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Eradicating Barrett's Esophagus Using Radiofrequency Ablation or a Novel Hybrid Argon Plasma Coagulation Technique (BURN)

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ClinicalTrials.gov Identifier: NCT03621319
Recruitment Status : Recruiting
First Posted : August 8, 2018
Last Update Posted : March 3, 2021
Sponsor:
Collaborators:
Erbe USA Incorporated
Kansas City Veteran Affairs Medical Center
Emissary International LLC
Information provided by (Responsible Party):
Erbe Elektromedizin GmbH

Tracking Information
First Submitted Date  ICMJE July 19, 2018
First Posted Date  ICMJE August 8, 2018
Last Update Posted Date March 3, 2021
Actual Study Start Date  ICMJE July 24, 2019
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2018)
Rate of stricture-free eradication of dysplastic BE [ Time Frame: 12 months ]
Freedom from strictures and complete eradication of dysplasia (CE-D) within 12 months after the last treatment will be measured as a composite safety and effectiveness endpoint. The composite endpoint evaluation is a traditional responder analysis with a single measure. The composite endpoint will have two possible outcome responses for each study subject: success or failure. The study or control treatment will be considered a success for a study subject only if both conditions are met: freedom from strictures and complete eradication of dysplasia. The number of successes and failures allows the estimation of success rates in the two study arms. These rates will be compared using standard statistical methods for rates (that is, binomial proportions).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2018)
  • Rate of eradication of intestinal metaplasia (CE-IM) [ Time Frame: 12 months ]
    Eradication of intestinal metaplasia (CE-IM) within 12 months after the last treatment will be measured
  • Post-operative pain [ Time Frame: 7 days ]
    Post-operative pain score at baseline and at 1st and 7th day visits post treatment utilizing a visual analog scale (VAS). The VAS scale consists of a straight line with the scale endpoints defining extreme limits such as 'no pain' at "0" up to 'worst possible pain' at "10". The higher the value in the scale, the higher the pain intensity. A continuous 10 cm interval on which a subject marks a position is turned into a measurement (usually a fractional value like 5.5 cm). A lower value is thus a better outcome whereas a higher number indicates a worse outcome, with respect to pain intensity.
  • Major complications [ Time Frame: 12 months ]
    Complications requiring additional Intervention (bleeding with drop of hemoglobin (Hb > 2 g/dl), fever persisting more than 24 hours, stricture, perforation)
  • Minor complications [ Time Frame: 12 months ]
    Complications without need for additional endotherapy (bleeding with drop in hemoglobin (Hb < 2 g/dl) fever persisting less than 24 hours, dysphagia)
  • Recurrence rate of dysplasia (CE-D) [ Time Frame: 12 months ]
    The recurrence rate of dysplasia after CE-D has been achieved will be measured
  • Recurrence rate of intestinal metaplasia (CE-IM) [ Time Frame: 12 months ]
    The recurrence rate of intestinal metaplasia after CE-IM has been achieved will be measured
  • Cost-effectiveness of HAPC vs. RFA in the treatment of dysplastic BE [ Time Frame: 12 months ]
    The cost effectiveness of HAPC compared to RFA for achieving CE-D will be based on a comparison of average treatment cost between the two groups. Data regarding the type of off-study medical services utilized during the study period that are possibly or definitely related to the ablative treatment will be collected.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Eradicating Barrett's Esophagus Using Radiofrequency Ablation or a Novel Hybrid Argon Plasma Coagulation Technique
Official Title  ICMJE Eradicating Barrett's Esophagus Using Radiofrequency Ablation or a Novel Hybrid Argon Plasma Coagulation Technique (BURN)
Brief Summary Lay summary: Barrett's Esophagus (BE) involves a change of the esophagus lining (BE epithelium) which in a small proportion of patients could be the starting point for the development of cancer (esophageal adenocarcinoma). Currently, there is evidence that this change is initiated by acid reflux from the stomach which then could progress in a stepwise manner from the healthy epithelium to cellular changes (intestinal metaplasia, low-grade and high-grade dysplasia) and finally to adenocarcinoma. Surgery is considered the standard therapy for this cancer which involves the risk of death and complications with quality of life impairments. New possibilities for treatment have evolved with endoscopic therapies which allow for treatment of early changes of the epithelium (intestinal metaplasia and dysplasia) prior to the occurrence of cancer using either argon plasma coagulation (APC) or radiofrequency ablation (RFA). Both are established methods for eradication of BE by thermal ablation of the BE epithelium using high frequency current (HF). More advanced BE epithelium with early visible cancers are being treated by endoscopic mucosal resection (EMR). After EMR the residual Barrett's epithelium can also be removed by ablation with RFA or APC. Currently radiofrequency ablation (RFA) has been suggested as the standard therapy for BE treatment. Although effective in the eradication of the BE epithelium after RFA treatment the re-appearance of BE epithelium and the occurrence of complications such as strictures causing swallowing impairments for food have also been observed in clinical studies. A recently developed method is Hybrid argon plasma coagulation (ablation) [HybridAPC® (HAPC)] which combines argon plasma coagulation (APC) with a fluid injection function by a water beam. The water beam allows to establish a fluid cushion (normal sterile saline) right beneath the BE-epithelium prior to thermal ablation thereby protecting the esophagus wall from heat during ablation of epithelium with APC. The goal of this randomized controlled study is to investigate if HAPC is non-inferior to RFA in the stricture-free eradication of the dysplastic BE epithelium.
Detailed Description

