Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Adenocarcinoma

Prostatic Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Hashim Ahmed

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.

PROState Pathway Embedded Comparative Trial

Rate of consent to inclusion to PROSPECT cohort at the original point of contact by the research team. This will be calculated on an ongoing basis and will be reviewed at 6 months and one year from opening and at the end of the study period

To investigate by interview the experiences and perspectives of patients who:

* Consented to inclusion in the cohort study,
* Declined to enter into the cohort,
* Consented to inclusion in the cohort initially but who subsequently requested to leave the cohort,

Structured thematic interviews will be conducted by the researchers who will follow the Interview Questionnaire Template. The interviews will be recorded and transcribed in house before analysis and theme-based extraction of the reasons behind men's decision regarding inclusion in the cohort. Recruitment for qualitative interviews will continue until no further themes emerge.

The opinions of healthcare professionals who regularly look after men with prostate problems will be sought through semi-structured interviews that focus on implementation, practicality and efficiency of PROSPECT. There will be a different Interview Questionnaire Template for interviews with healthcare professionals.

Evaluation of the number of men approached to enter PROSPECT against the number of men referred to the participating centres for investigation of prostate cancer.

PROSPECT will conduct a review of the pathway by which they approach men to invite them to the cohort. Part of this will be included in the qualitative interviews with men and healthcare professionals. Particular points of interest will be the timing of consent process, the trial personnel who gain consent, and the number of men who give consent who are subsequently not diagnosed with prostate cancer.

Participants will be given a standard Quality of Life Questionnaire (EQ5D-5L) at the point at which they consent to inclusion into PROSPECT. Data completeness will be calculated at 6 months after opening and on an ongoing basis as long as the study is open.

Participants will be given a standard Quality of Life Questionnaire (EQ5D-5L) at the point at which they consent to inclusion into PROSPECT. Data completeness will be calculated at 12 months after opening and on an ongoing basis as long as the study is open.

All participants will be asked to complete questionnaires on disease specific quality of life at the following points;

* Recruitment to cohort.
* 0-6, 6, 12, 18, 24 months from recruitment to cohort
* Yearly questionnaires thereafter during inclusion in the cohort if trial remains open (i.e., post pilot phase).

PROSPECT will use three self-reporting quality of life validated questionnaires. The responses from the questionnaires will be of value as they will provide an informative vignette of the experience of men after the diagnosis of prostate cancer and they can be compared against the experience of men who are investigated for but not diagnosed with prostate cancer. In terms of evaluating the feasibility of the cmRCT design, PROSPECT will calculate the rates of response from participants with these questionnaires. Questionnaire response rates will also inform PROSPECT of the understanding of the acceptability of the cmRCT design study to patients.

Feasibility of collecting data from the participating centres evidenced by the completeness of data for cohort participants including; i. Subject Data: age, co-morbidities, ECOG/WHO Performance Status, ethnic risk, family risk ii. Disease Characteristics: PSA, MRI (volume, score), biopsy findings (cancer or not, grade if cancer, length of maximum cancer, other pathology), TNM stage if cancer iii. Treatment Data: modality, follow-up, adjuvant and salvage treatments, mortality Analysis will be conducted at one year after opening the PROSPECT and yearly thereafter in order to monitor any trends in improving or faltering data accrual on participants, as long as the study is open.

The integrated qualitative component will explore patients who;

* Consented to inclusion in the cohort study,
* Declined to enter into the cohort,
* Consented to inclusion in the cohort initially but who subsequently requested to leave the cohort

Structured thematic interviews will be conducted by the researchers who will follow the Interview Questionnaire Template. The interviews will be recorded and transcribed in house before analysis and theme-based extraction of the reasons behind men's

The opinions of healthcare professionals who regularly look after men with prostate cancer will be sought through conducting semi-structured interviews that focus on ethics, implementation, practicality and efficiency of PROSPECT. There will be a different Interview Questionnaire Template for interviews with healthcare professionals.

