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Mechanisms of Action on Rectal Motricity of Intrarectal Botulinum Toxin Injections (MECA-TOX)

Primary Purpose

Fecal Incontinence

Status
Not yet recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
intra-rectal botulinum toxin injections
Sponsored by
University Hospital, Rouen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fecal Incontinence

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Active or predominantly active fecal incontinence with failure of 1st-line conservative treatments (normalization of transit, perineal re-education) Impairment of quality of life at investigator's discretion Patients at least 18 years of age Patients who have read and understood the information letter and signed the consent form Patients affiliated to the French Social Security system Women of childbearing age using effective contraception (Cf. CTFG) (estro- progestins or intrauterine device or tubal ligation) for at least 1 month and a negative B-HCG urine pregnancy test at inclusion and for the duration of the study. Postmenopausal women: confirmatory diagnosis (non-medically induced amenorrhea for at least 12 months prior to inclusion visit) Exclusion Criteria: General Pregnant women, women in labor, breastfeeding women, or women without proven contraception Patient deprived of liberty by administrative or judicial decision, or protected adult (under guardianship or trusteeship) Exclusive passive fecal incontinence Patient suffering from constipation (Rome IV criteria) Patient with an evolving inflammatory or cancerous digestive pathology Previous rectal surgery Person participating in another research protocol or having participated in another research protocol in the 4 weeks preceding the inclusion visit Linked to botulinum toxin injections Hypersensitivity to botulinum toxin or to one of the excipients (human albumin, sodium chloride) Neuromuscular junction pathology (myasthenia, Lambert-Eaton syndrome, etc.) Presence of infection at injection site(s) General anesthesia less than one month ago Association with aminoglycosides and anti-cholinesterase agents (risk of increased toxin effects) History of neurogenic damage such as polyradiculoneuritis History of dysphagia with esophageal or neurological stasis, swallowing disorders, inhalation pneumonitis Botulinum toxin injections in the 3 months preceding the study Clinical anal examination suggestive of anorectal abscess Recent history (<12 months) of myocardial infarction and/or rhythm disorders not reduced by appropriate treatment Peripheral motor neuropathies (such as amyotrophic lateral sclerosis or motor neuropathy) and underlying neurological disorders Current treatment with anticoagulants or anti-aggregants or haemostasis disorders according to recommendations (SFED). When patients are on anticoagulant or anti-aggregant therapy, the type of injections to be performed depends on the type of anticoagulation and the patient's thrombo-embolic risk: Patients on anticoagulant or anti-aggregant therapy with a major thrombo-embolic risk will not be included. Patients on anticoagulant or anti-aggregant therapy with a moderate or low thrombo-embolic risk may be included. If patients are taking a vitamin K antagonist, treatment will be continued provided that the INR is within the usual range of 2 to 3 (GETED, HAS, 2008). If patients are taking anti-aggregants, these can be continued (SFED, HAS, 2012). If patients are taking new oral anticoagulants, they should take a short break and not take the AOD the evening before or the morning of the injections (GIHP, 2015). Linked to rectosigmoidoscopy Local pathology preventing colonoscopy (anal stenosis) Allergy or hypersensitivity to silicone and/or latex Linked to laxatives Contraindication to DULCOLAX® 5 mg, gastro-resistant coated tablet Contraindication to XIMEPEG®, powder for oral solution Linked to high-resolution manometry Clinically diagnosed intestinal obstruction Severe coagulopathy or oral anticoagulants Cardiac disorders for which vagal stimulation is poorly tolerated

Sites / Locations

  • Univesity Hospital, Rouen

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

intra-rectal botulinum toxin injections

Arm Description

Patients with fecal incontinence who have failed conservative treatments and are candidates for intra-rectal botulinum toxin injections.

Outcomes

Primary Outcome Measures

high amplitude propagative contractions
The primary endpoint is the time to onset of high amplitude propagative contractions (HAPC) after instillation of DULCOLAX® in the sigmoid and rectum, before and 1 month after intrarectal botulinum toxin injections.

