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EPA for Metastasis Trial 2 (EMT2)

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ClinicalTrials.gov Identifier: NCT03428477
Recruitment Status : Recruiting
First Posted : February 9, 2018
Last Update Posted : May 11, 2018
Sponsor:
Collaborators:
Yorkshire Cancer Research
Amarin Pharma Inc.
Information provided by (Responsible Party):
University of Leeds

Brief Summary:
A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to the liver (metastases) develop disease recurrence and die from the disease. A previous small study (the EMT study) suggested a possible survival benefit in patients who took the naturally-occurring omega-3 fatty acid EPA (a fish oil supplement) before liver surgery. The EMT2 study is a larger study which will recruit 448 men and women with liver metastases from bowel cancer. Trial participants will receive either Icosapent Ethyl (pure EPA derived from fish oil) or placebo (dummy capsules). EMT2 will investigate whether patients who take this supplement before liver surgery and for up to four years after surgery, remain free of recurrence for longer than those who take placebo (dummy capsules)

Condition or disease Intervention/treatment Phase
Liver Metastasis Colon Cancer Drug: Icosapent Ethyl Other: Placebo Phase 3

Detailed Description:

Despite significant advances in diagnosis and treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the UK. The majority of deaths from CRC are related to distant metastasis, predominantly to the liver. Overall 5-year survival following liver resection and adjuvant chemotherapy for colorectal cancer liver metastases (CRCLM) is, at best, 40-60%. Despite surgery with curative intent, up to 60% of patients develop recurrence within 2 years of surgery. The preliminary EMT study was a Phase II RCT of EPA 2 g daily in patients (n=88) undergoing liver resection surgery for CRCLM. Although there was no difference in the primary endpoint (tumour proliferation index), metastases from the EPA arm had a lower vascularity score (suggesting possible anti-angiogenic activity) than placebo-treated tumours. Although EPA (or placebo) treatment was limited to the pre-operative period, overall survival (OS) and disease-free survival (DFS) were specified as exploratory end-points on the basis that oral dosing with EPA before liver surgery would provide tissue EPA exposure in the immediate peri-operative period with prolonged bioavailability in the post-operative period due to the slow tissue 'washout' kinetics of EPA. Survival analysis demonstrated that the median DFS in the EPA group was 22.6 months compared with 14.7 months in the placebo group. Any DFS benefit was explained by a reduction in CRC recurrence from 12 months after surgery onwards.

The EMT2 study is a randomised, double-blind, placebo-controlled, multi-centre, phase III trial of the omega-3 fatty acid (O3FA) eicosapentaenoic acid (EPA) as the ethyl ester (icosapent ethyl [IPE; Vascepa®]) in patients undergoing liver resection surgery for colorectal cancer liver metastasis (CRCLM) with curative intent designed to determine whether EPA treatment improves Progression-Free Survival (PFS). A key secondary objective is overall survival (OS).

Investigators will recruit adult individuals listed for CRCLM resection with curative intent.

Randomisation will be 1:1 to receive either IPE capsules or placebo capsules. 4 capsules per day containing IPE (equivalent to 4 g EPA-ethyl ester [EE] daily) or 4 placebo capsules per day. Participants will start treatment a minimum of 2 weeks prior to CRCLM surgery and will continue to receive treatment for a minimum of 2 years and a maximum of 4 years post-liver resection. Participants are followed up for 60 days beyond the end of treatment.

Participants are clinically assessed 6 months post-operatively (from liver resection) and at 6-monthly intervals thereafter for disease progression/recurrence.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 448 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomised Placebo-controlled Phase III Trial of the Effect of the Omega-3 Fatty Acid Eicosapentaenoic Acid (EPA) on Colorectal Cancer Recurrence and Survival After Surgery for Resectable Liver Metastases
Actual Study Start Date : March 16, 2018
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Icosapent Ethyl (EPA-EE)
Soft gelatin capsules containing 1g pure EPA-EE equivalent to 914mg EPA-FFA. Administered as 4g per day to be taken as 2 capsules in the morning and 2 capsules in the evening.
Drug: Icosapent Ethyl
Composition: soft amber to light yellow, oblong gelatin capsules. One capsule contains 1g pure EPA-EE Dose: 4 capsules per day
Other Name: Vascepa

Placebo Comparator: Placebo
Soft gelatin capsules containing light mineral oil. 4 capsules to be taken per day (2 in the morning and 2 in the evening).
Other: Placebo

Composition: soft, amber to light yellow, oblong gelatin capsules containing light mineral oil:

Dose: 4 capsules per day





Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Minimum of 2 years follow-up ]
    PFS is defined as the time from randomisation to death (from any cause), first documented evidence of disease progression, new recurrence or clinical deterioration unequivocally due to disease progression


