The reporting of the study follows the CONSORT statement recommendations [28].
Design
This 24-month feasibility study was a single-centre, single-blind, randomized study of two IMPs, ropinirole and pramipexole, in male and female patients with a confirmed primary diagnosis of idiopathic PD without cognitive impairment.
Patients were recruited on one of these agonists, and randomized in a 1:1 ratio to two treatment arms. The arms differed only in the sequence the IMPs were administered (pramipexole then ropinirole, or ropinirole then pramipexole).
Patient-participants commenced their first trial IMP without a ‘run-in’ or washout period. They were stabilized on this IMP for 6 weeks, and then, their memory was tested on two separate occasions in the following 2 weeks: in one session, the memory was tested 90 min after taking the IMP (ON), and on a separate occasion, the memory was assessed following 24–48 h of IMP withdrawal (OFF).
The OFF session was preceded by a withdrawal period that resulted in 93.75% (four half-lives) IMP elimination. After four half-lives, the amount of drug remaining (6.25%) is considered to be negligible regarding its therapeutic effects [29].
The order of ON and OFF sessions was counterbalanced.
A CONSORT diagram showing key stages of the study design is presented in Fig. 1.
Clinical trial authorization
Clinical trial authorization under The Medicines for Human Use (Clinical Trials) Regulations 2004 S.I. 2004/1031 was received from the Licensing Authority in November 2012.
Ethical approval and consent
The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The patients were sent approved participant invitation letters that included a reply slip and an information sheet for consideration. If a patient indicated interest by sending a positive reply slip, he/she was contacted by the research nurse and invited to a screening session with the chief investigator, who was also the principal investigator in this study.
Written informed consent was obtained at the screening interview by the chief investigator, with the research nurse present as the patient advocate. Patients were given an opportunity to ask any questions. Consent was obtained before any study procedures took place.
Recruitment
Recruitment commenced in April 2013. The target population was males and females aged 50–80 years with idiopathic, sporadic PD as determined by the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria, with a Hoehn–Yahr disease severity stage of 1–4 [30].
The target number of complete datasets was 50. The sample size was determined in terms of obtaining sufficiently precise estimates (as represented by the width of a 95% confidence interval) of key parameters that would inform a power calculation for a subsequent main trial. A figure of 50 is supported by reports on sample sizes for pilots with continuous outcomes [31, 32].
Eligible patients were identified from the sponsor’s (University Hospital of North Midlands NHS Trust) Department of Neurology using the PD database and clinic lists, the GPs in Staffordshire (acting as participant identification sites), the chief investigator’s private practice, local pharmacies, advertisements in local newspapers and recruitment talks given to local PD associations.
Patients entered the study on one of the two IMPs within the approved dosage range. The maximum dosage of each IMP, as specified in the summary of product characteristics, was pramipexole 0.52–3.15 mg once daily and ropinirole 2–12 mg once daily [33, 34].
Patients were maintained on the same or equivalent therapeutic dose for the stabilization periods and for the ON medication research session, using published conversion norms, unless clinical indications suggested modification [35].
Randomization procedure
Once the consent form had been signed, the chief investigator randomized the patient to the treatment arms.
Third-party randomization, in a 1:1 ratio, took place during the screening clinic visit using a locked system that automated the random assignment of treatment groups to randomization numbers. The third-party randomization protocol was a web-based programme, hosted by Keele University, and was on a password-protected site.
The patient’s randomization code was recorded in the medical records and case report form. This information was stored on-line, was read-only and could be accessed by the chief investigator and research nurse at any point during the trial.
Level and method of blinding
During the trial, the patients and the clinical members of the research team (chief investigator, research nurse) were not blind to the medication codes. The patients could not be blinded as they saw the physical nature of the tablets, and the chief investigator and research nurse managing the patients needed to know how to advise the patients at the beginning of each treatment phase of the trial, and when switching between the IMPs, and how to prepare for the medication withdrawal period.
Only the research assistant administering the cued recall memory test during the ON and OFF research sessions was blind to the medication codes. The medication codes were not made available to the research assistant until each patient had completed the trial, with his/her data scored and entered into the database.
Outcomes
The two primary outcomes were efficacy of processes and procedures used to manage symptoms during the washout period (measured in relation to adverse events) and estimates of cued recall performance (to inform the sample size calculation). The secondary outcomes were rates of consent and missing data, acceptability of the support provided for the OFF medication sessions and whether the OFF session itself was manageable, the experience of switching between IMPs (assessed at the semi-structured interview administered at the end of the trial) and barriers to participation for eligible patients and informal carer givers (semi-structured interview).
