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Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome (MesaCAPP)

Primary Purpose

Colorectal Cancer

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
mesalamine 2400 MG (5-ASA)
mesalamine 1200 MG
Placebo
Sponsored by
Christoph Gasche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Colorectal Cancer focused on measuring Lynch Syndrome, Chemoprevention, Mesalazine, 5-ASA

Eligibility Criteria

25 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

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

Sites / Locations

  • Department of Surgery, Medical University Vienna
  • HELIOS Universitätsklinikum Wuppertal, Zentrum für Hereditäre Tumorerkrankungen
  • Rabin Medical Center Beilinson Hospital Gastroenterology Department
  • Leiden University Medical Center
  • Department of Genetics and Pathomorphology of Pomeranian Medical University
  • Karolinska universitetsjukhuset, A6:00 Gastroenterologiskt öppenvårdscentrum, Mottagningen för ärftlig tarmcancer

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

2400 MG mesalamine (5-ASA) total

1200 MG mesalamine (5-ASA) total

Placebo

Arm Description

2400mg (1200mg mesalamine/1200mg) mesalamine once daily in the morning for the treatment phase of the study (24 months)

placebo/1200mg mesalamine once daily in the morning for the treatment phase of the study (24 months)

placebo/placebo once daily in the morning for the treatment phase of the study (24 months)

Outcomes

Primary Outcome Measures

Reduction in the occurrence of any colorectal neoplasia in LS patients
• 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.
Reduction in the occurrence of any colorectal neoplasia in LS patients
As above

Secondary Outcome Measures

Tumor multiplicity
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. It will be tested whether 5-ASA (low- and high-dose together) reduces the number of any colorectal neoplasia (both benign and malignant tumors; tumor multiplicity) compared to placebo in LS patients at the end of treatment and end of study. Advanced adenomas are defined by a diameter above 1 cm villous or tubulo-villous histology or high grade dysplasia. All tests are two-sided and a significance level of 5 % is used.
Tumor progress
The tumor progress in 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. It will be tested whether 5-ASA (low- and high-dose together) reduces tumor progression (compared 4 ordinal stages: no colorectal neoplasia / non-advanced adenoma / advanced adenoma / carcinoma) compared to placebo in LS patients at the end of treatment and end of study. Advanced adenomas are defined by a diameter above 1 cm villous or tubulo-villous histology or high grade dysplasia. All tests are two-sided and a significance level of 5 % is used.
Treatment effects
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. If differences between 5-ASA (low- and high-dose together) 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) will be investigated. All tests are two-sided and a significance level of 5 % is used.
High and low dose ASA
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 to investigate differences between low and high dose 5-ASA with respect to the occurrence of colorectal neoplasia, to tumor multiplicity and tumor progression. All tests are two-sided and a significance level of 5 % is used.
Significant findings & illnesses - adverse events
Safety data are described and compared between groups in an exploratory manner to determine the safety concerning 5-ASA in LS patient. Therefore significant findings/illnesses, reported after the start of the study and which meet the definition of an AE, will be recorded in the CRF. Intention to treat set: This analysis set includes subjects who were randomized (and received at least one dose study drug). This analysis set will be chosen for safety assessment. All tests are two-sided and a significance level of 5 % is used.

Full Information

First Posted
February 22, 2017
Last Updated
April 16, 2019
Sponsor
Christoph Gasche
Collaborators
Prof. Dr. Gabriela Möslein, Germany, Prof. Dr. Hans Vasen, The Netherlands, Prof. Dr. med. Jan Lubinski, Poland, Prof. Dr. med. Yaron Niv, Israel, Univ. Prof. Dr. Judith Karner-Hanusch, Austria, Ann-Sofie Backman, MD PhD, Sweden
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1. Study Identification

Unique Protocol Identification Number
NCT03070574
Brief Title
Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome
Acronym
MesaCAPP
Official Title
Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome - MesaCAPP
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Due to poor patient recruitment and insufficient financing.
Study Start Date
November 24, 2017 (Actual)
Primary Completion Date
April 10, 2019 (Actual)
Study Completion Date
April 10, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Christoph Gasche
Collaborators
Prof. Dr. Gabriela Möslein, Germany, Prof. Dr. Hans Vasen, The Netherlands, Prof. Dr. med. Jan Lubinski, Poland, Prof. Dr. med. Yaron Niv, Israel, Univ. Prof. Dr. Judith Karner-Hanusch, Austria, Ann-Sofie Backman, MD PhD, Sweden

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Multicenter, multinational, randomized, 3-arm, double-blind, phase II clinical study with 2400mg mesalamine, 1200mg mesalamine or placebo for prevention of colorectal neoplasia in Lynch Syndrome patients for 2 years.
Detailed Description
This is a multicenter, multinational, randomized, 3-arm, double-blind, phase II clinical study with 2400mg mesalamine (5-ASA), 1200mg mesalamine (5-ASA) or placebo in LS patients for a 2-year treatment. 540 tumor free carriers of a known genetic mutation in a major MMR gene (including patients in which the polyps are endoscopically removed) will be randomized 1:1:1 (180 each) to receive 2400mg mesalamine, 1200mg mesalamine or placebo. Patients will be identified through local or national registries and through collaboration with sites. Tumor free patients, assessed by white light high resolution colonoscopy, will be randomized to the study. A serum and stool sample will be taken to identify for mesalamine compliance and potential biomarkers. Biopsies of the normal tissue of ascending colon and rectum will be taken at the first and the last colonoscopy. The aim of the study is to investigate the effect of regular treatment with mesalamine (5-ASA) on the occurrence of any colorectal neoplasia, tumor multiplicity (the number of detected adenomas/carcinomas) and tumor progression in LS patients. A 50% reduction of the occurrence of colorectal neoplasia in mesalamine-treated patients is expected. Tumor multiplicity and tumor progression (severity of the neoplastic lesions) will be investigated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
Lynch Syndrome, Chemoprevention, Mesalazine, 5-ASA

