| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer (breast, colorectal, gastro-oesophageal and prostate) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancers of the breast, bowel, stomach, oesophagus (food pipe) and prostate |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary aim of this study is to assess whether regular aspirin use after completion of primary treatment (given with curative intent) for common non-metastatic solid tumours prevents tumour recurrence and prolongs survival. The question will be addressed in four common cancers (breast, colorectal, gastro-oesophageal and prostate). |
|
| E.2.2 | Secondary objectives of the trial |
- To demonstrate that the implementation of the intervention in Add-Aspirin is feasible in a range of settings.
- To collect data and assess the potential overall health benefits of regular aspirin, including collecting data on cardiovascular outcomes, that can complement other data sets and inform guidelines on the use of aspirin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants must not meet any of the common or their tumour-specific exclusion criteria.
COMMON INCLUSION CRITERIA
1. Written informed consent
2. WHO performance status 0, 1 or 2
3. Previous or current participants of other primary treatment trials if agreed in advance between trials
4. No clinical or radiological evidence of residual or distant disease
BREAST COHORT INCLUSION CRITERIA
1. Men or women with histologically confirmed invasive breast cancer.
2. Patients have undergone complete primary invasive tumour excision with clear radial margins as judged by the multidisciplinary team.
3. Surgical staging of the axilla must have been undertaken by sentinel node biopsy, axillary sampling or dissection.
4. In those patients with a positive sentinel node biopsy:
a. If 1, 2 or 3 nodes are positive, subsequent management of the axilla (with surgery, radiotherapy or no further
intervention) should follow institutional policy.
b. If 4 or more nodes are involved, patients must have undergone completion axillary node dissection.
5. Radiotherapy:
a. Patients who have undergone breast-conserving surgery should receive adjuvant radiotherapy.
b. Patients who have undergone mastectomy should receive radiotherapy if they have more than 3 axillary lymph nodes involved.
c. Patients who have undergone mastectomy and have T3 tumours and/or 1, 2 or 3 involved lymph nodes may (or not) receive radiation as per local practice.
6. Final histology must fall within at least one of these groups:
a. For patients not receiving neoadjuvant chemotherapy:
i. Node positive,
ii. Node negative with high-risk features, defined as two or more of:
ER negative (Allred score <3/8 or negative according to institutional criteria)
HER2 positive
Grade 3
Lymphovascular invasion present
Age less than 35
Oncotype Dx score of >25
Prosignia score (PAM50) of >60
-Patients are permitted to have had neoadjuvant endocrine therapy for up to 6 months, as long as final surgical
pathology falls within one of the above two groups.
-In the above definitions patients with micrometastases should be regarded as node positive. Patients with isolated
tumour cells should be regarded as node negative.
b. Patients who have received neo-adjuvant chemotherapy or radiotherapy must fall into one of the following 3 categories:
i. Hormone receptor negative and HER2 negative tumour AND has not achieved a complete pathological response, or,
ii. A HER2 positive tumour (any hormone receptor status) AND not achieved a pathological complete response,
iii. A hormone receptor positive, HER2 negative tumour which is grade 3 AND has not achieved a pathological
complete response.
7. Patients who received standard neo-adjuvant and/or adjuvant chemotherapy or radiotherapy are eligible.
8. Known HER2 and ER status.
COLORECTAL COHORT INCLUSION CRITERIA
1. Histologically confirmed stage II or III adenocarcinoma of the colon or rectum and patients who have undergone
resection of liver metastases with clear margins and no residual metastatic disease
2. Patients with synchronous tumours if one of the tumours is at least stage II or III
3. Serum CEA ideally ≤1.5 x upper limit of normal
4. Have undergone curative (R0) resection with clear margins
GASTRO-OESOPHAGEAL COHORT INCLUSION CRITERIA
1. Patients with histologically confirmed adenocarcinoma, adenosquamous carcinoma or squamous cell cancer of the oesophagus, gastro-oesophageal junction or stomach
2.Patients who have undergone surgery with curative intent must have either:
a.A curative (R0) resection with clear margins (margin ≥1mmor as judged by the multidisciplinary team).
b.An R1 resection with circumferential margin microscopically positive within 1mm in patients who have undergone an oesophagogectomy.
PROSTATE COHORT INCLUSION CRITERIA
1. Men with histologically confirmed node negative non-metastatic adenocarcinoma of the prostate
2. Have undergone curative treatment, either:
a. Radical prostatectomy
b. Radical RT
c. Salvage RT (following rise in PSA after prostatectomy)
3. Intermediate or high risk according to D’Amico classification
Treatment pathway specific inclusion criteria:
(a) Prostatectomy patients
Open, laparoscopic or robotic radical prostatectomy
Men treated with immediate adjuvant RT
Men receiving adjuvant hormone therapy planned for a maximum duration of 3 yrs
Men randomised to any of the 3 arms of RADICALS HD are eligible
(b) Radical RT patients
Men receiving neo-adjuvant and/or adjuvant hormone therapy (LHRH agonists, LHRH antagonists, bicalutamide monotherapy) planned for a maximum duration of three years are eligible, and this treatment may be ongoing at the time of registration in Add-Aspirin. |
|
| E.4 | Principal exclusion criteria |
Participants must not meet any of the common or their tumour-specific exclusion criteria.
