Botulinum Toxin Injection in the UES for R-CPD (BOTUS R-CPD)

Botulinum Toxin Injection in the Upper Esophageal Sphincter for Retrograde-cricopharyngeus Dysfunction: a Prospective, Double Blind, Placebo-controlled Trial

The aim of this study is to assess the effect of botulinum toxin injection into the upper esophageal sphincter in a double blind, placebo controlled study. Investigators want to assess the effect on symptoms short term (1-20 weeks after BT injection), and long term (48 weeks after BT injection).

This is a prospective double-blind randomized placebo-controlled study. Questionnaires assessing symptoms will be filled out on several occasions. At 20 weeks, a reassessment of symptoms will be done, without unblinding patients or investigator. Failures (to BT or placebo, defined as no clinical improvement or improvement less than 50%) will get the chance to receive a second procedure with active treatment (BT) in open label.

Study Overview

• Status: Active, not recruiting
• Conditions: Retrograde Cricopharyngeus Dysfunction
• Intervention / Treatment: Drug: botulinum toxin type A; Drug: Sodium Chloride 0.9% Inj

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Roeselare, Belgium
    • AZ Delta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Participants eligible for inclusion in this Trial must meet all of the following criteria:

1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
2. Use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner.
3. Between 18 and 65 years old

4. Inability to belch, which is bothersome enough to consider treatment*, present for at least 6 months prior to inclusion, and in fulfillment of both categories a and b below:,

   1. presence of associated gastrointestinal symptoms such as abdominal bloating and discomfort/nausea, flatulence, gurgling noises from the chest or lower neck.
   2. Absence of other pharyngeal and esophageal pathologies, determined on the basis of history taking and diagnostic tests.

5. Typical findings on high resolution impedance manometry with belch provocation test (10). These typical findings include: No relaxation upon gastroesophageal gas reflux, no air clearance via the UES but instead an increased air presence time include air entrapment and oscillations.

   • Bothersome = severe enough to impact on usual activities, according to the Rome IV diagnostic criteria (11, 12).

Participants eligible for this Trial must not meet any of the following criteria:

1. Participant has a history of surgery in the upper GI tract, that might interfere with the belch reflex (such as anti-reflux surgery)
2. Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol
3. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial, to be decided at the discretion of the investigator.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential (WOCBP) and not using an adequate, highly effective contraceptive
5. Participation in another interventional Trial with an investigational medicinal product (IMP) or device
6. >65 years old; < 18 years of age
7. Known hypersensitivity to botulinum toxin type A or to human albumin or sodium chloride
8. Presence of infection at the proposed injection site(s).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botulinum toxin injection	Drug: botulinum toxin type A; Botulinum toxin type A 75U dissolved in 3mL physiological serum injection in the upper esophageal sphincter
Placebo Comparator: Placebo injection	Drug: Sodium Chloride 0.9% Inj; Placebo: physiological serum 3mL injection in the upper esophageal sphincter

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to Botox versus placebo, 12 weeks after treatment.	This questionnaire is a treatment effect measure specific for inability to belch, where the change in symptoms from baseline is assessed, on a scale from 0% to 100%. 100% means complete resolution of symptoms, 0% means no improvement.	week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to botox versus placebo 48 weeks after treatment.	We will use the questionnaire of 'Difficulties with belching', and response is defined as at least a 50% improvement on question 6A 'To what extent have the symptoms of 'difficulty burping air' been reduced after treatment?'.	48 weeks
Safety: count of each type of (serious) adverse events in each group	Safety: assessed by the number and type of (serious) adverse events that occurred in each group by week 48	4 weeks
Safety on swallowing: with SSQ	assessed by the Sydney Swallow Questionnaire 1 week and 4 weeks after the procedure.	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HRQOL	HRQOL using EQ-5D VAS score short-term (1, 4,12 weeks) and long-term (20 - 48 weeks after the procedure).	1 to 48 weeks
Patients experience and satisfaction of the treatment using overall treatment effect	Patients experience and satisfaction of the treatment based on OTE short-term (1, 4, 12 weeks after the procedure), and long-term (20 - 48 weeks after the procedure) OTE is an outcome measure with 9 choices: going from -4: it has become insupportable, in the middle 0: unchanged, and at the end +4: the symptoms have completely resolved.	1-48 weeks
Patients experience and satisfaction of the treatment using overall symptom severity	Patients experience and satisfaction of the treatment based on OSS short-term (1, 4, 12 weeks after the procedure), and long-term (20 - 48 weeks after the procedure)	1-48 weeks
Evolution of associated abdominal bloating using a VAS score for symptom severity	Evolution of associated abdominal bloating short-term (1, 4, 12 weeks) and long-term (20 - 48 weeks after the procedure).	1-48 weeks
Evolution of associated abdominal/thoracic pain using a VAS score for symptom severity	Evolution of associated abdominal/thoracic pain short-term (1, 4, 12 weeks) and long-term (20 - 48 weeks after the procedure).	1-48 weeks
Evolution of associated flatulence using a VAS score for symptom severity	Evolution of associated flatulence short-term (1, 4, 12 weeks) and long-term (20 - 48 weeks after the procedure).	1-48 weeks
Evolution of associated gurgling noises using a VAS score for symptom severity	Evolution of associated gurgling noises short-term (1, 4, 12 weeks) and long-term (20 - 48 weeks after the procedure).	1-48 weeks
Safety during follow-up, with SSQ at week 12, 20 and 48.	Safety during follow-up, with SSQ at week 12, 20 and 48.	12-48 weeks
Change in objective measurement of UES pressure upon belching during high resolution impedance manometry	Change in objective measurements after, versus before BT injeciton using high resolution impedance manometry at week 20, and comparing with baseline.	20 weeks
Change in objective measurement of oscillatory movement of air during high resolution impedance manometry	Change in objective measurements after, versus before BT injeciton using high resolution impedance manometry at week 20, and comparing with baseline.	20 weeks
Improvement of symptoms not reaching primary outcome	Improvement in symptoms after Botox versus placebo, 12 and 48 weeks after treatment. We will use the questionnaire of 'Difficulties with belching', using a cut-off for improvement of 30% on question 6A 'To what extent have the symptoms of 'difficulty burping air' been reduced after treatment?'.	48 weeks

Collaborators and Investigators

• Sponsor: AZ Delta
• Collaborators: KU Leuven
• Investigators: Principal Investigator: Kathelijne G Delsupehe, MD, AZ Delta

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: March 20, 2024
• First Submitted That Met QC Criteria: April 8, 2024
• First Posted (Actual): April 10, 2024

Study Record Updates

• Last Update Posted (Actual): December 8, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Hydrolases; Enzymes; Enzymes and Coenzymes; Inorganic Chemicals; Chlorine Compounds; Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Metalloproteases; Bacterial Proteins; Bacterial Toxins; Toxins, Biological; Sodium Compounds; Chlorides; Hydrochloric Acid; Botulinum Toxins, Type A; Sodium Chloride
• Other Study ID Numbers: 52082; 2024-512546-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No