Secondary Outcome Measures

Characteristics of contractions in the rectum and sigmoid
Amplitude of contractions in the rectum and sigmoid
Probe expulsion
Probe expulsion (which is an indirect sign of colorectal motricity efficiency) and time to probe expulsion.
Anal incontinence severity score
Anal incontinence severity score (Cleveland Score) and stool schedule before and 1 month after botulinum toxin injections.
Quality of life score
Quality of life score (FIQL Score, Appendix 4) before and 1 month after botulinum toxin injections.
Adverse events
Adverse events will be collected at each visits

Full Information

First Posted
August 2, 2023
Last Updated
August 10, 2023
Sponsor
University Hospital, Rouen
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1. Study Identification

Unique Protocol Identification Number
NCT05998187
Brief Title
Mechanisms of Action on Rectal Motricity of Intrarectal Botulinum Toxin Injections
Acronym
MECA-TOX
Official Title
Mechanisms of Action on Rectal Motricity of Intrarectal Botulinum Toxin Injections in Patients With Fecal Incontinence
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 1, 2023 (Anticipated)
Primary Completion Date
June 1, 2027 (Anticipated)
Study Completion Date
December 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Rouen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Previous studies have demonstrated the efficacy of this treatment in certain patients suffering from fecal incontinence, but it is not yet reimbursed in this indication as it is still in the evaluation phase. Indeed, little is known about botulinum toxin mechanisms of action. The aim of this study is to better understand the mechanisms of action of intra-rectal botulinum toxin injections, so that the investigators can identify the patients most likely to benefit from this treatment in the future.
Detailed Description
Fecal incontinence is a common condition, affecting around 5 to 6% of general population. Although not a serious condition, it severely impairs quality of life and leads to social isolation. Fecal incontinence also has a significant medico-economic cost. When first-line medical treatments fail (transit-regulating therapies, perineal re-education), fecal incontinence patients can be offered treatment with sacral nerve neuromodulation. However, this therapy will only be effective in the long term, and in terms of intention to treat, in less than half of patients who have had the device definitively implanted. Today, no other treatments are available apart from sphincter repair, for which the indications are very limited, or colostomy. The investigator's team has therefore developed another therapeutic option, intra-rectal injections of botulinum toxin, in patients suffering from active fecal incontinence (i.e., preceded by defecatory urgency). The investigator have conducted two pilot studies, which demonstrated the efficacy of this treatment in an open-label setting, and the investigator are currently completing a randomized, double-blind, controlled study to confirm its efficacy (PHRCN 2014-003650-14). Nevertheless, the mechanisms of action of intra-rectal botulinum toxin injections remain hypothetical. By analogy with the intra-detrusor injections used for over 20 years to treat overactive bladder disease, it is possible that the toxin plays an inhibitory role on rectal motricity. Botulinum toxin inhibits the release of acetylcholine at the neuromuscular junction. Without this release, smooth muscle contraction cannot take place. In one of the two pilot, intra-rectal injections of botulinum toxin were performed in 6 patients with fecal incontinence and hyperactivity of the rectum or colonic reservoir after resection. In addition to the clinically demonstrated effect of these injections, there was a significant reduction in the amplitude of rectal contractions after injection. However, there was no correlation between the observed motor effect of botulinum toxin and the efficacy of the injections. Moreover, some patients did not exhibit colonic or rectal hypermotricity and still benefited from the injections. The investigator would like to continue exploring the motor effect of intra-rectal toxin injections on a larger group of patients suffering from faecal incontinence, using a more powerful motor recording system than anorectal manometry. For this work, we hypothesize that intra-rectal botulinum toxin injections act primarily via a motor effect by inhibiting propagated rectal contractions. To test this hypothesis, a high-resolution recto-sigmoid manometry probe will be used to evaluate rectal and sigmoidal motricity spontaneously and in response to stimulant laxative injection, before and after intra-rectal injection of botulinum toxin. Patients included will be those suffering from faecal incontinence who have failed conservative treatments and are candidates for intra-rectal injections of botulinum toxin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fecal Incontinence

