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A Prospective Pilot Study to Assess the Efficacy of BOTOX-A in Patients With Low Anterior Resection Syndrome (LARS>20) and Refractory Medical Treatment After Rectal Resection (BOTOX-TME)

Primary Purpose

Low Anterior Resection Syndrome (LARS>20), Refractory Medical Treatment After Rectal Resection

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
BOTOX-A
Sponsored by
University Hospital, Bordeaux
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Low Anterior Resection Syndrome (LARS>20) focused on measuring Rectal surgery, Low Anterior Resection syndrome, Refractory medical treatment, Fecal incontinence

Eligibility Criteria

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

Inclusion Criteria:

  • Patient: male and female, age ≥18 years
  • Tumour: rectal cancer
  • Surgery: anterior resection (high or low) with colorectal or coloanal anastomosis, or intersphincteric resection, or pull-through
  • Symptoms: Low Anterior Resection Syndrome (LARS score >20) refractory to medical treatment at 3 months after rectal surgery (or after temporary stoma closed)
  • Straight or pouch colonic reconstruction
  • Surgery alone or with neoadjuvant therapy (chemoradiotherapy, short course radiotherapy, induction chemotherapy)
  • Signed and dated informed consent
  • Patient affiliated to a social security system or beneficiary of the same
  • Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

  • Anal cancer
  • Anal surgery in the last 3 months
  • Acute/painful perianal disease
  • Ongoing adjuvant treatment
  • Contraindication for BOTOX-A (known hypersensitivity to botulinum toxin type A or to albumin, infection at the proposed injection site, severe myasthenia)
  • Have received BOTOX-A in perianal region in the previous 3 months
  • General anesthesia performed less than a month
  • Impossibility of performing a rectoscopy (eg: anal stenosis)
  • Recent history (<12 months) of myocardial infarction and / or arrhythmias not reduced by appropriate treatment
  • Subject with a significant deficit of clinical or subclinical neuromuscular transmission (myasthenia or Lambert-Eaton syndrome) or with peripheral motor neuropathy (such as amyotrophic lateral sclerosis or motor neuropathy)
  • Treatment that directly or indirectly interferes with neuromuscular transmission (aminoglycosides, curare, anticholinesterase, aminoquinoline, cyclosporine, etc.)
  • History of neuromuscular disorders
  • Anal clinical examination suggesting the presence of an anorectal abscess
  • Pregnant woman or breastfeeding woman
  • Women of child-bearing potential (WOCBP)* not using effective contraception (oestrogen-progesteron combined contraceptives or intra uterine device) since at least 7 days and during all the duration of the study
  • Persons deprived of their liberty or under measure of judicial protection (curatorship or guardianship) or unable to give their consent
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule, as assessed by investigator.

Sites / Locations

  • CHU BordeauxRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BOTOX-A

Arm Description

Outcomes

Primary Outcome Measures

Proportion of patients with LARS > 20

Secondary Outcome Measures

Compliance to treatment
Proportion of patients receiving full injections, 10 injections of 20U of toxin. A total of 200U of BOTOX A will be injected
Tolerance to treatment
Number of patients with adverse events
Functional outcome with LARS score
The LARS questionnaire (Low Anterior Resection Syndrome) was the primary end-pointy and evaluate bowel function. Five questions regarding incontinence for flatus and liquid stools, frequency, clustering and urgency for defecation are taken into account. The score ranges from 0 to 42 is divides into no LARS (0 to 20 points), minor LARS (21 to 29 points), and major LARS (30 to 42 points)
Faecal incontinence with Wexner score
The Wexner score assesses the importance of anal incontinence, it varies from 0 to 20, 20 corresponding to total incontinence
Quality of life (QLQ C-30)
The scores of questionnaire QLQ C-30 will be examined The EORTC QLQ-C30 is a patients self-rating questionnaire that measures physical, role, social, emotional, and cognitive functions as well as overall QoL. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.
Quality of life (QLQ CR-29)
The scores of questionnaire QLQ CR-29 will be examined The EORTC QLQ-CR29 has five functional and 18 symptom scales. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.
Evaluation of Anxiety profil (STAI-Y : State-Trait Anxiety Inventory )
For evaluation of Anxiety profil , the "state" instructions is used, which require participants to report how they feel "right now, at this moment," and the "trait" instruction, which ask them to indicate how they "generally"feel. . For each subscales, scores range from 10 to 40, with higher scores correlating with greater state or trait anxiety.
Evaluation of manometry
Manometry will measure the pressure in mmHg of the ano-rectal passage, specifically pressures corresponding to the internal and external sphincter, and rectum. The resting pressure and squeeze pressure will be assessed. Sensitivity test to assess first sensation of gas, urge to defecate, and urgency will also be assessed.
Evaluation of barostat
Barostat allows the measurement of rectal capacity (ml) and compliance (ml/mmHg). Compliance is a dynamic property of the rectum, calculated from a sigmoid curve of pressure vs volume created by a step wise incremental distention sequence of a balloon placed in the rectum. Compliance of the patient population (post TME surgery) can be compared to compliance of non-operated rectums from published data. The investigators anticipate that our patient population will have a less compliant neo-rectum and hope to see a difference after Botox-A injection
Proportion of patients with LARS ≤ 20
Correlation between LARS and physiologic tests
The correlation of objective physiologic measures such as manometry and barostat will be compared and correlated to the symptoms described by the patient in the LARS questionnaire before and after injection of Botox-A in the neo-rectum.The investigators anticipate a correlation of increased compliance in the neo rectum with improvement of symptoms (lower LARS score) post Botox-A injection

