Comparing Proton Therapy to Photon Radiation Therapy for Esophageal Cancer

Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Trial

Official title:

Phase III Randomized Trial of Proton Beam Therapy (PBT) Versus Intensity Modulated Photon Radiotherapy (IMRT) for the Treatment of Esophageal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03801876
• Other study ID #: NRG-GI006
• Secondary ID: NCI-2018-03378NR
• Status: Recruiting
• Phase: Phase 3
• Start date: March 15, 2019
• Est. completion date: December 21, 2031

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial studies how well proton beam radiation therapy compared with intensity modulated photon radiotherapy works in treating patients with stage I-IVA esophageal cancer. Proton beam radiation therapy uses a beam of protons (rather than x-rays) to send radiation inside the body to the tumor without damaging much of the healthy tissue around it. Intensity modulated photon radiotherapy uses high-energy x-rays to deliver radiation directly to the tumor without damaging much of the healthy tissue around it. It is not yet known whether proton beam therapy or intensity modulated photon radiotherapy will work better in treating patients with esophageal cancer.

Description:

PRIMARY OBJECTIVES: I. To determine if overall survival (OS) is improved with proton beam radiation therapy (PBT) treatment as compared to intensity modulated photon radiation therapy (IMRT) as part of planned protocol treatment for patients with esophageal cancer. II. To determine if OS with PBT is non-inferior to IMRT as part of planned protocol treatment and that there will be less grade 3+ cardiopulmonary toxicity with PBT than with IMRT. SECONDARY OBJECTIVES: I. To compare the symptom burden and impact on functioning of patients between treatment modalities based on Patient Reported Outcome (PRO) measures of symptoms using MD Anderson Symptom Inventory (MDASI) and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue. II. To compare the Quality-Adjusted Life Years (QALY) using EuroQol five-dimensional questionnaire (EQ5D) as a health outcome between PBT and IMRT, if the protocol primary endpoint is met. III. To assess the pathologic response rate between PBT and IMRT. IV. To assess the cost-benefit economic analysis of treatment between radiation modalities. V. To compare the length of hospitalization after protocol surgery between PBT and IMRT. VI. To compare the incidence of grade 4 lymphopenia during chemoradiation between PBT and IMRT. VII. To compare lymphocyte nadir at first follow-up visit after completion of chemoradiation between PBT & IMRT. VIII. To estimate the locoregional failure, distant metastatic free survival, and progression-free survival of patients treated with PBT versus IMRT. IX. To compare incidence of both early (< 90 days from treatment start) and late (≥ 90 days from treatment start) cardiovascular and pulmonary events between PBT versus IMRT. X. To compare the Total Toxicity Burden (TTB) of IMRT versus PBT based on a composite index of 9 individual cardiopulmonary toxicities. EXPLORATORY OBJECTIVES: I. To collect biospecimens for future analyses, for example to assess cardiac and inflammatory biomarkers in association with treatment complications. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients undergo PBT over 28 fractions 5 days a week for 5.5 weeks. Patients also receive paclitaxel intravenously (IV) and carboplatin IV on days 1, 8, 15, 22, 29, and 36 while undergoing PBT. GROUP II: Patients undergo IMRT over 28 fractions 5 days a week for 5.5 weeks. Patients also receive paclitaxel IV and carboplatin IV on days 1, 8, 15, 22, 29, and 36 while undergoing IMRT. In both groups, within 4-8 weeks after completion of chemotherapy and radiation therapy, patients may undergo an esophagectomy per physician discretion. After completion of study treatment, patients are followed up every 3-6 months for 3 years and then annually thereafter.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 21, 2031
• Est. primary completion date: December 21, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION:
• Histologically proven diagnosis of adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal junction (Siewert I-II)
• Stage I-IVA, excluding T4b, according to the American Joint Committee on Cancer (AJCC)

8th edition based on the following diagnostic workup:

