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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03070574
Recruitment Status : Terminated (Due to poor patient recruitment and insufficient financing.)
First Posted : March 3, 2017
Last Update Posted : April 18, 2019
Sponsor:
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
Information provided by (Responsible Party):
Christoph Gasche, Medical University of Vienna

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.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: mesalamine 2400 MG (5-ASA) Drug: mesalamine 1200 MG Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome - MesaCAPP
Actual Study Start Date : November 24, 2017
Actual Primary Completion Date : April 10, 2019
Actual Study Completion Date : April 10, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 2400 MG mesalamine (5-ASA) total
2400mg (1200mg mesalamine/1200mg) mesalamine once daily in the morning for the treatment phase of the study (24 months)
Drug: mesalamine 2400 MG (5-ASA)
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.
Other Names:
  • Mezavant
  • Mesalazine
  • 5-aminosalicylic acid (5-ASA)

Experimental: 1200 MG mesalamine (5-ASA) total
placebo/1200mg mesalamine once daily in the morning for the treatment phase of the study (24 months)
Drug: mesalamine 1200 MG
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.
Other Names:
  • Mezavant
  • Mesalazine
  • 5-aminosalicylic acid (5-ASA)

Other: Placebo
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.

Placebo Comparator: Placebo
placebo/placebo once daily in the morning for the treatment phase of the study (24 months)
Other: Placebo
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 Measures :
  1. Reduction in the occurrence of any colorectal neoplasia in LS patients [ Time Frame: End of treatment at 24 months +/- 1 month ]
    • 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.

  2. Reduction in the occurrence of any colorectal neoplasia in LS patients [ Time Frame: End of study at year 6 +/- 3 months ]
    As above


Secondary Outcome Measures :
  1. Tumor multiplicity [ Time Frame: End of treatment at 24 months +/- 1 month ]

    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.


  2. Tumor progress [ Time Frame: End of treatment at 24 months +/- 1 month ]

    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.


  3. Treatment effects [ Time Frame: End of treatment at 24 months +/- 1 month ]

    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.


  4. High and low dose ASA [ Time Frame: End of treatment at 24 months +/- 1 month ]

    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.


  5. Significant findings & illnesses - adverse events [ Time Frame: End of treatment at 24 months +/- 1 month ]

    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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   25 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03070574


Locations
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Austria
Department of Surgery, Medical University Vienna
Vienna, Austria, 1090
Germany
HELIOS Universitätsklinikum Wuppertal, Zentrum für Hereditäre Tumorerkrankungen
Wuppertal, Nordrhein-Westfalen, Germany, 42883
Israel
Rabin Medical Center Beilinson Hospital Gastroenterology Department
Petah Tikva, Israel, 4941492
Netherlands
Leiden University Medical Center
Leiden, Netherlands, 2333ZA
Poland
Department of Genetics and Pathomorphology of Pomeranian Medical University
Stettin, Poland, 71-252
Sweden
Karolinska universitetsjukhuset, A6:00 Gastroenterologiskt öppenvårdscentrum, Mottagningen för ärftlig tarmcancer
Solna, Sweden, 17176
Sponsors and Collaborators
Christoph Gasche
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
Additional Information:
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Responsible Party: Christoph Gasche, Univ. Prof. Dr. Christoph Gasche - Coordinating Investigator, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT03070574    
Obsolete Identifiers: NCT02864979
Other Study ID Numbers: MesaCAPP
First Posted: March 3, 2017    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Christoph Gasche, Medical University of Vienna:
Lynch Syndrome
Chemoprevention
Mesalazine
5-ASA
Additional relevant MeSH terms:
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Colorectal Neoplasms
Colorectal Neoplasms, Hereditary Nonpolyposis
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Syndromes, Hereditary
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Aminosalicylic Acid
Mesalamine
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents