EMT2: EPA for Metastasis Trial 2

Sponsor

Mark A Hull, PhD FRCP (Other)

Overall Status

Recruiting

CT.gov ID

NCT03428477

Collaborator

Yorkshire Cancer Research (Other), Amarin Pharma Inc. (Industry)

448

Enrollment

Locations

Arms

Anticipated Duration (Months)

37.3

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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 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 Design

Study Type:

Interventional

Anticipated 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 :

May 2, 2018

Anticipated Primary Completion Date :

Jul 31, 2024

Anticipated Study Completion Date :

Jul 31, 2025

Arms and Interventions

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 Names: 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

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 Names:

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

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [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

Overall Survival (OS) [Minimum of 2 years follow-up]
The time from randomisation to death, from any cause (key secondary endpoint)
Safety and Tolerability of Icosapent Ethyl [Minimum of 2 years follow-up]
The number of participants with treatment-emergent adverse events as defined by CTCAE v4.0
Patient reported quality of life 1 [Minimum of 2 years follow-up]
Measured using the EQ-5D questionnaire
Patient reported quality of life 2 [Minimum of 2 years follow-up]
Measured using the EORTC QLQ-C30 questionnaire
Patient reported quality of life 3 [Minimum of 2 years follow-up]
Measured using the QLQ-LMC21 questionnaire
New Primary Cancers [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

Red Blood Cell Membrane EPA content (exploratory endpoint) [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
Change in lean body mass (exploratory endpoint) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 IMP prior to colorectal cancer liver metastases surgery

Exclusion Criteria:

Previous CRCLM surgery for the management of the current metastatic disease
Incurable extra-hepatic metastases
Current (in the last 2 months) or planned regular (>3 doses per week) use of O3FA-containing drugs or supplements, including Vazkepa®, Omacor®, fish oil and cod-liver oil supplements
Fish/seafood allergy
Diagnosis of hereditary fructose intolerance
Soya or peanut allergy
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hampshire Hospitals NHS Foundation Trust	Basingstoke	Royal Hampshire	United Kingdom	RG24 9NA
2	Aintree University Hospitals NHS Foundation Trust	Aintree		United Kingdom
3	University Hospitals Birmingham NHS Foundation Trust	Birmingham		United Kingdom
4	Cambridge UniversityHospitals NHS Foundation Trust	Cambridge		United Kingdom
5	University Hospital of Wales	Cardiff		United Kingdom
6	Leeds Teaching Hospitals NHS Foundation Trust	Leeds		United Kingdom
7	King's College London	London		United Kingdom
8	Royal Free London NHS Foundation Trust	London		United Kingdom
9	Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle		United Kingdom
10	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom
11	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield		United Kingdom
12	University Hospital Southampton NHS Foundation Trust	Southampton		United Kingdom