• History/physical examination
• Whole-body fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) with or without (+/-) contrast (preferred) or chest/abdominal (include pelvic if clinically indicated) CT with contrast
• For patients who DID NOT receive induction chemotherapy, scan must occur within 30 days prior to Step 1 registration
• For patients who DID receive induction chemotherapy, scan must occur:
• Within 30 days after final induction chemotherapy dose; OR
• Within 30 days prior to Step 1 registration
• Note: Patients who had prior endoscopic mucosal resection (EMR) with a diagnosis of AJCC stage I-IVA, excluding T4b, esophageal cancer are eligible
• Surgical consultation to determine whether or not the patient is a candidate for resection after completion of chemoradiation
• Induction chemotherapy for the current malignancy prior to concurrent chemoradiation allowed if last dose is no more than 90 days and no less than 10 days prior to Step 1 registration. Only FOLFOX will be allowed as the induction chemotherapy regimen.
• Zubrod performance status 0, 1, or 2
• Absolute neutrophil count (ANC) (within 30 days prior to Step 1 registration)
• For patients who DID NOT receive induction chemotherapy: ANC >= 1,500 cells/mm^3
• For patients who DID receive induction chemotherapy: ANC >= 1,000 cells/mm^3
• Platelets (within 30 days prior to Step 1 registration)
• For patients who DID NOT receive induction chemotherapy: Platelets >= 100,000/uL
• For patients who DID receive induction chemotherapy: Platelets >= 75,000/uL
• Hemoglobin >= 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >= 8.0 g/dl is acceptable) (within 30 days prior to Step 1 registration)
• Serum creatinine = 1.5 x upper limit of normal (ULN) or Creatinine clearance > 40 mL/min estimated by Cockcroft-Gault formula (within 30 days prior to Step 1 registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 30 days prior to Step 1 registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 30 days prior to Step 1 registration)
• Negative pregnancy test (serum or urine) within 14 days prior to Step 1 registration for women of child bearing potential
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Cervical esophageal cancers arisen from 15-18 cm from the incisors
• Patients with T4b disease according to the AJCC 8th edition
• Definitive clinical or radiologic evidence of metastatic disease
• Any active malignancy within 2 years of study registration that may alter the course of esophageal cancer treatment
• Prior thoracic radiotherapy that would result in overlap of radiation therapy fields
• Severe, active co-morbidity defined as follows:
• Active uncontrolled infection requiring IV antibiotics at the time of Step 1 registration
• Uncontrolled symptomatic congestive heart failure, unstable angina, or cardiac arrhythmia not controlled by any device or medication at the time of Step 1 registration
• Myocardial infarction within 3 months prior to Step 1 registration
• Pregnant and/or nursing females
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive
• PRIOR TO STEP 2 REGISTRATION:
• Unable to obtain confirmation of payment coverage (insurance or other) for either possible radiation treatment

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Carcinoma, Squamous Cell
• Clinical Stage I Esophageal Adenocarcinoma AJCC v8
• Clinical Stage I Esophageal Squamous Cell Carcinoma AJCC v8
• Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage II Esophageal Adenocarcinoma AJCC v8
• Clinical Stage II Esophageal Squamous Cell Carcinoma AJCC v8
• Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8
• Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8
• Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage III Esophageal Adenocarcinoma AJCC v8
• Clinical Stage III Esophageal Squamous Cell Carcinoma AJCC v8
• Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8
• Clinical Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
• Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Esophageal Neoplasms
• Esophageal Squamous Cell Carcinoma
• Pathologic Stage I Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage I Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IA Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IA Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IB Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage II Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage II Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IIA Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IIB Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage III Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage III Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8
• Pathologic Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
• Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage I Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage I Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage II Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage II Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage III Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IVA Esophageal Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
• Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Thoracic Esophagus Squamous Cell Carcinoma

Intervention

Drug:
• Carboplatin
Given IV

Procedure:
• Esophagectomy
Undergo esophagectomy

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Drug:
• Paclitaxel
Given IV

Radiation:
• Proton Beam Radiation Therapy
Undergo PBT

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Drug:
• FOLFOX regimen
Folinic acid, flurouracil and oxaliplatin
• CAPOX regimen
Capecitabine combined with oxaliplatin
• Docetaxel
Chemotherapy
• 5FU
Chemotherapy