Imperial Clinical Trials Unit (ICTU)

Wellcome Trust

Imperial College London

Skin and Connective Tissue Diseases

Wounds and Injuries

Breast Neoplasms

Radiation Injuries

Breast Diseases

Skin Diseases

Hyperbaric oxygen therapy consists of 30-40 treatment sessions (1 session per day during 5 days per week). During the hyperbaric oxygen (HBO) sessions the pressure will be raised to 2.4 atmospheres absolute in a hyperbaric chamber and patients breath in 100% oxygen during 4 times 20 minutes.

Usual care may consist of physiotherapy, analgetics, edema therapy

Hyperbaric oxygen therapy in a multiperson hyperbaric oxygen chamber. Standard hyperbaric oxygen therapy provided as reimbursed by insurers.

Hyperbaric oxygen therapy

Helena M Verkooijen, MD, PhD

The "Hyperbaric OxygeN therapy on brEast cancer patients with late radiation toxicity" (HONEY) trial aims to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the trial within cohorts (TwiCs) design.

Objective: The aim of this study is to assess whether HBOT reduces pain, and improves physical functioning and QoL in breast cancer patients with late radiation toxicity.

Study design: Randomized controlled trial, nested within the prospective UMBRELLA breast cancer cohort according to the TWiC's design. UMBRELLA is a prospective cohort study including all breast cancer patients visiting the University Medical Center (UMC) Utrecht department of Radiotherapy. In total 120 patients will be randomized in a ratio of 2:1.

Study population: Breast cancer patients participating in the UMBRELLA cohort who have given informed consent to be invited for future research (e.g. cmRCT's), and who have reported symptoms of late radiation toxicity.

Intervention: Eligible patients will be referred to the HBO center for a standard HBO treatment. HBOT consists of 30-40 treatment sessions (1 session per day during 5 days per week). During the hyperbaric oxygen (HBO) sessions patients breath in 100% oxygen during 4 times 20 minutes in a hyperbaric chamber.

Main study parameters/endpoints: The primary endpoint of this study is patient reported breast/chest wall pain. Secondary endpoints are: physical functioning, QoL cosmetic outcome, physician reported pain and radiation toxicity (according to CTCAE criteria version 4.03, tissue oxygenation previous to HBOT and after HBOT and side-effects of HBOT.

The Effect of Hyperbaric OxygeN Therapy on brEast Cancer Patients With Late Radiation toxicitY - UMBRELLA HONEY Trial

The Effect of Hyperbaric Oxygen Therapy on Breast Cancer Patients With Late Radiation Toxicity

The primary endpoint of this study is the difference in proportion of patient-reported breast/chest wall pain grade 3-4 between control and intervention group. Pain is assessed by means of the EORTC QLQ-BR23 questionnaire on a 4-point Likert scale. At baseline all patients have a pain score of 3 or 4 (see inclusion criteria). The proportion of patients with 3-4 at 6 months will be compared between intervention and control group. A higher score indicates more pain.

Quality of life (QoL) measured by European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30. QoL will be scored on a scale of 0-100. A higher score indicates a better outcome. Change in score between baseline and 6 months will be compared between intervention and control group.

Late radiation toxicity is assessed by means of a late radiation toxicity questionnaire (ability to move the arm, (breast) edema, fibrosis) in both control group and intervention group. Change in patient reported late radiation toxicity will be compared between intervention and control group. Late radiation toxicity will be assessed on a 4-point Likert scale. A higher score indicates worse outcomes.

Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 only in intervention group. CTCAE criteria are assessed on a scale of 0-3.

Assessed by means of the breast cancer questionnaire (BREAST-Q) in both control group and intervention group. BREAST-Q scores will be assessed using the BREAST-Q scoring tables.

Reported by means of medical photograph (cosmetic outcome judged by group of experts and "Breast Cancer Conservative Treatment - cosmetic results" (BCCT.core) program) and with physical examination using the Patient and Observer Scar Assessment Scale (POSAS) score v2.0. Physician reported cosmetic outcome will only be assessed in the intervention group.

Side effects of HBOT will be monitored using the MacFie classification only in the intervention group.

Skin oxygenation will be measured prior to HBOT and after last treatment session using transcutaneous oxygen measurement. The contralateral breast will be used as a reference. Only assessed in the intervention group.

UMC Utrecht

Prof. dr.