Barrett's Esophagus (BE) is a pre-malignant condition and may progress to low grade dysplasia, high grade dysplasia and ultimately esophageal adenocarcinoma which has poor prognosis with a 5-year survival rate of only 5 - 20 %. Radiofrequency ablation (RFA) is a standard modality and well-studied endoscopic treatment for dysplastic BE. HybridAPC® (HAPC) is a newer technique for endoscopic treatment of dysplastic BE that involves submucosal fluid injection prior to performing APC. The study aim of this non-inferiority study is to show that HAPC is at least as safe and effective as RFA in the stricture-free eradication of dysplasia (CE-D).

The study is a multi-center, parallel group (HAPC/RFA) prospective, single blind, non-inferiority, randomized controlled study to assess the safety and effectiveness of HAPC (treatment arm) compared to RFA (control arm) in the treatment of BE in up to 144 male and female adult patients. Participants of the study will be enrolled in up to 15 centers in the US. Both techniques have never been directly compared in the treatment of BE.

The specific aim of this non-inferiority study is to show that HAPC is at least as safe and effective as RFA in the stricture-free eradication of dysplasia (CE-D), by inducing complete eradication of dysplasia (CE-D) within 12 months after last treatment as confirmed by endoscopy and histology.

HybridAPC® is an endoscopic technique that is used with the HybridAPC® Probe, the Water Jet Model ERBEJET 2 and an ERBE Argon Plasma Coagulator (APC) Model APC 2/Electrosurgical Unit (ESU) VIO Model System. The Water Jet delivers pressurized sterile 0.9 % sodium chloride solution (normal saline) through the HybridAPC® Probe into the submucosa of the Barrett mucosa. Reduction/limitation of unwanted tissue damage (penetration depth) is being ensured by the saline cushion when applying argon plasma coagulation to ablate Barrett's mucosa with subsequent regeneration of esophageal squamous mucosa.

Radiofrequency ablation (RFA) applied in the control arm using BarrxTM FLEX RFA Generator is an endoscopic technique that delivers high radiofrequency waves using either circumferential (balloon inserted over an endoscopically placed guidewire) device of focal (probe attached to the tip of the endoscope) device to damage the Barrett's mucosa with subsequent regeneration of esophageal squamous mucosa. While a circumferential device can be used to treat larger BE areas, focal device (Halo 60, 90 or through the scope device) can be used to treat small islands of residual BE. The depth of the injury is controlled by regular spacing of the electrodes and the delivery of a pre-set amount of energy through the probes. The PI/Co-investigators will be instructed to operate the BarrxTM FLEX RFA Generator and above referenced catheters according to the cleared labeling.

Patients with dysplastic BE will be identified at each participating center, and defined as those with LGD within previous 6 months and HGD/cancer within previous 6 months, both timed from date of consent. All histology slides from biopsies and endoscopic mucosal resection (EMR) specimens will be read by the local pathologist for patient management purposes and separately by a single independent reference pathologist to confirm patient eligibility for randomization.

Eligible patients will be block randomized at each participating study center at a ratio of 1 : 1 to receive treatment of dysplasia with HAPC or RFA after EMR of visible lesions (if present) has been performed as per standard of care. All patients will be assigned a unique registration number allocated by the Electronic Data Capture (EDC) system following details submitted on a web form. Due to the nature of the intervention only the patient will be blinded (single blinding), and not the PI or Co-investigators. The assigned HAPC ablation or RFA procedure will be performed at 8 to 12-week intervals until eradication of BE has been achieved. A maximum number of 4 treatment sessions is allowed.