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
2400 MG mesalamine (5-ASA) total
Arm Type
Experimental
Arm Description
2400mg (1200mg mesalamine/1200mg) mesalamine once daily in the morning for the treatment phase of the study (24 months)
Arm Title
1200 MG mesalamine (5-ASA) total
Arm Type
Experimental
Arm Description
placebo/1200mg mesalamine once daily in the morning for the treatment phase of the study (24 months)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
placebo/placebo once daily in the morning for the treatment phase of the study (24 months)
Intervention Type
Drug
Intervention Name(s)
mesalamine 2400 MG (5-ASA)
Other Intervention Name(s)
Mezavant, Mesalazine, 5-aminosalicylic acid (5-ASA)
Intervention Description
For this study IMP will be supplied as film-coated tablets packed in containers. Each patient will receive two different containers, each 1200mg of IMP (= 2400 mg), every 3 months (± 1 week), 100 tablets per container. The containers will be marked in different colours, to prevent the patients from taking two tablets from one container accidentally.
Intervention Type
Drug
Intervention Name(s)
mesalamine 1200 MG
Other Intervention Name(s)
Mezavant, Mesalazine, 5-aminosalicylic acid (5-ASA)
Intervention Description
For this study IMP will be supplied as film-coated tablets packed in containers. Each patient will receive two different containers of IMP (1200 mg/placebo) every 3 months (± 1 week), 100 tablets per container. The containers will be marked in different colours, to prevent the patients from taking two tablets from one container accidentally.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
For this study IMP will be supplied as film-coated tablets packed in containers. Each patient will receive two different containers of IMP (placebo/placebo) every 3 months (± 1 week), 100 tablets per container. The containers will be marked in different colours, to prevent the patients from taking two tablets from one container accidentally.
Primary Outcome Measure Information:
Title
Reduction in the occurrence of any colorectal neoplasia in LS patients
Description
• 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.
Time Frame
End of treatment at 24 months +/- 1 month
Title
Reduction in the occurrence of any colorectal neoplasia in LS patients
Description
As above
Time Frame
End of study at year 6 +/- 3 months
Secondary Outcome Measure Information:
Title
Tumor multiplicity
Description
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. It will be tested whether 5-ASA (low- and high-dose together) reduces the number of any colorectal neoplasia (both benign and malignant tumors; tumor multiplicity) compared to placebo in LS patients at the end of treatment and end of study. Advanced adenomas are defined by a diameter above 1 cm villous or tubulo-villous histology or high grade dysplasia. All tests are two-sided and a significance level of 5 % is used.
Time Frame
End of treatment at 24 months +/- 1 month
Title
Tumor progress
Description
The tumor progress in 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. It will be tested whether 5-ASA (low- and high-dose together) reduces tumor progression (compared 4 ordinal stages: no colorectal neoplasia / non-advanced adenoma / advanced adenoma / carcinoma) compared to placebo in LS patients at the end of treatment and end of study. Advanced adenomas are defined by a diameter above 1 cm villous or tubulo-villous histology or high grade dysplasia. All tests are two-sided and a significance level of 5 % is used.
Time Frame
End of treatment at 24 months +/- 1 month
Title
Treatment effects
Description
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. If differences between 5-ASA (low- and high-dose together) 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) will be investigated. All tests are two-sided and a significance level of 5 % is used.
Time Frame
End of treatment at 24 months +/- 1 month
Title
High and low dose ASA
Description
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 to investigate differences between low and high dose 5-ASA with respect to the occurrence of colorectal neoplasia, to tumor multiplicity and tumor progression. All tests are two-sided and a significance level of 5 % is used.
Time Frame
End of treatment at 24 months +/- 1 month
Title
Significant findings & illnesses - adverse events
Description
Safety data are described and compared between groups in an exploratory manner to determine the safety concerning 5-ASA in LS patient. Therefore significant findings/illnesses, reported after the start of the study and which meet the definition of an AE, will be recorded in the CRF. Intention to treat set: This analysis set includes subjects who were randomized (and received at least one dose study drug). This analysis set will be chosen for safety assessment. All tests are two-sided and a significance level of 5 % is used.
Time Frame
End of treatment at 24 months +/- 1 month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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 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
Facility Information:
Facility Name
Department of Surgery, Medical University Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
HELIOS Universitätsklinikum Wuppertal, Zentrum für Hereditäre Tumorerkrankungen
City
Wuppertal
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
42883
Country
Germany
Facility Name
Rabin Medical Center Beilinson Hospital Gastroenterology Department
City
Petah Tikva
ZIP/Postal Code
4941492
Country
Israel
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333ZA
Country
Netherlands
Facility Name
Department of Genetics and Pathomorphology of Pomeranian Medical University
City
Stettin
ZIP/Postal Code
71-252
Country
Poland
Facility Name
Karolinska universitetsjukhuset, A6:00 Gastroenterologiskt öppenvårdscentrum, Mottagningen för ärftlig tarmcancer
City
Solna
ZIP/Postal Code
17176
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.transcanfp7.eu/index.php/abstract/mesacapp.html
Description
Related Info

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Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome

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