship between adherence and these variables, as shown in Table 21.

TABLE 21

Relationship between adherence, MMSE, dexterity and visual acuity

One correlation coefficient was statistically significantly different from zero. This was for the relationship between adherence and dexterity of the left hand (r_s = –0.516; p = 0.014). This value was negative, indicating that the longer the time to complete the dexterity test with the left hand, the lower the adherence score was likely to be. No other coefficient was statistically significant.

Adverse events

A total of five AEs (n = 3) or SAEs (n = 2) were identified in the 25 participants receiving the intervention. Events comprised a hypoglycaemic episode, three falls leading to hip fracture, with death in one patient, and one temporary physical incapacitation. All five events were identified in groups randomised to receive MODs. Using Fisher’s exact test (two-tailed), the association between groups (MODs/usual care) and outcomes (harm/no harm) was statistically significant (p = 0.0391). Two events occurred in participants receiving care on a monthly basis and three in those receiving on a weekly basis. Using Fisher’s exact test (two-tailed), the association between groups (weekly care/monthly care) and outcomes (harm/no harm) was not statistically significant (p = 1.000). The SAEs and AEs are detailed in Tables 22–26. No events were identified in participants randomised to usual care.

TABLE 22

Serious adverse event 1

TABLE 26

Adverse event 3

TABLE 23

Serious adverse event 2

TABLE 24

Adverse event 1

TABLE 25

Adverse event 2

Pharmacists were asked to record any near misses and the type of near miss for the duration of the RCT. Pharmacy data collection forms were returned for all participants; the two near misses that were reported are presented in Table 27.

TABLE 27

Reported near misses