Percutaneous Infracoccygeal Botulinum Toxin Injection to Puborectalis for the Treatment of Dyssynergic Defaecation: a Prospective Observational Study
Conditions: Dyssynergic Defaecation, Evacuation Disorder, Anismus, Defecation Disorder
Sponsor: Queen Mary University of London

 
 
 
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JRMO Research Protocol for  
Interventional Studies  
 
 
 
Full Title  
Percutaneous infracoccygeal Botulinum toxin 
injection to puborectalis for the treatment of 
dyssynergic defaecation: a prospective 
observational study 
 
Short Title 
Infracoccygeal Botox for Dyssynergia 
 
Sponsor 
Queen Mary University of London  
 
Contact person: 
 
Dr Mays Jawad 
Governance Operations Manager 
Joint Research Management Office 
 
Empire House 
                                                           67-75 New Road  
                                                           Whitechapel, E1 1HH 
 
Phone: 020 7882 7275/6574 
 
Email: research.governance@qmul.ac.uk 
 
 
IRAS Number 
291709 
 
Edge Number 
139999 
 
REC Reference 
21/NS/0088 
 
Chief Investigator (CI) 
Professor Charles Knowles 
 
Professor of Surgery & Hon. consultant 
colorectal surgeon Barts Health NHS Trust  
 
Director National Bowel Research Centre 
 
Deputy Director of Research, The Blizard 
Institute. 
 
Barts and the London School of Medicine and 
Dentistry, 
 
Queen Mary University of London, 
 
4 Newark Street, 
 
London, E1 2AT. 
 
Phone: 020 7882 8752 
 
List of sites 
The Royal London Hospital 
 
Professor Charles Knowles 
The Royal London Hospital 
Barts Health NHS Trust 
Whitechapel Road, E1 1FR  
 

 
 
 
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List of central facilities 
National Bowel Research Centre,  
Barts and the London School of Medicine and 
Dentistry, 
Professor Charles Knowles 
4 Newark Street, 
 
London, E1 2AT. 

 
 
 
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1. Contents 
 
1. 
Contents ......................................................................................................... 3 
2. 
Glossary ......................................................................................................... 6 
3. 
Signature page ............................................................................................... 7 
4. 
Summary and synopsis .................................................................................. 8 
5. 
Introduction ..................................................................................................... 9 
5.1 
Background ................................................................................................. 9 
5.2 
Rationale ................................................................................................... 10 
5.3 
Risks / benefits .......................................................................................... 11 
5.3.1 
Botulinum Toxin Type A related risks ............................................... 11 
5.3.2 
Risks related to injection .................................................................. 12 
5.3.3 
Risks related to NHS care (not part of proposed R&D) ................Error! 
Bookmark not defined. 
 
6. 
Study objectives ........................................................................................... 13 
6.1 
Primary objective....................................................................................... 13 
6.2 
Secondary objective .................................................................................. 13 
6.3 
Primary endpoint ....................................................................................... 13 
6.4 
Secondary endpoint .................................................................................. 13 
6.4.1 
Safety ............................................................................................... 14 
6.4.2 
Treatment acceptability .................................................................... 14 
6.4.3 
Clinical efficacy ................................................................................ 15 
 
7. 
Study population ........................................................................................... 15 
7.1 
Inclusion criteria ........................................................................................ 15 
7.2 
Exclusion criteria ....................................................................................... 16 
8. 
Study design ................................................................................................. 17 
9. 
Study procedures ......................................................................................... 17 
10. 
Assessment and management of risk ........................................................... 20 
11. 
Statistical considerations .............................................................................. 20 
11.1 Sample size .............................................................................................. 20 

 
 
 
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11.2 Method of analysis .................................................................................... 20 
12. 
Ethics ........................................................................................................... 21 
12.1 Annual Safety Reporting ........................................................................... 21 
13. 
Public Involvement........................................................................................ 21 
14. 
Data handling and record keeping ................................................................ 21 
14.1 Data management ..................................................................................... 21 
14.2 Source data ............................................................................................... 22 
14.3 Confidentiality ........................................................................................... 22 
14.4 Record Retention and Archiving ................................................................ 22 
15. 
Interventions and tools <delete any sections that are not applicable> ........... 23 
15.1 Devices ........................................................ Error! Bookmark not defined. 
15.2 Techniques and interventions ................................................................... 23 
15.3 Tools ......................................................................................................... 23 
15.4 Medicinal product ...................................................................................... 23 
15.5 Other biological or chemical products ........... Error! Bookmark not defined. 
16. 
Safety reporting ............................................................................................ 24 
16.1 Adverse Events (AEs) ............................................................................... 24 
16.2 Adverse Reaction (ARs) ............................................................................ 24 
16.3 Notification and reporting of Adverse Events and Reactions ..................... 24 
16.4 Serious Adverse Events (SAEs) or reactions ............................................ 24 
16.5 Notification and reporting of Serious Adverse Events ................................ 25 
16.6 Urgent Safety Measures ............................................................................ 25 
16.7 Annual Safety Reporting ........................................................................... 25 
16.8 Overview of the Safety Reporting responsibilities ...................................... 25 
17. 
Monitoring and auditing ................................................................................ 25 
18. 
Trial committees ........................................................................................... 26 
19. 
Finance and funding ..................................................................................... 26 
20. 
Indemnity ...................................................................................................... 26 