Full Information

First Posted
June 25, 2021
Last Updated
August 12, 2022
Sponsor
University Hospital, Bordeaux
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1. Study Identification

Unique Protocol Identification Number
NCT04991688
Brief Title
A Prospective Pilot Study to Assess the Efficacy of BOTOX-A in Patients With Low Anterior Resection Syndrome (LARS>20) and Refractory Medical Treatment After Rectal Resection
Acronym
BOTOX-TME
Official Title
A Prospective Pilot Study to Assess the Efficacy of Botox-A in Patients With Low Anterior Resection Syndrome (LARS>20) and Refractory Medical Treatment After Rectal Resection
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 1, 2021 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

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

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
After rectal resection for cancer (with or without stoma), patients may have digestive sequelae. LARS (Low Anterior Resection Syndrome) includes bowel frequency, stool fragmentation, urgency, and faecal incontinence. The goal of this study is to test intra-rectal BOTOX-A on functional outcomes and quality of life of patients with LARS refractory to medical treatment at 3 months after surgery.
Detailed Description
Bowel dysfunction after low anterior resection (rectal excision) is referred as Low Anterior Resection Syndrome (LARS). LARS includes bowel frequency, stool fragmentation, urgency, and faecal incontinence. LARS negatively affects patients' quality of life by impacting emotional, physical, social, and role functioning. Symptoms may persist up to 15 years after surgery. The treatment options for LARS include successively conservative options, as medical drugs and biofeedback, and aggressive options, as retrograde colonic washout, sacral neuromodulation, antegrade colonic enema via a caecostomy, or a definitive colostomy. The effectiveness of conservative treatment remains uncertain and the aggressive treatments are associated with daily constraints and potential morbidity. These findings highlight the need for more efficient treatments BOTOX-A is a neurotoxin inhibiting acetylcholine release at the neuromuscular junction. BOTOX-A has displayed significant benefits in patients with urinary incontinence, demonstrating significant efficacy as compared to placebo. Intra-rectal injections of Botox-A has been trialed for the treatment of over active rectum induced fecal incontinence. Improvement of symptoms and quality of life have been demonstrated. Currently an ongoing national multicenter trial in France, IF Toxine (N° CLINICAL TRIAL: NCT02414425), has included 200 patients to assess Botox-A intra-rectal injections as a treatment option for fecal incontinence, without any safety concerns observed. The investigators anticipate that BOTOX-A injections could represent a medical option to treat digestive dysfunction (LARS) after surgery for rectal cancer, by reducing the spasm of the smooth muscle in the colon working as a neorectum. Globally 50% of patients were refractory to medical treatment (LARS score > 20) at 3 months after surgery. Of those, only 30% of them were improved by prolonged medical treatment between 3 and 6 months. The investigators anticipate that 60 % of them will be improved by association of medical treatment and BOTOX-A injection. The objective is to assess the efficacy of BOTOX-A on the proportion of patients with bowel dysfunction (LARS score > 20) at 3 months after injection.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Low Anterior Resection Syndrome (LARS>20), Refractory Medical Treatment After Rectal Resection
Keywords
Rectal surgery, Low Anterior Resection syndrome, Refractory medical treatment, Fecal incontinence

