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The Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia (PROBAN)

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ClinicalTrials.gov Identifier: NCT04155242
Recruitment Status : Not yet recruiting
First Posted : November 7, 2019
Last Update Posted : November 15, 2019
Sponsor:
Collaborator:
University of Nottingham
Information provided by (Responsible Party):
Massimiliano di Pietro, MD, University of Cambridge

Study Description
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Brief Summary:

This prospective cohort study aims to assess the utility of a panel of molecular biomarkers for predicting the risk of relapse of Barrett's Oesophagus after endoscopic treatment of early oesophageal neoplasia with RadioFrequency Ablation (RFA). Patients who received endoscopic treatment of early oesophageal neoplasia with RFA and achieved endoscopic remission will be recruited. During the surveillance visits patients will receive a Cytosponge test followed by an endoscopy with Narrow Band Imaging (NBI) magnification and biopsies. Patients will receive an endoscopy every 6 months and Cytosponge every 12 months for at least 2 years. Molecular biomarkers including a methylation panel on DNA and immunohistochemical markers on formalin fixed paraffin embedded samples. After 2 years of intensive endoscopic follow up, patients will be prospectively tracked for up to 3 years.

The investigators will also evaluate:

  • The risk of progression to dysplasia or oesophageal intestinal metaplasia (IM) in patients with IM at the GOJ post RFA in the absence of retreatment
  • the diagnostic accuracy of NBI for IM/dysplasia at the GOJ .

Condition or disease Intervention/treatment Phase
Barrett's Oesophagus Diagnostic Test: Cytosponge test Diagnostic Test: Assessment of the panel of molecular biomarkers: IM-SCORE, TFF3 protein expression, methylation panel, p53 mutation Diagnostic Test: Oesophagogastroduodenoscopy Not Applicable

Detailed Description:

The panel of predetermined molecular biomarkers includes:

  1. IM-SCORE - a score quantifying the extent of intestinal metaplasia at GOJ, which uses a 4-tier system based on the number of glands and the number of biopsies with features of IM. The score has been developed in a pilot study (manuscript under submission) and will be validated in this study
  2. Methylation markers- assessed by a PCR-based method (Methylight) on Cytosponge samples.
  3. P53 status.
  4. TFF3 protein expression.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 147 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Prospective Study on the Use of Biomarkers to Guide Management of Patients Treated With Radiofrequency Ablation for Early Oesophageal Neoplasia
Estimated Study Start Date : December 1, 2019
Estimated Primary Completion Date : December 1, 2024
Estimated Study Completion Date : December 1, 2024
Arms and Interventions
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Arm Intervention/treatment
Experimental: Study group
As part of the post RFA treatment follow up patients will receive a Cytosponge test followed by an endoscopy with NBI magnification and biopsies. Four endoscopies will be performed during 2 years of active follow up together with up to 2 Cytosponge procedures. Molecular biomarkers including a methylation panel on DNA and immunohistochemical markers on formalin fixed paraffin embedded samples obtained during the examinations will be assessed. Patients will be then followed up for up to 3 years with standard endoscopy to assess for relapse of Barrett's oesophagus/IM/dysplasia.
 Diagnostic Test: Cytosponge test
The Cytosponge will be administered by the study nurse prior to the participant having the endoscopy, usually as part of the same visit to hospital. The capsule along with the string is swallowed by drinking a small glass of water. The participant is asked to hold the Cytosponge in situ for 5 minutes. The sponge contained within expands and is then drawn back by the research nurse up the oesophagus by the attached string, collecting cells as it moves upwards. This device received a letter of no objection by the MHRA for use in the BEST pilot trial (LRQ 0939857) but it is not CE marked. Cytosponge and research endoscopic biopsies will be couriered to the Fitzgerald laboratory, at the MRC Cancer Cell Unit on a regular basis. The specimens will be processed in conjunction with the Cambridge University Hospitals' NHS Foundation Trust tissue bank which is accredited to GLP standards.

Diagnostic Test: Assessment of the panel of molecular biomarkers: IM-SCORE, TFF3 protein expression, methylation panel, p53 mutation
Molecular analysis of the specimen obtained by Cytosponge or endoscopic biopsies - TFF3 protein expression, methylation panel, p53 mutation. Endoscopic biopsies will be assessed for the presence of IM (according to the IM-score).

Diagnostic Test: Oesophagogastroduodenoscopy
  • Endoscopy will be carried out with white light and NBI with optical magnification or near focus to inspect oesophagus and GOJ.
  • NBI magnification will be used to assess systematically the mucosal pit pattern at the GOJ and to look for light blue crest (LBC) sign.
  • Targeted biopsies will be taken from either areas with LBC or irregular pit pattern on NBI, followed by random biopsies as per clinical standard. A maximum of 6 biopsies will be taken at the GOJ (maximum 4 targeted and 4 random.. During the first 2 post RFA follow up, at discretion of the endoscopists, neo-suqamous biopsies can be taken in line with local policies.
  • Argon plasma coagulation ablation is allowed in a single island up to 5mm or up to 3 islands <3mm within the study endoscopy as long as this does not represent an obstacle to GOJ biopsies.


