Condition category
Cancer
Date applied
08/01/2020
Date assigned
11/05/2020
Last edited
11/05/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Public

Primary contact

Dr Sacha Howell

ORCID ID

Contact details

Division of Cancer Sciences
Faculty of Biology
Medicine and Health
The University of Manchester
Oglesby Cancer Research Centre
555 Wilmslow Road
Mancester
M20 4GJ
United Kingdom
+44 (0)161 4468347
sacha.howell@christie.nhs.uk

Type

Public

Additional contact

Prof Emma Crosbie

ORCID ID

Contact details

Division of Cancer Sciences
Faculty of Biology
Medicine and Health
University of Manchester
5th Floor – Research
St. Mary’s Hospital
Oxford Road
Manchester
M13 9WL
United Kingdom
+44 (0)161 7016942
emma.crosbie@manchester.ac.uk

Type

Scientific

Additional contact

Prof Robert Clarke

ORCID ID

Contact details

The Oglesby Cancer Research Centre
University of Manchester
555 Wilmslow Road
Manchester
M20 4GJ
United Kingdom
+44 (0)161 306 0802
robert.clarke@manchester.ac.uk

Type

Public

Additional contact

Dr MIchelle Harvie

ORCID ID

Contact details

Nightingale and Prevent Breast Cancer Research Centre
Manchester University Hospital NHS Foundation Trust
Southmoor Road
Manchester
M23 9LT
United Kingdom
+44 (0)161 291 4410
michelle.harvie@manchester.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

B00754, CPMS 44943, IRAS 274621

Study information

Scientific title

Defining the feasibility and molecular impact of total diet replacement for the prevention of breast and endometrial cancer

Acronym

ProBE-TDR

Study hypothesis

To determine the effects of 12+/- 4 weeks of Total Diet Replacement (TDR) on cancer risk markers in the breast and endometrium of women at increased risk of breast and/or endometrial cancer as compared to a normal diet control group

Ethics approval

Approval pending, North West Preston Regional Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8056; nrescommittee.northwest-preston@nhs.net), ref: 20/NW/0095

Study design

Interventional randomized controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Community

Trial type

Prevention

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Cancer prevention

Intervention

Women will either be approached in clinics or by invitation through mailshot from the Nightingale Family History clinic. Posters will also be placed in clinics and staff invited to join if they fulfil eligibility criteria. Women will either be sent or handed the PIS and will have at least 24 hours to consider whether they wish to participate. If so they will sign informed consent form with an investigator and commence screening.

Screening will consist of measurement of height and weight to calculate BMI, the trial of an Optifast® drink in clinic, unless previously tried and exclusion of pregnancy through urine pregnancy test. Medical history will be taken and screening questionnaires completed: Alcohol Use Disorders Identification Test (AUDIT), Binge Eating Scale (BES), Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder scale (GAD-7).

If eligibility is confirmed baseline breast biopsy and blood sampling will be undertaken in the luteal phase (one week before expected menstruation) of the menstrual cycle, endometrial sampling will then be undertaken in the follicular phase (week following menstruation) of the menstrual cycle.

This study will involve 47 women. Thirty-one will be placed in an immediate 850 calorie diet group (group 1), and 16 will be placed in a delayed 850 calorie diet group (group 2).

Randomisation:
Via minimisation routine software package. Stratified based upon:
1. Above or below a BMI of 35 kg/m²
2. Above or below projected median lifetime risk of breast cancer ≥17% remaining lifetime risk (Tyrer-Cuzick score)

The delayed diet group will be asked to maintain their normal diet for the first three months until they have had their baseline and 3-month biopsies, before commencing the 12-month weight loss programme. This is to act as a control, to show us if the dietary intervention does indeed have any positive change.

These will be repeated after at least 8 weeks of total diet replacement (TDR) in the same phase of the menstrual cycle as the baseline tests. The control group will provide vital analytical controls for the TDR arm of the study.

Participants will remain on the TDR until they have undergone their second breast and endometrial biopsies (with blood tests again at the time of second breast biopsy) which will be undertaken after 12 +/-4 weeks of TDR.

Once this is complete, the TDR group will move into diet reintroduction over a 4 week period, gradually increasing daily calorie intake to 1500 kcal/day. This will be maintained then for 8 months, following a Mediterranean style diet. A structured exercise programme will be introduced alongside.