Symptoms and General Pathology

Digestive System Diseases

Behaviors and Mental Disorders

Syndrome

Low Anterior Resection Syndrome

Colonic Diseases

Intestinal Diseases

Gastrointestinal Diseases

Rectal Diseases

Postoperative Complications

Quality of Life

Herbal and Botanical

All Drugs and Chemicals

Cola

Patients who have undergone colonic resection for colorectal cancer in the last 10 years. Patient reported outcome measures collected at 3-monthly intervals.

Cohort participants who are identified as having 'major LARS' at any point are treated with Optimised Conservative Managements, consisting of medication, dietary advice, lifestyle advice and physiotherapy.

Cohort participants who are identified as having 'major LARS' at any point are treated with Trans-anal irrigation, in additional to receiving optimised conservative management. Transanal irrigation system will be decided upon with the participant and procured locally.

Cohort participants who are identified as having 'major LARS' at any point are treated with Sacral Neuromodulation system, in addition to receiving optimised conservative management. Medtronic Interstim system will be used.

Sacral Neuromodulation group will include up-to 20 patients with major LARS. Medtronic Interstim system will be used, including 2 week trial device.

Sacral NeuroModulation

Trans-Anal irrigation group will include up-to 20 patients with major LARS. Specific system will be agreed with the patient, depending on eligibility and preference.

Trans-Anal Irrigation

Optimised conservative management will include up-to 30 patients with major LARS. They will be provided with a resource booklet which includes dietary and lifestyle advice as well as exercises that can be undertaken independently.

Optimised Conservative Management

Julie A Cornish

Currently, no standard exists for the treatment and management of Low Anterior Resection Syndrome (LARS)- a common disorder that affects patients who have had part of their bowel removed due to colorectal cancer. Decisions about which treatment patients receive is at the discretion of local clinicians, leading to a variation in both clinical practice and the outcomes of these patients. As a result, there is a need for research to assess what treatments are most effective in treating or managing LARS to establish a consensus and develop a treatment pathway in the UK. This study aims to assess the feasibility of undertaking such a trial utilising a novel 'trial within cohorts (TWiCs)' study design, with a view to informing the design of a full-scale trial.

Rectal cancer (cancer of the lower part of the bowel) is one of the most prevalent forms of cancer, and affects approximately 14,000 people each year in the UK. The treatment for the majority of these patients is surgical removal of the affected part of the bowel, following which the bowel is joined back together. Some patients may also require chemotherapy and radiotherapy. One consequence of the treatment of bowel cancer is a severe form of bowel dysfunction called major Low Anterior Resection Syndrome (LARS).

LARS is a constellation of symptoms including incontinence to stool, urgency and frequency of bowel movements and incomplete evacuation; it is diagnosed using the LARS scoring tool. Major LARS can have a huge impact on the persons quality of life resulting in social isolation. Currently there are no guidelines for the management of LARS. The aim of the POLARiS study is to investigate three different treatments for major LARS; optimised conservative management, a combination of diet, medication, bowel retraining and pelvic floor exercises; transanal irrigation, washing out the back passage of stool with warmed water; and sacral nerve stimulation where an electrical impulse delivered to the sacral nerve to help with bowel function. This feasibility study aims to test the study design ahead of a larger fully powered randomised control trial. The study will firstly recruit any consenting adult who has had surgery for rectal cancer (called an anterior resection) and who does not have a stoma, into a cohort and then follow up those patients every 3 months with bowel function and quality of life assessments. Any patient found to have major LARS (LARS score over 30) will be invited into the randomised control trial where the above three treatments will be tested.

Pathway of Low Anterior Resection Syndrome Relief After Surgery: a Feasibility Study

A Feasibility, Multicentre Randomised Control Trial Assessing the Treatment Options for Patient With Major Low Anterior Resection Syndrome to Establish a Pathway Of Low Anterior Resection Syndrome Relief After Surgery

The total number of participants enrolled into the study over the recruitment period.

We will record basic demographics, medical history and prevalence of relative symptoms of participants enrolled in the cohort study to describe the characteristics of no- minor- and major- LARS patients

The number of participants in the cohort that meet the criteria for 'major low anterior resection syndrome (LARS)', as measured by the LARS scoring tool. LARS scoring tool produces a score from 0 - 42, which represents the severity of symptoms, where 0 is least severe and 42 is most severe. Score =\>30 is considered 'major LARS'. LARS score will be measured at 5 times at 3-monthly intervals over 12 months.