Outcome Measures
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Primary Outcome Measures :
  1. Diagnostic accuracy of methylation panel for diffuse IM at the GOJ [ Time Frame: 5 years ]
    Diagnostic accuracy of a panel of methylation markers (ZNF345, ZNF569 and TFPI2 loci) for diffuse IM at the GOJ assessed by Methylight on DNA extracted from GOJ biopsies (separately random and targeted biopsies) and Cytosponge samples.


Secondary Outcome Measures :
  1. Proportion of patients developing true BE recurrence [ Time Frame: 5 years ]
    Number of patients with GOJ IM with different IM score that will develop true BE recurrence during the observation period defined as oesophageal IM or dysplasia.

  2. Biomarker score for BE recurrence [ Time Frame: 5 years ]

    The accuracy of a biomarker panel to predict risk of BE recurrence. The following biomarkers will be assessed:

    • P53 status by immunohistochemistry
    • TFF3 expression by immunohistochemistry
    • IM-SCORE (defined in the Study Description section)
    • methylation markers (defined in the Outcome 1 Description section).

  3. Accuracy of Light Blue Crest sign [ Time Frame: 5 years ]
    Diagnostic accuracy of a Light Blue Crest (LBC) sign in NBI for the diagnosis of GOJ IM. During each performed endoscopy, NBI magnification will be used to assess systematically the mucosal pit pattern at the GOJ and to look for the LBC sign. In order to assess the accuracy of LBC, targeted biopsies will be taken from all the areas with LBC.

  4. Safety of Cytosponge [ Time Frame: 5 years ]

    Number of participants with Cytosponge procedure-related serious adverse events defined as an event that:

    Results in death Is life-threatening Requires hospitalisation or prolongation of existing hospitalisation Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is otherwise considered medically significant by the investigator (eg. a further procedure is required for the patient).



Eligibility Criteria
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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

  1. Previous RFA for dysplastic BE or following EMR for BE-related neoplasia
  2. No definite endoscopic evidence of BE defined as at least 1cm tongue of columnar oesophagus or oesophageal BE islands larger than 5mm.
  3. No histological evidence of oesophageal IM including buried BE at first post RFA follow up. GOJ IM is allowed
  4. No evidence of suspicious lesions with dysplasia at the GOJ.

Exclusion criteria

  1. Evidence of BE requiring additional RFA
  2. Anticoagulant or antiplatelet therapy for high risk conditions, whereby discontinuation of the treatment is not recommended.
  3. Individuals with a diagnosis of an oro-pharynx, oesophageal or gastro-oesophageal tumour (T2 staging and above), or symptoms of dysphagia,
  4. Oesophageal varices, stricture or requiring dilatation of the oesophagus
  5. Individuals who have had a myocardial infarction or any cardiac event less than six months ago
  6. Patients whose primary previous ablative treatment was different from RFA, such as Photodynamic therapy (PDT), APC or Cryotherapy
  7. Participants who are unable to provide informed consent.
  8. Participants under age 18.
  9. Endoscopy is generally avoided in pregnant women and therefore it is unlikely that any pregnant women will be included although pregnancy would not be an absolute contraindication. Pregnancy/ pregnancy test will not be recorded as part of the trial.
Contacts and Locations
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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): NCT04155242


Contacts
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Contact: Massimiliano Di Pietro, MD 01223763349 md460@mrc-cu.cam.ac.uk

Locations
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United Kingdom
MRC Cancer Unit
Cambridge, United Kingdom, CB2 0XZ
Sponsors and Collaborators
University of Cambridge
University of Nottingham
Investigators
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Principal Investigator: Massimiliano Di Pietro, MD MRC Cancer Unit, Hutchison-MRC Research Hon. Consultant Gastroenterologist, Addenbrooke's Hospital, Cambridge.
More Information
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Responsible Party: Massimiliano di Pietro, MD, Dr Massimiliano di Pietro, Senior Clinical Investigator Scientist, MRC Cancer Unit, Hutchison-MRC Research Hon. Consultant Gastroenterologist, Addenbrooke's Hospital, Cambridge., University of Cambridge
ClinicalTrials.gov Identifier: NCT04155242     History of Changes
Other Study ID Numbers: ISRCTN12730505
First Posted: November 7, 2019    Key Record Dates
Last Update Posted: November 15, 2019
Last Verified: November 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
Keywords provided by Massimiliano di Pietro, MD, University of Cambridge:
Barrett's oesophagus
Radiofrequency ablation
Early Oesophageal Neoplasia
Additional relevant MeSH terms:
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Barrett Esophagus
Neoplasms
Precancerous Conditions
 Esophageal Diseases
Gastrointestinal Diseases
Digestive System Diseases