The control arm will move onto 12 weeks of TDR after the initial 12 week control phase and then move into the 9 month diet reintroduction/weight maintenance/exercise programme.

Blood and urine tests will be repeated at 3, 6 and 9 months after the second biopsies. At the same time the women will be asked to complete PROMs to evaluate quality of life, levels of anxiety and depression and also self efficacy and self satisfaction.

The 12-month weight loss programme
This has three diet phases:
Phase 1: 3 months of an 850-calorie total diet replacement using Optifast® liquid meal replacements and 8 portions of vegetables each day. Optifast® ready to drink shakes are nutritionally complete and are delivered free to the participants' homes. They are available in a range of flavours but are not suitable for anyone with allergies to milk, shellfish and soya.

Phase 2: 4 weeks of a food reintroduction with a progressively increased calorie intake food-based diet (1000–1500 calories/day).

Phase 3: The remainder of the 12-month study period involves a food-based calorie-controlled healthy Mediterranean diet aimed at either further weight loss or weight maintenance if participants have reached participants weight loss goal. A Mediterranean diet includes low-fat meats, fish, fruit, vegetables, wholegrain starchy foods (e.g. wholegrain bread and cereals), beans, pulses, low-fat dairy products and healthy fats found in foods like nuts, seeds and olive/rapeseed oil. If participants gain weight in this time participants have the option to return to the 850-calorie total diet replacement for a short time to help participants lose the weight they have gained.

Physical Activity
Participants will be encouraged to do some simple specific muscle strengthening exercises 3 times a week during phase 1 of the diet. The remainder of the programme includes the 3 weekly muscle strengthening exercises as well as 150-300 minutes of moderate-intensity physical activity a week (i.e. 30-60 minutes 5 times per week).

Advice and support
All participants will receive personalised one to one advice and support from a specialist dietitian throughout the programme. This will be provided by a mixture of face to face and/or remote smartphone/tablet telephone/text reviews using a specialist health care smartphone/tablet app (Oviva app). The app also allows participants to record participants' weight, food intake and any physical activity participants have done and send messages to the dietitian. Participants may also be offered professional support with the emotional and behavioural aspects of weight loss from a clinical psychologist. Some medications may need to be adjusted when following these diets (i.e. blood pressure medications). Any changes to medicines will be advised from the doctors working on the study.

Intervention type

Mixed

Phase

Drug names

Primary outcome measure

Epithelial cell proliferation (Ki67) in the breast and endometrium at baseline and 12 +/- 4 weeks measured using biopsy

Secondary outcome measures

1. Cancer risk biomarkers; including fasting insulin, lipids, glucose, inflammatory markers inc. CRP, leptin, adiponectin, methylation, insulin like growth factor -1 (IGF-1) measured using blood tests at baseline, 3, 6, 9, and 12 months
2. Uptake, retention and adherence to TDR and 12-month weight loss programme measured using patient records at end of study
3. Weight (kg) measured at baseline, 3, 6, 9, and 12 months
4. Body fat measured using bioelectrical impedance at baseline, 3, 6, 9, and 12 months
5. Fat free mass (kg) measured using bioelectrical impedance at baseline, 3, 6, 9, and 12 months
6. Waist and hip circumference measured at baseline, 3, 6, 9, and 12 months
7. Blood and tissue markers of breast and endometrial cancer and cardiovascular disease measured using a blood test and biopsy at baseline, 3, 6, 9, and 12 months
8. Quality of life (anxiety, depression, quality of life, self-efficacy, self-satisfaction with weight loss during the programme measured using: Generalised Anxiety Disorder-7 [GAD-7] scale, Participant Health Questionnaire-9 [PHQ-9], EQ-5D-3L, Weight Efficacy Lifestyle Questionnaire Short Form [WEL-SF], Obesity and Weight Loss Quality of Life [OWL-QOL] baseline, 3 months, 6 months, 9 months, 12 months, 15 months (control group only)
9. Adverse effects measured using patient records at end of study
10. Diet measured using a 7 day food diary questionnaire at baseline, 3 months, 6 months, 9 months, 12 months, 15 months (control group only)
11. Physical activity behaviours measured using IPAQ at baseline, 3 months, 6 months, 9 months, 12 months, 15 months (control group only)
12. Fidelity of delivery of the 12-month TDR and weight loss programme measured using adherence (7 day food diary)/compliance (weight loss) /loss to follow-up - evaluated at close of trial