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Model Description
Single arm
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
intra-rectal botulinum toxin injections
Arm Type
Experimental
Arm Description
Patients with fecal incontinence who have failed conservative treatments and are candidates for intra-rectal botulinum toxin injections.
Intervention Type
Drug
Intervention Name(s)
intra-rectal botulinum toxin injections
Intervention Description
Patients with fecal incontinence who have failed conservative treatments and are candidates for intra-rectal botulinum toxin injections.
Primary Outcome Measure Information:
Title
high amplitude propagative contractions
Description
The primary endpoint is the time to onset of high amplitude propagative contractions (HAPC) after instillation of DULCOLAX® in the sigmoid and rectum, before and 1 month after intrarectal botulinum toxin injections.
Time Frame
before and 1 month after intrarectal botulinum toxin injections.
Secondary Outcome Measure Information:
Title
Characteristics of contractions in the rectum and sigmoid
Description
Amplitude of contractions in the rectum and sigmoid
Time Frame
before and 1 month after intrarectal botulinum toxin injections.
Title
Probe expulsion
Description
Probe expulsion (which is an indirect sign of colorectal motricity efficiency) and time to probe expulsion.
Time Frame
before and 1 month after intrarectal botulinum toxin injections.
Title
Anal incontinence severity score
Description
Anal incontinence severity score (Cleveland Score) and stool schedule before and 1 month after botulinum toxin injections.
Time Frame
before and 1 month after botulinum toxin injections.
Title
Quality of life score
Description
Quality of life score (FIQL Score, Appendix 4) before and 1 month after botulinum toxin injections.
Time Frame
before and 1 month after botulinum toxin injections.
Title
Adverse events
Description
Adverse events will be collected at each visits
Time Frame
at each visit, during 4 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Active or predominantly active fecal incontinence with failure of 1st-line conservative treatments (normalization of transit, perineal re-education) Impairment of quality of life at investigator's discretion Patients at least 18 years of age Patients who have read and understood the information letter and signed the consent form Patients affiliated to the French Social Security system Women of childbearing age using effective contraception (Cf. CTFG) (estro- progestins or intrauterine device or tubal ligation) for at least 1 month and a negative B-HCG urine pregnancy test at inclusion and for the duration of the study. Postmenopausal women: confirmatory diagnosis (non-medically induced amenorrhea for at least 12 months prior to inclusion visit) Exclusion Criteria: General Pregnant women, women in labor, breastfeeding women, or women without proven contraception Patient deprived of liberty by administrative or judicial decision, or protected adult (under guardianship or trusteeship) Exclusive passive fecal incontinence Patient suffering from constipation (Rome IV criteria) Patient with an evolving inflammatory or cancerous digestive pathology Previous rectal surgery Person participating in another research protocol or having participated in another research protocol in the 4 weeks preceding the inclusion visit Linked to botulinum toxin injections Hypersensitivity to botulinum toxin or to one of the excipients (human albumin, sodium chloride) Neuromuscular junction pathology (myasthenia, Lambert-Eaton syndrome, etc.) Presence of infection at injection site(s) General anesthesia less than one month ago Association with aminoglycosides and anti-cholinesterase agents (risk of increased toxin effects) History of neurogenic damage such as polyradiculoneuritis History of dysphagia with esophageal or neurological stasis, swallowing disorders, inhalation pneumonitis Botulinum toxin injections in the 3 months preceding the study Clinical anal examination suggestive of anorectal abscess Recent history (<12 months) of myocardial infarction and/or rhythm disorders not reduced by appropriate treatment Peripheral motor neuropathies (such as amyotrophic lateral sclerosis or motor neuropathy) and underlying neurological disorders Current treatment with anticoagulants or anti-aggregants or haemostasis disorders according to recommendations (SFED). When patients are on anticoagulant or anti-aggregant therapy, the type of injections to be performed depends on the type of anticoagulation and the patient's thrombo-embolic risk: Patients on anticoagulant or anti-aggregant therapy with a major thrombo-embolic risk will not be included. Patients on anticoagulant or anti-aggregant therapy with a moderate or low thrombo-embolic risk may be included. If patients are taking a vitamin K antagonist, treatment will be continued provided that the INR is within the usual range of 2 to 3 (GETED, HAS, 2008). If patients are taking anti-aggregants, these can be continued (SFED, HAS, 2012). If patients are taking new oral anticoagulants, they should take a short break and not take the AOD the evening before or the morning of the injections (GIHP, 2015). Linked to rectosigmoidoscopy Local pathology preventing colonoscopy (anal stenosis) Allergy or hypersensitivity to silicone and/or latex Linked to laxatives Contraindication to DULCOLAX® 5 mg, gastro-resistant coated tablet Contraindication to XIMEPEG®, powder for oral solution Linked to high-resolution manometry Clinically diagnosed intestinal obstruction Severe coagulopathy or oral anticoagulants Cardiac disorders for which vagal stimulation is poorly tolerated
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Charlotte DESPREZ
Phone
0232888039
Email
charlotte.desprez@chu-rouen.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charlotte DESPREZ
Organizational Affiliation
Rouen University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Univesity Hospital, Rouen
City
Rouen
ZIP/Postal Code
76031
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florian VALLIN
Phone
0232886697
Email
florian.vallin@chu-rouen.fr
First Name & Middle Initial & Last Name & Degree
David MALLET
Phone
0232888265
Email
secretariat.drc@chu-rouen.fr
First Name & Middle Initial & Last Name & Degree
Charlotte DESPREZ