The time (in months) from resection surgery to onset of 'major LARS' symptoms, as reported by the LARS scoring tool.

The time (in months) from completing radiotherapy treatment to onset of 'major LARS' symptoms, as reported by the LARS scoring tool.

The total number of cohort participants that are enrolled into the randomised trial part of the study, over the recruitment period.

The proportion of randomised participants that meet the criteria for, and are allocated to, each of the three trial arms (transanal irrigation; sacral neuromodulation; optimised conservative management).

Where possible, we will record patient's previous treatments and interactions with health services in relation to their bowel dysfunction symptoms. This will be used to describe the variation in UK clinical practice in terms of diagnosis, management and treatment pathways.

The proportion of participants that complete and return follow-up questionnaires (four questionnaires at 3-month intervals).

The proportion of patients that continue to receive the treatment assigned to them at the end of the follow-up period.

LARS score will be measured at 5 time points (at 3-monthly intervals from baseline to 12 months) to assess severity of bowel dysfunction. Self-reported by participants using the LARS scoring tool (min 0, max 42) where higher score denotes greater severity of symptoms.

Patient-reported quality of life will be measured using the EuroQuol 5-Dimension Health-related Quality of Life instrument (5-level) (EQ-5D-5L) at 5 time-points (3-monthly intervals from baseline to 12 months). Quality of life total score will be calculated (min 5; max 25), where reduction in total score represents improvement in quality of life.

Quality of life will be self-reported by participants using the European Organisation for Research and Treatment of Cancer Colorectal Quality of Life Questionnaire (EORTC QLQ-CR29) at 5 time-points (3-monthly intervals, from baseline to 12 months). Quality of life total score will be calculated (min 26; max 104) where reduction in total score represents improvement in quality of life.

Quality of life will be self-reported by participants using the European Organisation for Research and Treatment of Cancer Cancer Quality of Life Questionnaire (EORTC QLQ-C30). This will be recorded at 5 time-points (3-monthly intervals, from baseline to 12 months). Total score will be calculated (min 30; max 128), where reduction in total score represents improvement in quality of life.

Measure Yourself Medical Outcome Profile (MYMOP) 2 will be used to record patient-reported medical outcome profile at 5 time-points (3-montly intervals from baseline to 12 months). Change in patient-reported severity (min 0; max 5) will be measured, where change ≥ 1.0 is considered clinically significant.

We will record any adverse events reported by randomised patients in relation to each of the treatments they receive, which impairs their adherence to the study protocol, treatment programme or safety.

Treatments offered to manage individual patient's LARS symptoms will be recorded, along with duration of treatment and reasons for stopping. This will be used to support the description of standard care variation and patient characteristics.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PROState Pathway Embedded Comparative Trial	NCT04400656	Prostate Cancer Non-metastatic ... Metastatic Pros... Prostate Adenoc... Metastatic Pros... Prostate Cancer...		18 Years -	Imperial College London
The Effect of Hyperbaric OxygeN Therapy on brEast Cancer Patients With Late Radiation toxicitY - UMBRELLA HONEY Trial	NCT04193722	Breast Cancer Radiation Toxic...	Hyperbaric oxyg...	18 Years -	UMC Utrecht
The Effect of Hyperbaric OxygeN Therapy on brEast Cancer Patients With Late Radiation toxicitY - UMBRELLA HONEY Trial	NCT04193722	Breast Cancer Radiation Toxic...	Hyperbaric oxyg...	18 Years -	UMC Utrecht
The Effect of Hyperbaric OxygeN Therapy on brEast Cancer Patients With Late Radiation toxicitY - UMBRELLA HONEY Trial	NCT04193722	Breast Cancer Radiation Toxic...	Hyperbaric oxyg...	18 Years -	UMC Utrecht
Pathway of Low Anterior Resection Syndrome Relief After Surgery: a Feasibility Study	NCT05319054	Low Anterior Re...	Sacral NeuroMod... Trans-Anal Irri... Optimised Conse...	18 Years -	Cardiff and Vale University Health Board

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