Exploratory outcome measures:
13. Markers of the cellular hierarchy in breast +/- endometrium measured using dual immunofluorescence/FACS sorting, using paired biopsy samples from months 0 and 3
14. Transcriptional and proteomic changes measured using RNAseq/qRT-PCR, using paired biopsy samples from months 0 and 3
15. Mammographic density of the breast assessed at baseline and trial exit, scored using Bi-RADS

Overall trial start date

01/10/2019

Overall trial end date

01/11/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Women aged 30-50 years
2. BMI ≥30 kg/m2 or ≥27.5 mg/m2 in Asian and South Asian women
3. Pre-menopausal, with regular menstrual cycles (cycle length 21 to 40 days)
4. Have access to and be able to use a smartphone or tablet running iOS or Android and be able to use the Oviva app OR access and ability to use a telephone
5. Willing to follow the TDR using Optifast® drinks and have previously sampled them
6. Agree to maintain non-hormonal contraception (barrier or abstinence) until both sets of biopsies are complete and must have a negative urine pregnancy test at screening.
7. Women with Type 2 Diabetes Mellitus on diet +/- Metformin control can be included.
8. Must be able to read, understand and communicate in English

Participant type

Healthy volunteer

Age group

Adult

Gender

Female

Target number of participants

47

Participant exclusion criteria

1. Prior history of breast or endometrial cancer or preinvasive breast disease (Ductal Carcinoma in situ (DCiS), Lobular Carcinoma in situ (LCiS), Atypical Ductal Hyperplasia (ADH), Atypical Lobular Hyperplasia (ALH))
2. Any hormonal contraceptive (including progestin releasing IUCD, such as Mirena®) in the 12 weeks prior to study entry
3. Preventative Tamoxifen therapy within the last 6 months
4. Prior anti-progestin therapy (e.g. Ulipristal Acetate) within the last 6 months
5. Carrier of the BRCA 1 or 2 gene
6. Confirmed pregnant via a pregnancy test at screening, planning pregnancy in the next 12 months, or currently breast feeding
7. Taking prohibited medications (see Appendix 1) including warfarin or novel anticoagulants (NOAC), low molecular weight heparin (LMWH) or equivalent anti-coagulants, anti-psychotic medication, anti-diabetic medication other than Metformin
8. Currently on treatment with Orlistat or other pharmacological treatments for weight loss
9. Chronic use of steroids (more than 20mg daily of prednisolone or its equivalent)
10. Previously had bariatric surgery for weight loss including gastric bypass and sleeve gastrectomy
11. Hypersensitivity to any of the ingredients of Optifast® e.g. lactose intolerance
12. Allergies to the ingredients of Optifast® e.g. fish, milk, soy
13. Substance abuse or harmful alcohol use as indicated by a score of 16 or above on the Alcohol Use Disorders Identification Test (AUDIT)
14. Diagnosed with an eating disorder, or patients with severe binge eating assessed by a score of 27 or more on the Binge Eating Scale (BES)
15. Severe depression assessed by a score of 15 or more on the Patient Health Questionnaire-9 (PHQ-9) questionnaire.
16. Severe anxiety assessed by a score of 15 or more on the General Anxiety Disorder (GAD-7) questionnaire.
17. Psychiatric or physical comorbidity or scheduled for major surgery, which in the opinion of the treating medical physician, or the Chief Investigator (CI), would compromise their safety or adherence to the study
18. Lack capacity or are unable to read or understand written or verbal instructions in English

Recruitment start date

01/08/2020

Recruitment end date

28/02/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Manchester University NHS Foundation Trust
Cobbett House Oxford Road
Manchester
M13 9WL
United Kingdom

Sponsor information

Organisation

Manchester University NHS Foundation Trust

Sponsor details

First floor
Nowgen Building
Grafton Street
Manchester
M13 9WU
United Kingdom
+44 (0)161 701 5057
research.sponsor@mft.nhs.uk

Sponsor type

Hospital/treatment centre

Website

https://mft.nhs.uk/

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Trial protocol publication before end of recruitment. Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement:
All data generated or analysed during this study will be included in the subsequent results publication

Intention to publish date

01/11/2024

Participant level data

Other

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

17/01/2020: Trial’s existence confirmed by The University of Manchester