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
BOTOX-A
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
BOTOX-A
Intervention Description
10 injections of 20 U of toxin will be made into the rectum 5, 10 and 15 cm above the pectinate line. At each level, 3 injections of 20 U will be performed in the submucosa, circumferentially.The last injection is made 20 cm above the pectinate line. Total does not exceed 200U of Botox-A
Primary Outcome Measure Information:
Title
Proportion of patients with LARS > 20
Time Frame
At 3 months after injection
Secondary Outcome Measure Information:
Title
Compliance to treatment
Description
Proportion of patients receiving full injections, 10 injections of 20U of toxin. A total of 200U of BOTOX A will be injected
Time Frame
At 3 months after injection
Title
Tolerance to treatment
Description
Number of patients with adverse events
Time Frame
At 3 months after injection
Title
Functional outcome with LARS score
Description
The LARS questionnaire (Low Anterior Resection Syndrome) was the primary end-pointy and evaluate bowel function. Five questions regarding incontinence for flatus and liquid stools, frequency, clustering and urgency for defecation are taken into account. The score ranges from 0 to 42 is divides into no LARS (0 to 20 points), minor LARS (21 to 29 points), and major LARS (30 to 42 points)
Time Frame
At 0, 1, 2, 3 and 6 months
Title
Faecal incontinence with Wexner score
Description
The Wexner score assesses the importance of anal incontinence, it varies from 0 to 20, 20 corresponding to total incontinence
Time Frame
At 0, 1, 2, 3 and 6 months
Title
Quality of life (QLQ C-30)
Description
The scores of questionnaire QLQ C-30 will be examined The EORTC QLQ-C30 is a patients self-rating questionnaire that measures physical, role, social, emotional, and cognitive functions as well as overall QoL. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.
Time Frame
At 0, 1, 3 and 6 months
Title
Quality of life (QLQ CR-29)
Description
The scores of questionnaire QLQ CR-29 will be examined The EORTC QLQ-CR29 has five functional and 18 symptom scales. Scores can be linearly transformed to provide a score from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms of the symptom scales.
Time Frame
At 0, 1, 3 and 6 months
Title
Evaluation of Anxiety profil (STAI-Y : State-Trait Anxiety Inventory )
Description
For evaluation of Anxiety profil , the "state" instructions is used, which require participants to report how they feel "right now, at this moment," and the "trait" instruction, which ask them to indicate how they "generally"feel. . For each subscales, scores range from 10 to 40, with higher scores correlating with greater state or trait anxiety.
Time Frame
At 0, 1, 3 and 6 months
Title
Evaluation of manometry
Description
Manometry will measure the pressure in mmHg of the ano-rectal passage, specifically pressures corresponding to the internal and external sphincter, and rectum. The resting pressure and squeeze pressure will be assessed. Sensitivity test to assess first sensation of gas, urge to defecate, and urgency will also be assessed.
Time Frame
At 0, 1, 3 and 6 months
Title
Evaluation of barostat
Description
Barostat allows the measurement of rectal capacity (ml) and compliance (ml/mmHg). Compliance is a dynamic property of the rectum, calculated from a sigmoid curve of pressure vs volume created by a step wise incremental distention sequence of a balloon placed in the rectum. Compliance of the patient population (post TME surgery) can be compared to compliance of non-operated rectums from published data. The investigators anticipate that our patient population will have a less compliant neo-rectum and hope to see a difference after Botox-A injection
Time Frame
At 0, 1, 3 and 6 months
Title
Proportion of patients with LARS ≤ 20
Time Frame
At 6 months
Title
Correlation between LARS and physiologic tests
Description
The correlation of objective physiologic measures such as manometry and barostat will be compared and correlated to the symptoms described by the patient in the LARS questionnaire before and after injection of Botox-A in the neo-rectum.The investigators anticipate a correlation of increased compliance in the neo rectum with improvement of symptoms (lower LARS score) post Botox-A injection
Time Frame
At 0, 1, 2, 3 and 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient: male and female, age ≥18 years Tumour: rectal cancer Surgery: anterior resection (high or low) with colorectal or coloanal anastomosis, or intersphincteric resection, or pull-through Symptoms: Low Anterior Resection Syndrome (LARS score >20) refractory to medical treatment at 3 months after rectal surgery (or after temporary stoma closed) Straight or pouch colonic reconstruction Surgery alone or with neoadjuvant therapy (chemoradiotherapy, short course radiotherapy, induction chemotherapy) Signed and dated informed consent Patient affiliated to a social security system or beneficiary of the same Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Exclusion Criteria: Anal cancer Anal surgery in the last 3 months Acute/painful perianal disease Ongoing adjuvant treatment Contraindication for BOTOX-A (known hypersensitivity to botulinum toxin type A or to albumin, infection at the proposed injection site, severe myasthenia) Have received BOTOX-A in perianal region in the previous 3 months General anesthesia performed less than a month Impossibility of performing a rectoscopy (eg: anal stenosis) Recent history (<12 months) of myocardial infarction and / or arrhythmias not reduced by appropriate treatment Subject with a significant deficit of clinical or subclinical neuromuscular transmission (myasthenia or Lambert-Eaton syndrome) or with peripheral motor neuropathy (such as amyotrophic lateral sclerosis or motor neuropathy) Treatment that directly or indirectly interferes with neuromuscular transmission (aminoglycosides, curare, anticholinesterase, aminoquinoline, cyclosporine, etc.) History of neuromuscular disorders Anal clinical examination suggesting the presence of an anorectal abscess Pregnant woman or breastfeeding woman Women of child-bearing potential (WOCBP)* not using effective contraception (oestrogen-progesteron combined contraceptives or intra uterine device) since at least 7 days and during all the duration of the study Persons deprived of their liberty or under measure of judicial protection (curatorship or guardianship) or unable to give their consent Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule, as assessed by investigator.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Eric RULLIER
Phone
05 56 79 58 10
Email
eric.rullier@chu-bordeaux.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Franck ZERBIB
Email
franck.zerbib@chu-bordeaux.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eric RULLIER
Organizational Affiliation
University Hospital, Bordeaux
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Bordeaux
City
Bordeaux
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eric RULLIER
Email
eric.rullier@chu-bordeaux.fr

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

A Prospective Pilot Study to Assess the Efficacy of BOTOX-A in Patients With Low Anterior Resection Syndrome (LARS>20) and Refractory Medical Treatment After Rectal Resection

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