Once the BE has been eradicated endoscopically, 4 quadrant biopsies every 1-2 cm will be performed to confirm complete eradication of dysplasia/IM (standard of care) and slides sent for confirmation by the central pathologist.

Primary statistical analysis will compare the proportions of patients in whom stricture-free eradication of dysplastic BE has been achieved.

As secondary endpoints complete endoscopic and histological eradication of intestinal metaplasia (CE-IM), stricture rate, post-operative pain, cost-effectiveness and recurrence of intestinal metaplasia and dysplasia will be documented and reported. No formal tests of hypothesis will be applied for these secondary endpoints.

Data from the trial will be entered into a database (VISION EDC, version 8, Prelude Dynamics, Austin, TX) and all statistical analyses will be performed using validated software (SAS, version 9.4; IBM/SPSS, version 23; Cytel StatXact, version 11; or R).

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Barrett's Esophagus
  • High-grade Dysplasia in Barrett Esophagus
  • Low Grade Dysplasia in Barrett Esophagus
Intervention  ICMJE
  • Device: Hybrid argon plasma ablation (HAPC)
    -The assigned HAPC ablation will be performed at 8 to 12 week intervals until eradication of BE has been achieved or a total of 4 treatments have been performed
  • Device: Radiofrequency ablation (RFA)
    -The assigned RFA procedure will be performed at 8 to 12 week intervals until eradication of BE has been achieved or a total of 4 treatments have been performed
Study Arms  ICMJE
  • Active Comparator: Hybrid argon plasma ablation (HAPC)
    Eligible participants will be randomized to receive ablation of dysplasia with Hybrid argon plasma coagulation (HAPC) after EMR of visible lesions (if present) has been performed as per standard of care.
    Intervention: Device: Hybrid argon plasma ablation (HAPC)
  • Active Comparator: Radiofrequency ablation (RFA)
    Eligible participants will be randomized to receive treatment of dysplasia with RFA after EMR of visible lesions (if present) has been performed as per standard of care.
    Intervention: Device: Radiofrequency ablation (RFA)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 6, 2018)
144
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age of 18-85 years (inclusive)
  • Dysplastic BE, confirmed by the central pathologist; specifically:

    • Low grade dysplasia documented on biopsy within 6 months of consent date or
    • High grade dysplasia documented on biopsy within 6 months of consent date
  • Barrett's extent of: C/M≥1 cm and C/M ≤ 6 cm using the Prague criteria [C = circumferential extent of disease / M = maximum extent of disease]
  • Ability to provide written and informed consent

Exclusion Criteria:

  • Barrett's extent of: C/M <1 cm or a C/M-value > 6 cm using the Prague criteria
  • Prior EMR (endoscopic mucosal resection) for G3/G4; L1; V1; R1 (vertical margin only) or submucosal invasion;
  • Presence of endoscopically visible abnormalities at the time of initial study treatment with HAPC or RFA. These participants can undergo EMR and then continue in the trial after a suitable healing period, provided randomization can occur within 90 days of consent.
  • Presence of invasive cancer on biopsy
  • Known pregnancy or plans to become pregnant
  • Complete eradication is not considered a relevant treatment goal or in whom additional treatment is contraindicated;
  • pre-existing significant esophageal pain or dysphagia;
  • BE >80% has been resected by EMR;
  • incomplete wound healing 3 months post-EMR despite adequate PPImedication;
  • Prior ablative therapy in the esophagus but prior EMR allowed
  • Active esophagitis or stricture precluding passage of scope
  • Presence of esophageal varices
  • Anticoagulant therapy (apart from aspirin or NSAIDS) that cannot be discontinued prior to therapy or uncorrectable hemostatic disorders
  • Life expectancy less than 2 years
  • Previous gastrectomy or other gastric surgery other than uncomplicated fundoplication
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 86 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: April Higbee, R.N., B.S.N. 816-861-4700 ext 57456 april.higbee@va.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03621319
Other Study ID Numbers  ICMJE 2015_1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Erbe Elektromedizin GmbH
Study Sponsor  ICMJE Erbe Elektromedizin GmbH
Collaborators  ICMJE
  • Erbe USA Incorporated
  • Kansas City Veteran Affairs Medical Center
  • Emissary International LLC
Investigators  ICMJE
Principal Investigator: Prateek Sharma, MD Kansas City Veterans Affairs Medical
PRS Account Erbe Elektromedizin GmbH
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP