E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Colorectal Cancer Prevention in Lynch syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Colorectal Cancer Prevention in Lynch syndrome |
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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 | LLT |
E.1.2 | Classification code | 10051981 |
E.1.2 | Term | Lynch syndrome |
E.1.2 | System Organ Class | 100000004850 |
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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 objective of the study is to test whether 5-ASA (low- and high-dose together) reduces the occurrence of any colorectal neoplasia, both benign or malignant tumors, compared to placebo in LS patients as detected by any colonoscopy until the end of treatment and end of study. |
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E.2.2 | Secondary objectives of the trial |
• To test whether 5-ASA reduces the number of any colorectal neoplasia, both benign and malignant tumors, (tumor multiplicity) and tumor progression to placebo in LS patients at defined time points. Advanced adenomas are defined by a diameter above 1 cm villous or tubulovillous histology or high grade dysplasia. • To investigate if differences between 5-ASA effects and placebo effects on the occurrence of colorectal neoplasia, tumor multiplicity or tumor progression depend on the history of colorectal cancer, sex and patients age (LS patients below 45 years of age or 45 years of age and older). • To investigate differences between low and high dose 5-ASA with respect to the occurrence of colorectal neoplasia, to tumor multiplicity and tumor progression. • To determine the safety concerning 5-ASA in LS patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Proven tumor-free (including patients in which the polyps are removed endoscopically) carriers of a germline pathologic mutation on one of the MMR genes including MLH1, MSH2 (including EpCAM) and MSH6 • Male or female subjects with the age > 25 years • Females who have been post-menopausal more than one (1) year or females of childbearing potential using a highly efficient method of contraception with less than 1% failure rate (i.e. oral hormonal contraceptives, hormone implants, hormone injections, sterilization, hormonal or copper intrauterine device, sterilized/vasectomized partner, or diaphragm in combination with a condom, spermicide or birth control pills) or should agree to abstain from heterosexual activity during treatment period. Females of childbearing potential must have a negative pregnancy test at screening and before randomization. • Signed written informed consent prior to inclusion in the study
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E.4 | Principal exclusion criteria |
• Presence of colorectal endoscopically non-removable benign neoplasia (patient can be included if the adenoma is removed) • Carriers of germline mutations in PMS2 • Patients with history of stage 3 and 4 colorectal cancer (CRC) are excluded • Presence of metastatic disease • Regular use of acetylsalicylic acid (ASA or aspirin): daily use of ≥100mg in more than 3 continuous months within the last year • Regular use of NSAIDs or COX-2 inhibitors: daily use in more than 3 continuous months within the last year • Hypersensitivity to 5-ASA • Patients after total or subtotal colectomy • Colorectal surgery within the previous 6 months • Unwillingness to participate or who is considered incompetent to give an informed consent • Pregnant or breastfeeding women • Participation in another clinical study investigating another IMP within 3 months prior to screening • Renal insufficiency (GFR <30ml/min/1.73m2) • Severe liver disease or liver failure (elevation of liver enzymes above 3xULN) • Current or history of serious psychiatric disorder or alcohol/drug abuse that in the opinion of the investigator may impact the assessment of IMP safety andefficacy or protocol adherence • Prior history of myocarditis or pericarditis. Other severe acute or chronic medical condition (such as severe chronic lung (COPD, including asthma), kidney or heart diseases) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or ability to comply with study procedures, IMP administration and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
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E.5 End points |
E.5.1 | Primary end point(s) |
Occurrence of any colorectal neoplasia (both benign and malignant tumors) between groups is described by absolute frequencies and percentages with 95 % confidence intervals. A logistic regression is used to assess differences between active treatment and placebo for the occurrence of any colorectal neoplasia, adjusted for country and history of cancer before randomization. Treatment effects are assessed by odds-ratios and corresponding 95 % confidence intervals.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
active treatment period and follow up period |
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E.5.2 | Secondary end point(s) |
• The number of colorectal neoplasia (both benign and malignant tumors)per patient will be tested between groups by an analysis of variance, adjusting for country and history of cancer before randomization. In case of non-normally distributed residuals a suitable transformation to achieve normal distribution is considered. • The tumor progress in the 4 ordered stages will be tested between groups by a chi-square trend test stratified for country and history of cancer before randomization and modelled by an ordinal logistic regression. • The dependence of treatment effects on history of colorectal cancer, sex and patients age (<45 years and ≥45 years) will be assessed by modelling interactions between these factors and treatment in the corresponding regression models. • Differences between high and low dose ASA for the occurrence of colorectal neoplasia, tumor multiplicity and tumor progression will be analysed by the same methods as for the comparison between ASA and placebo. • Safety data are described and compared between groups in an exploratory manner. All tests are two-sided and a significance level of 5 % is used. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
active treatment period and follow up period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Austria |
Germany |
Israel |
Netherlands |
Poland |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
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 | 6 |
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 |