Locations

Country	Name	City	State
United States	Mayo Clinic Health System in Albert Lea	Albert Lea	Minnesota
United States	Inova Alexandria Hospital	Alexandria	Virginia
United States	Alton Memorial Hospital	Alton	Illinois
United States	Emory Proton Therapy Center	Atlanta	Georgia
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	Maryland Proton Treatment Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Geauga Hospital	Chardon	Ohio
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	MD Anderson in The Woodlands	Conroe	Texas
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Mayo Clinic Health System-Eau Claire Clinic	Eau Claire	Wisconsin
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	Inova Fair Oaks Hospital	Fairfax	Virginia
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Unity Hospital	Fridley	Minnesota
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	M D Anderson Cancer Center	Houston	Texas
United States	MD Anderson West Houston	Houston	Texas
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Thompson Cancer Survival Center - West	Knoxville	Tennessee
United States	Thompson Proton Center	Knoxville	Tennessee
United States	Karmanos Cancer Institute at McLaren Greater Lansing	Lansing	Michigan
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	MD Anderson League City	League City	Texas
United States	Inova Loudoun Hospital	Leesburg	Virginia
United States	Mayo Clinic Health Systems-Mankato	Mankato	Minnesota
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Thompson Oncology Group-Maryville	Maryville	Tennessee
United States	UH Seidman Cancer Center at Landerbrook Health Center	Mayfield Heights	Ohio
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	UH Seidman Cancer Center at Southwest General Hospital	Middleburg Heights	Ohio
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York Proton Center	New York	New York
United States	Mayo Clinic Radiation Therapy-Northfield	Northfield	Minnesota
United States	Thompson Oncology Group-Oak Ridge	Oak Ridge	Tennessee
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	McLaren Cancer Institute-Owosso	Owosso	Michigan
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	UH Seidman Cancer Center at Firelands Regional Medical Center	Sandusky	Ohio
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Memorial Hospital East	Shiloh	Illinois
United States	MD Anderson in Sugar Land	Sugar Land	Texas
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	University Hospitals Sharon Health Center	Wadsworth	Ohio
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	UH Seidman Cancer Center at Saint John Medical Center	Westlake	Ohio
United States	UHHS-Westlake Medical Center	Westlake	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS)	Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test.	From the date of randomization to the date of death due to any cause or date of last follow-up for patients without an OS event reported. This analysis occurs after 173 deaths; estimated to occur 4 years after accrual completion
Primary	Incidence of specific grade 3+ cardiopulmonary adverse events (AEs) that are definitely, probably, or possibly related to protocol treatment	Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Difference in proportion of defined cardiopulmonary AEs will be analyzed with a chi-squared test.	From baseline up to 8 years
Secondary	Pathologic response rate	A Chi-square test will be used to compare the pathologic response rates between the treatment arms.	At time of surgery
Secondary	Grade 4 lymphopenia during chemoradiation	Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. The proportion of patients experiencing grade 4 lymphopenia during chemoradiation will be compared between treatment arms using a chi-squared test.	From the start of chemoradiation to the end of chemoradiation treatment assessed up to 31 days
Secondary	Lymphocyte counts	Mean lymphocyte counts at first post chemoradiation follow-up will be compared between treatment arms using a t-test. If the data do not satisfy the normality assumption, a Wilcoxin test may be used instead.	From the last date of chemoradiation up to 8 weeks post chemoradiation
Secondary	Locoregional failure (LRF)	Will be defined as local/regional recurrence or progression. Will be estimated by the cumulative incidence method, with death as a competing risk. The distribution of LRF estimates between the two arms will be compared using Gray?s test. The Fine-Gray regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with LRF.	From the date of randomization to the date of first LRF or date of last follow-up for patients without an LRF event reported, assessed up to 8 years
Secondary	Distant metastatic-free survival (DMFS)	Will be defined as appearance of distant metastasis or death due to any cause. Will be estimated by the Kaplan-Meier method and estimates between the two treatment arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with DMFS.	From the date of randomization to the date of first DMFS failure or last follow-up for patients without a reported DMFS event, assessed up to 8 years
Secondary	Progression-free survival	Will be defined as appearance of local/regional/distant failure or death due to any cause. Will be estimated by the Kaplan-Meier method and estimates between the two treatment arms will be compared using the log rank test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS.	From the date of randomization to the date of first PFS failure or last follow-up for patients without a reported PFS event, assessed up to 8 years
Secondary	Quality-adjusted life years (QALY)	Will be evaluated and compared using EuroQol five-dimensional questionnaire (EQ-5D) only if the primary endpoint is met.	Assessed up to 8 years
Secondary	Cost-benefit economic analysis of treatment	Will be calculated by the visual analog scale (VAS) and index scores form the EQ-5D-5L only be done if primary endpoint is met. Will be compared between treatment arms using a t-test with a 2-sided significance level of 0.05. If there are significant differences, then a cost analysis will be conducted.	Assessed up to 8 years