PROState Pathway Embedded Comparative Trial

The proposal will explore a trial design called the cohort-multiple RCT (cmRCT) or as it has been recently coined, the Trials WithIn Cohorts (TWICS) design. This design has been used in a number of disease areas, both benign and cancer. Prostate conditions have been chosen since they are extremely common and if malignancy occurs the majority of men with the disease are regarded as living with a chronic condition due to its long natural history and in which innovative approaches, interventions, treatments or changes in management might have a significant patient benefit and impact on the NHS. It therefore fits the cmRCT design very well. Nonetheless, the lessons learned in this study will be of relevance to other disease spaces.

The TWICS or cmRCT design is currently being used in elderly patients, risk of falls, depression, hip fracture, Yorkshire Health Study, scleroderma, breast cancer, colorectal cancer, bladder cancer and kidney cancer, to name a few. In total, a recent systematic review showed that there were 18 ongoing cmRCT studies with 6 in the UK.

The acceptability and feasibility of the cmRCT in the prostate pathway will be tested. This is the first time this method will be tested and therefore piloted. In the first part of the study, the following will be evaluated. What is the accrual rate? What do patients and their healthcare professionals think of the cmRCT design? Is the data collected robust? What are the resource requirements of such a study?A number of novel interventions or changes in the pathway will then be tested and compared to standard care in the cohort that was recruited.

TRIAL AIMS

The pilot phase of PROSPECT is interested in investigating the a) acceptability and feasibility of establishing the cohort of men, i.e. putting the questions of Point of Consent One to men being referred for investigation of prostate cancer, and b) observing the cohort over the study period and collecting data on the participants pertaining to their disease, their treatment and their health status.

A) Acceptability

AIM 1.1: To determine what proportion of men with a clinical suspicion for prostate cancer will participate in an cmRCT.

OBJECTIVE 1.1a: To evaluate proportion of patients approached who agree to participate in the longitudinal cohort. This will be done by calculating the participation rates from men approached for invitation to PROSPECT.

AIM 1.2: To explore barriers and facilitators to implementation of a cmRCT in order to improve and inform patient and/or physician trial information, study processes, interventions, and recruitment and retention of patients. This will be carried out by qualitative assessments in the following areas.

OBJECTIVE 1.2a: To investigate by interview the patient experiences and perspectives on;

* Trial participation,
* The point at which men are approached by the research team to enter the cohort,
* Barriers and facilitators to consent to participate in the cohort,
* Barriers and facilitators to consent to future random selection to undergo a new healthcare intervention,
* Acceptability of monitoring of health status and the tools used to do this in the cohort.

OBJECTIVE 1.2b: To investigate by interview the experiences and perspectives of healthcare professionals (doctors, nurses and admin staff) on;

* Trial design and information to patients and healthcare professionals,
* Feasibility of future random invitation of participants to interventions,
* Tools used for measuring health status.

B) FEASIBILITY

AIM 2.1: To determine the feasibility of recruitment and logistical implementation of PROSPECT in different data collecting centres based in different institutions. This will be broken down into the following sub-questions;

OBJECTIVE 2.1a: Evaluating how the patients are successfully identified and the option of how inclusion in the trial is presented to them.

OBJECTIVE 2.1b: Evaluate patient questionnaire response rates for pre-treatment quality of life.

OBJECTIVE 2.1c: Evaluate patient questionnaire response rates at pre-determined intervals following on from the point of recruitment into the trial to determine how to promote optimal patient response rate and improve data collection.

OBJECTIVE 2.1d: To evaluate completeness and fidelity of clinical data on the men who participate in the cohort.