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
27144630
Citation
Rao SS, Bharucha AE, Chiarioni G, Felt-Bersma R, Knowles C, Malcolm A, Wald A. Functional Anorectal Disorders. Gastroenterology. 2016 Mar 25:S0016-5085(16)00175-X 10.1053/j.gastro.2016.02.009. doi: 10.1053/j.gastro.2016.02.009. Online ahead of print.
Results Reference
background
PubMed Identifier
22513438
Citation
Xu X, Menees SB, Zochowski MK, Fenner DE. Economic cost of fecal incontinence. Dis Colon Rectum. 2012 May;55(5):586-98. doi: 10.1097/DCR.0b013e31823dfd6d.
Results Reference
background
PubMed Identifier
32740249
Citation
Desprez C, Damon H, Meurette G, Mege D, Faucheron JL, Brochard C, Lambrescak E, Gourcerol G, Mion F, Wyart V, Sielezneff I, Siproudhis L, Etienney I, Ajamie N, Lehur PA, Duflot T, Bridoux V, Leroi AM; Club NEMO. Ten-year Evaluation of a Large Retrospective Cohort Treated by Sacral Nerve Modulation for Fecal Incontinence: Results of a French Multicenter Study. Ann Surg. 2022 Apr 1;275(4):735-742. doi: 10.1097/SLA.0000000000004251.
Results Reference
background
PubMed Identifier
21689287
Citation
Bridoux V, Gourcerol G, Kianifard B, Touchais JY, Ducrotte P, Leroi AM, Michot F, Tuech JJ. Botulinum A toxin as a treatment for overactive rectum with associated faecal incontinence. Colorectal Dis. 2012 Mar;14(3):342-8. doi: 10.1111/j.1463-1318.2011.02585.x.
Results Reference
background
PubMed Identifier
26448532
Citation
Gourcerol G, Benard C, Melchior C, Touchais JY, Ducrotte P, Menard JF, Bridoux V, Leroi AM. Botulinum toxin: an endoscopic approach for treating fecal incontinence. Endoscopy. 2016 May;48(5):484-8. doi: 10.1055/s-0034-1393242. Epub 2015 Oct 8.
Results Reference
background

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Mechanisms of Action on Rectal Motricity of Intrarectal Botulinum Toxin Injections

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