COMMON EXCLUSION CRITERIA
1. Current or previous regular use of aspirin (at any dose) or current use of another NSAID for any indication.
2. A past history of adverse reaction or hypersensitivity to NSAIDs, celecoxib, aspirin or other salicylates or sulphonamides, including asthma, that is exacerbated by use of NSAIDs.
3. Current use of anti-coagulants.
4. Current or long-term use of oral corticosteroids. The treating physician should make the clinical decision whether a patient has been exposed to long-term therapy.
5. Active or previous peptic ulceration or gastrointestinal bleeding within the last year, except where the cause of
bleeding has been surgically removed.
6. Active or previous history of inflammatory bowel disease.
7. History of moderate or severe renal impairment, with eGFR<45ml/min/1.73m2.
8. Previous invasive or non-invasive malignancy except:
- DCIS where treatment consisted of resection alone.
- Prostate cancer initially treated with prostatectomy and now being treated with salvage radiotherapy following a rise
in PSA.
- Cervical carcinoma in situ where treatment consisted of resection alone.
- Basal cell carcinoma where treatment consisted of resection alone or radiotherapy.
- Superficial bladder carcinoma where treatment consisted of resection alone.
- Other cancers where the patient has been disease-free for ≥15 years.
- Other cancers with very low potential for recurrence can be discussed with MRC CTU at UCL where eligibility will be
considered on an individual basis.
9. Any other physical condition which is associated with increased risk of aspirin-related morbidity or, in the opinion of
the Investigator, makes the patient unsuitable for the trial, including but not limited to severe asthma, haemophilia and
other bleeding diatheses, macular degeneration and patients with a high-risk of mortality from another cause within
the trial treatment period.
10. Known glucose-6-phosphate dehydrogenase deficiency.
11. Known lactose intolerance
12. LFTs greater than 1.5x the upper limit of normal unless agreed with TMG.
13. Anticipated difficulties in complying with trial treatment or follow-up schedules.
14. <16 years old.
15. Participants in other treatment trials where this has not been agreed in advance by both trial teams.
16. Pregnant or breast feeding, or intending to become pregnant or breast feed during the trial treatment period.
BREAST COHORT EXCLUSION CRITERIA
1. Metastatic or bilateral breast cancer.
COLORECTAL COHORT EXCLUSION CRITERIA
1. Proven (or clinically suspected) metastatic disease (patients who have undergone resection of liver metastases
with clear margins and no residual metastatic disease are eligible).
GASTRO-OESOPHAGEAL COHORT EXCLUSION CRITERIA
1. Proven (or clinically suspected) metastatic disease.
PROSTATE COHORT PARTICIPANT CRITERIA
1. Biopsy proven or radiologically suspected nodal involvement, or distant metastases from prostate cancer.
2. Adjuvant hormone therapy planned for >3 years.
3. Bilateral orchidectomy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary outcome measure for all participants is overall survival. There will also be separate co-primary
outcome measures for each of the cohorts:
Breast cancer: invasive disease-free survival
Colorectal cancer: disease-free survival
Gastro-oesophageal: overall survival
Prostate cancer: biochemical recurrence-free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For each cohort-specific comparison, the exact timing of analysis will be based on the number of primary outcome events that have been observed in the control arm, and this will be monitored by the Independent Data Monitoring Committee throughout the trial. The sample sizes needed to observe the required number of events are estimated based on anticipated recruitment rates (including allowance for slower accrual/participants having incomplete follow-up data).
Following the four cohort-specific analyses, a combined cohort analysis is planned. For the combined cohort analysis, the primary outcome measure will be time to death from any cause. Data collected during the trial period will be supplemented by long-term follow-up data from national registries and healthcare datasets. |
|
| E.5.2 | Secondary end point(s) |
There are a number of secondary outcome measures that are common to all the tumour site studies within Add-
Aspirin as well as some disease-specific outcomes.
All Tumour Types:
- Adherence
- Toxicity
- Serious haemorrhage
- Serious vascular events
- Thrombotic events
- Diabetes and associated complications
- Second malignancies
- Age-related macular degeneration (AMD)
- Cognitive assessment
- Dementia
Breast Cancer:
- Breast cancer-specific survival
- Bone metastases-free survival
- Invasive disease-free survival including DCIS (ductal carcinoma in situ) as an event
Colorectal:
- Colorectal cancer-specific survival
Gastro-oesophageal:
- Disease-free survival
Prostate:
- Prostate cancer-specific survival
- Time to initiation of salvage treatment
- Bone metastases-free survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary outcome measures will be analysed at the time of the primary cohort-specific analysis for each of the four cohorts, with the timing based on the observed numbers of primary outcome events as indicated above.
Secondary outcome measures will also be considered as part of the combined cohort analysis, for which the primary outcome measure will be time to death from any cause.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 133 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial will be when the last participant enrolled completes all follow-up, all available data have been obtained and the database has been locked. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 19 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 19 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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