STUDY DESIGN

Design

The key features of a cmRCT are;

1. Explicitly consented recruitment of a large cohort of patients with the condition of interest.
2. Regular measurement of relevant outcome measures for the whole cohort prospectively in the long-term.
3. Facility to re-approach cohort participants, who are randomly selected from eligible patients within the cohort, inviting them to undergo intervention of interest to researchers with eligible patients not randomly selected entering the control standard care group (see study flowchart 3.3 / 3.4).
4. "Patient-centred" informed consent. The consent process aims to replicate that used in the routine health care setting. Once the patient has been randomly selected for a randomised novel intervention from the eligible patients within the cohort, the second consent process should include detailed and specific information pertaining to the particular intervention or change in management they are being invited to undergo for comparison. Such information will be written and advised using patient representatives and undergo review following submission to REC.
5. Comparison of the outcomes in the randomly selected patients with the outcomes in eligible patients not randomly selected.
6. Capacity for multiple randomised controlled trials over time within the cohort simultaneously.

CONSENT

For men who are participating in the cmRCT there are two points of consent:

POINT OF CONSENT ONE

At Point of Consent One men who are referred for investigation of prostate cancer will be asked two questions. The first question relates to whether they are willing to join the cohort and have data collected directly from them over time on a regular basis. This data will include health-related quality-of-life data (at recruitment, 0-6, 6, 12, 18 \& 24 months post recruitment), linkage to their medical records so that researchers can know what happens to them over time, and access to other data about them held on national health registry databases. Also, at point of consent one, prospective participants will be asked (second question) whether they agree to being randomly selected in the future to interventions or changes in management in order to compare to standard care. It will be explained that this second invitation will be on a random basis. In other words, everyone eligible within the cohort will have the same chance of being randomly selected. The patient would still have the option of saying 'no' after the random selection when they are approached.

POINT OF CONSENT TWO

The second point of consent is the invitation to undergo an intervention or change in management that the research team wishes to compare to standard care. Participants will have already agreed to the possibility of being invited to undergo intervention at Point of Consent One (i.e. enrolment into the cmRCT). The participant will have been randomly selected from amongst all the eligible men for the given intervention from within the large cmRCT cohort prior to being approached by the trial team. Then, the trial team will approach the participant and invite him to undergo the intervention. This will entail a comprehensive consent process that pertains directly to the intervention being proposed in a patient-centred manner. The participant can agree or refuse to undergo the intervention. If he does not wish to undergo the treatment he will continue under follow-up in PROSPECT.

Participants undergoing intervention will continue to have follow-up in the same manner as men who have not been randomised from within the cohort and thus provide outcome data to form the control arm. Comparison of the outcomes of those men who underwent trial intervention against those who did not will allow us to analyse the effectiveness of the intervention in as robust a manner as possible given that the key feature of randomisation when creating the control vs. the intervention arms has been preserved. As such, the control arm of the cmRCT will be similar to the intervention arm in all features, known and unknown, except the intervention of interest. This will allow for the maintenance of epistemological superiority of the data produced for evaluating new tests or treatments whilst getting to this point in a way that might be more acceptable to patients and therefore more likely to be successful and efficient for researchers.

The second stage of PROSPECT will be to investigate and evaluate in a similarly careful manner the feasibility and acceptability of randomising men from the cohort of eligible men to interventions or changes in management that require evaluation, following submission to REC. As part of the cmRCT design, these men randomly selected are re-approached and invited to consider undergoing the intervention of interest. Patients who are randomly allocated to the control arm will also receive standard of care, and are not informed about their participation in the control arm. This additional consent will be obtained at the time of consent for the cohort study.

STUDY SETTING AND POPULATION

All men referred for investigation of prostate cancer. The inclusion criteria for this cohort is deliberately broad.

Eligibility Criteria:
Inclusion Criteria:

1. Men aged 18 years old and over who are referred for investigations for urinary symptoms or elevated serum prostate specific antigen (PSA) levels or other risk factors for possible prostate malignancy.
2. An understanding of the English language sufficient to understand written and verbal information about the trial and consent process.
3. Estimated life expectancy of 5 years or more.
4. Signed informed consent.

Exclusion Criteria:

1. Men who are unable to give informed consent.