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Minimum of 2 years follow-up ]
    The time from randomisation to death, from any cause (key secondary endpoint)

  2. Safety and Tolerability of Icosapent Ethyl [ Time Frame: Minimum of 2 years follow-up ]
    The number of participants with treatment-emergent adverse events as defined by CTCAE v4.0

  3. Patient reported quality of life 1 [ Time Frame: Minimum of 2 years follow-up ]
    Measured using the EQ-5D questionnaire

  4. Patient reported quality of life 2 [ Time Frame: Minimum of 2 years follow-up ]
    Measured using the EORTC QLQ-C30 questionnaire

  5. Patient reported quality of life 3 [ Time Frame: Minimum of 2 years follow-up ]
    Measured using the QLQ-LMC21 questionnaire

  6. New Primary Cancers [ Time Frame: Minimum of 2 years follow-up ]
    Excluding DCIS, cervical carcinoma in situ, superficial bladder carcinoma where treatment consisted of resection only and non-melanoma skin cancer where treatment consisted of resection or radiotherapy only)


Other Outcome Measures:
  1. Red Blood Cell Membrane EPA content (exploratory endpoint) [ Time Frame: Samples taken at baseline, surgery and 6 months after surgery ]
    EPA content measured at baseline, surgery and 6 months after surgery. Samples taken at selected sites only

  2. Change in lean body mass (exploratory endpoint) [ Time Frame: 6 months and up to 4 years follow up ]
    Change in lean body mass measured by CT scanning during follow-up as assessed by the L3 skeletal muscle index score. Scans reviewed from selected sites only



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged ≥ 18 years
  • Able to provide written informed consent
  • Histological diagnosis of colorectal cancer with evidence of liver metastases
  • Planned liver resection surgery for colorectal cancer liver metastases with curative intent, including repeat 're-do' colorectal cancer liver metastases surgery (a second independent resection for a separate colorectal cancer liver recurrence)
  • Intention to receive ≥ 2 weeks treatment with IMP prior to colorectal cancer liver metastases surgery

Exclusion Criteria:

  • Incurable extra-hepatic metastases
  • Current (in the last 2 months) or planned regular (>3 doses per week) use of O3FA containing supplements, including fish oil and cod-liver oil supplements
  • Fish/seafood allergy
  • <2 weeks before planned colorectal cancer liver metastases surgery
  • Inability to comply with trial treatment and follow-up schedule
  • Known bleeding tendency/condition (e.g. von Willebrand disease)
  • A previous malignancy within the last 5 years other than:

    • colorectal cancer
    • non-melanoma skin cancer where treatment consisted of resection only or radiotherapy
    • ductal carcinoma in situ (DCIS) where treatment consisted of resection only
    • cervical carcinoma in situ where treatment consisted of resection only
    • superficial bladder carcinoma where treatment consisted of resection only
  • A previous malignancy where the patient has been disease free for ≤ 5 years
  • Pregnant or breastfeeding women or women of childbearing potential not willing to use effective contraceptive measures. Women of childbearing potential are defined as fertile, following menarche and until becoming post-menopausal, unless permanently sterile
  • Men defined as fertile (post-pubescent and not permanently sterile by vasectomy or bilateral orchidectomy) and not willing to use effective contraceptive measures if appropriate.

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): NCT03428477


Contacts
Contact: Mark Hull 0113 343 8650 m.a.hull@leeds.ac.uk

Locations
United Kingdom
Hampshire Hospitals NHS Foundation Trust Recruiting
Basingstoke, Royal Hampshire, United Kingdom, RG24 9NA
Contact: Fenella Welsh         
University Hospital Southampton NHS Foundation Trust Recruiting
Southampton, United Kingdom
Contact: Zaed Hamady         
Sponsors and Collaborators
University of Leeds
Yorkshire Cancer Research
Amarin Pharma Inc.
Investigators
Principal Investigator: Mark Hull University of Leeds
  Study Documents (Full-Text)

Documents provided by University of Leeds:
Study Protocol  [PDF] May 25, 2017


Responsible Party: University of Leeds
ClinicalTrials.gov Identifier: NCT03428477     History of Changes
Other Study ID Numbers: MO16/053
First Posted: February 9, 2018    Key Record Dates
Last Update Posted: May 11, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by University of Leeds:
Liver metastases
Colon Cancer

Additional relevant MeSH terms:
Platelet Aggregation Inhibitors
Neoplasm Metastasis
Neoplasms, Second Primary
Colonic Neoplasms
Liver Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Liver Diseases
Eicosapentaenoic acid ethyl ester