Enrolment and study visits
Patients completing the feasibility trial were intended to participate for a maximum period of no longer than 16 weeks. During this period, they were involved in eight separate sessions:
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Three involved the chief investigator and research nurse and took place during research-dedicated clinics in a UHNM research facility:
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○ Screening visit in week 1 (visit 1)
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○ Mid-study follow-up appointment, taking place between weeks 6 and 8 (visit 4)
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○ An end-of-study follow-up appointment, between weeks 14 and 16 (visit 7)
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Four involved the research assistant and took place in the patient’s home, around 9 or 10 a.m. in the morning:
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○ Separate ON and OFF medication sessions for the first IMP, between weeks 6 and 7 (visits 2 and 3)
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○ Separate ON and OFF medication sessions for the second IMP, between weeks 13 and 15 (visits 5 and 6)
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One visit with the research assistant followed the end-of-study clinic visit, for the purposes of completing a semi-structured interview about participation, between weeks 14 and 16 (visit 8).
For the ON research session, medication was taken as usual roughly 60 min before the session commenced. For the OFF session, medication was delayed prior to the session. Medication was resumed following completion of the session, according to criteria discussed with the chief investigator. The ON medication and OFF medication sessions for each drug should have taken place during a 7-day window, on separate days separated by at least 3 days. The order of the ON and OFF research sessions was determined by the randomization programme.
Washout periods
A single washout period, between the first and second IMP, was used to eliminate a carryover effect. The elimination half-life for each drug is 8–12 h for pramipexole in older patients, falling at the upper end of the range: 6 h for ropinirole and 3 h for l-dopa and monoamine oxidase B inhibitors.
To achieve 93.75% elimination of each drug (equating to four half-lives), the following washout periods were required: pramipexole, 48 h (4 × 12 h); ropinirole, 24 h (4 × 6 h); l-dopa and monoamine oxidase B inhibitors, 12 h (4 × 3 h). At the mid-study clinic visit, patients were given the second IMP, which they took until the end-of-study visit.
During the washout period, patients continued to take l-dopa and/or monoamine oxidase B inhibitor as usual. The half-lives of these drugs are shorter than those of the IMPs, and therefore, the washout period required for 93.75% elimination of l-dopa and monoamine oxidase inhibitor (half-life is between 2 and 3 h) is 12 h. l-dopa and monoamine oxidase inhibitors were withdrawn 12 h (overnight) before the OFF research session. The OFF session took place in the morning, following a washout period resulting in four half-lives of the drug being eliminated (i.e. 93.75%).
Data security and monitoring
A research risk assessment of the feasibility trial was carried out by the chief investigator and the regulatory research associate from the sponsor’s research and development department, prior to the preparation of the protocol. The first risk assessment was assessed as moderate by 1 point initially (1 point over the low to moderate risk boundary), but reassessed later as low-risk, requiring minimal mitigation.
Validation procedures included regular data entry checks performed on a minimum of 25% of complete patient data by the monitor. All source data and trial documentation were available for trial-related monitoring. The patients consented for this within the consent process.
Patients’ contact details were disclosed to the research assistant, for the purposes of arranging the four home visits to complete the memory assessment. All patient data collected by the research assistant were identified using a unique study code. This same code was used to enter patient data into the Microsoft Excel© database. Copies of signed informed consent forms were placed in the patient’s medical records and originals retained in the trial file and kept separate from the data.
Monitoring procedures were carried out by the sponsor and were in accordance with standard operating procedures. The monitor checked the case report forms, trial master file and other trial documentation for completeness and the compliance of the trial team with the protocol and good clinical practice (GCP) standards. The initial monitoring visit occurred before the trial started to ensure that the trial complied with the protocol and GCP standards. Further monitoring visits took place at regular intervals (approximately twice per year), with a final monitoring visit conducted to close the trial.
Study committees
A steering group was formed comprising a lay chair, lead researcher (Edelstyn), chief investigator (Ellis), research nurse representatives, research assistant (Shepherd), pharmacy representatives, research and development department representatives (Longshaw, Watts) and up to four patient-public representatives.
Membership of the operational group included the lead researcher (chair), chief investigator, research nurse representatives, research assistant, trial pharmacists, sponsor research and development representatives. The operational group met on a monthly basis.