 
 
 
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The insurance that Queen Mary University of London has in place provides cover for 
the design and management of the study as well as "No Fault Compensation" for 
participants, which provides an indemnity to participants for negligent and non-
negligent harm. ....................................................................................................... 26 
21. 
Dissemination of research findings ............................................................... 26 
22. 
References ................................................................................................... 26 
 
 

 
 
 
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2. Glossary 
 
AE 
 
Adverse Event 
AR 
 
Adverse Reaction 
BHT 
 
Barts Health NHS Trust 
BSFS   
Bristol Stool Form Scale 
BTXA   
Botulinum Toxin type A 
CI 
 
Chief investigator 
CCCS    
Cleveland Clinic constipation score 
CRF   
Case Report Form 
CTIMP  
Clinical Trial of an Investigational Medicinal Product 
DD  
  
Dyssynergic defaecation 
EMG    
Electromyography   
FI 
 
Faecal Incontinence 
GP 
 
General Practitioner 
IBS  
  
Irritable bowel syndrome  
IBS-C  
Irritable bowel syndrome with predominant constipation 
ICF 
 
Informed Consent Form 
MDT 
 
Multidisciplinary Team 
NBRC  
National Bowel Research Centre 
NICE  
The National Institute for Clinical Excellence 
PI 
 
Principal Investigator 
PIS 
 
Participant Information Sheet 
REC 
 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SMG  
Study Management Group 
SMIS  
St. Mark’s incontinence score 
USS   
Ultrasound scan 

 
 
 
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3. Signature page 
 
 
CI Agreement 
 
The study, as detailed within this Research Protocol, will be conducted in accordance 
with the principles of Good Clinical Practice (GCP), the UK Policy Framework for 
Health and Social Care Research, and the Declaration of Helsinki and any other 
applicable regulations. I agree to take responsibility for the statistical analysis and 
oversight of this study. 
 
 
CI Name: 
Prof CH Knowles____________ 
 
Signature: 
_________________ 
 
Date: 
03.10.19_________________ 
 
 
 

 
 
 
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4. Summary and synopsis 
 
Short title 
Infracoccygeal Botox for Dyssynergia 
Methodology 
Prospective observational study  
Research Site 
Royal London Hospital – Barts Health NHS Trust 
Objectives / aims 
Primary objective: 
- 
To demonstrate technical feasibility of percutaneous 
infracoccygeal Botulinum toxin type A (BTXA) 
injection as an alternative to transanal injection to 
puborectalis muscle for the treatment of dyssynergic 
defaecation. 
Secondary objectives: 
- 
To assess safety of this technique 
- 
To assess patient acceptability of this technique  
- 
To derive pilot clinical efficacy data to inform future 
trials 
Number of 
participants 
10 
Inclusion and 
exclusion criteria 
Inclusion criteria:  
- 
Adult patients (age 18 - 80) 
- 
Diagnosis of dyssynergic defaecation by published 
criteria  
- 
Ability to understand written and spoken English 
- 
Ability and willingness to give informed consent 
Exclusion criteria: 
- 
Paediatric patients (age under 18) 
- 
Contraindications to BTXA, including pregnancy 
- 
Contraindications to infracoccygeal injection 
- 
Morbid obesity (BMI ≥ 40)  
Statistical 
methodology and 
analysis (if 
applicable) 
Not applicable (descriptive summary statistics only)  
Study duration 
12 months  
 

 
 
 
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5. Introduction 
 
5.1 Background  
 
Patients with dyssynergic defaecation represent a subgroup of a larger group of 
patients presenting with symptoms of chronic constipation. The disorder is 
characterised by impaired stool expulsion as a result of inappropriate contraction 
of the pelvic floor musculation despite normal propulsive force during attempted 
defaecation.1 Failure of the puborectalis and/or anal sphincter muscles to relax 
during evacuation leads to a closed anal canal which prevents the emptying of 
stools. 1, 2 
  
A Cochrane review in 20142 on the treatment of chronic constipation in adults 
demonstrated a high prevalence of dyssynergic defaecation and a variety of 
treatments. In this group, biofeedback was found to be superior to oral 
diazepam, sham treatment, and laxatives; while surgical procedures such as 
partial division of the puborectalis muscle were more efficacious, the risks of 
adverse reaction, namely incontinence, were high. Thus, biofeedback therapy is 
the current gold-standard for the treatment of dyssynergia.1 The success rate of 
biofeedback in correcting or improving the symptoms in patients with 
dyssynergia varies between 33% and 80%.2 Difficulty arises in those in whom 
biofeedback is unsuccessful, as there is little, and conflicting, low quality 
evidence on alternative therapies.2 
 
One further therapeutic option uses injection of Botulinum toxin type A (BTXA) 
into the puborectalis and/or external anal sphincter muscles. This is currently the 
second-line treatment for dyssynergic defaecation in whom biofeedback has 
failed. A systematic review in 20163 on the use of BTXA in patients with 
‘anismus’, a term previously used to describe dyssynergic defaecation, 
demonstrated initial clinical improvement in symptoms in 77.4% of patients. Two 
of the seven studies were conducted on participants in whom biofeedback 
therapy had failed. Complications were reported in 7.4% of patients (0 to 22.6%) 
and included faecal incontinence, which was minor and transient,3 posterior anal 
fissure, and rectal prolapse. The effect of BTXA was not permanent, with clinical 
improvement declining to 46% at four months after the injection. For this reason, 
several studies4-6 offered repeated treatments.  
 
The delivery of BTXA injection varied between studies and institutions in terms of 
dosage and position of injection, but all were performed via perianal or transanal 
approaches, often requiring sedation or anaesthesia. There are several 
disadvantages of this approach including cost (operating theatre utilisation) and 
risks associated with anaesthesia and infection from passing the needle through 
a contaminated7 operative field. In addition, the injection site is defined blind by 
the surgeon’s finger (an issue of accuracy of injection and hazard of needle stick 
injury). 
 
The proposed study aims to demonstrate the technical feasibility of an 
alternative approach to delivering BTXA injection in adult patients with 
dyssynergic defaecation. This novel technique injects BTXA into the puborectalis 
muscle percutaneously using an infracoccygeal approach under ultrasound 
guidance. This allows the procedure to be performed in an outpatient radiology 
setting without the need for any form of anaesthesia or analgesia. The injection 

 
 
 
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is performed in a clean operative field away from the anus, minimising risk of 
infection and the muscle can be clearly visualised (see below). These 
advantages will be particularly valuable in patients who require repeated 
procedures or those with multiple co-morbidities at high anaesthetic risk.  
 
 
5.2 Rationale 
 
The utilisation of BTXA in human is well established. This medication is licensed 
for use in focal spasticity8 with well-established side-effects and interactions. 
Current evidence for the use of BTXA in dyssynergic defaecation is based on the 
conventional transanal approach, with report on efficacy and complications as 
previously stated.  
 
Figure 1. Anatomy of the anal canal and rectum 
 
Rao et al, 20161 
 
The puborectalis (see Figure 1.) is easily accessible below the coccyx, and is the 
site for ultrasonic assessment in the paediatric population.9 The identification of 
puborectalis muscle in the infracoccygeal position has not been described in the 
literature in the adult population. However, pilot imaging studies on a small 
number of non-obese subjects have been successful in easily identifying the 
puborectalis using ultrasound scan (see Figure 2.). This approach has the 
potential to allow accurate administration of BTXA injection under ultrasonic 
guidance in the outpatient setting without the need for anaesthesia or operating 
theatre utilisation.   

 
 
 
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Figure 2. Ultrasound scan of the puborectalis 
 
 
P = Puborectalis, Co = Coccyx, R = Rectum 
 
       (In prone position) 
 
The general aim of this study is to demonstrate that percutaneous infracoccygeal 
BTXA injection is a valid alternative approach to transanal injection for the 
treatment of dyssynergic defaecation. Specifically, we will determine technical 
feasibility (including pilot proof of mechanism), patient acceptability, safety, and 
pilot efficacy outcomes for a future definitive trial.  
 
5.3 Risks / benefits  
 
5.3.1 Botulinum Toxin Type A related risks 
 
The use of BTXA injection into the puborectalis and/or external anal 
sphincter muscles in patients with dyssynergic defaecation using the 
conventional transanal approach demonstrated initial clinical improvement 
in symptoms in 77.4% of patients, however in 46% of patients the effect 
was temporary and a repeat injection required.3  
 
The general side-effects of BTXA are stated in the British National 
Formulary8. On review of current evidence (11 studies pertaining to 246 
subjects), reported procedure specific side-effects relating to BTXA 
injection for the treatment of dyssynergic defaecation based on transanal 
injection include: 
1. Temporary incontinence – faecal incontinence occurred in 17 
cases (6.9%) from three studies10-12 and flatus incontinence 

 
 
 
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occurred in 10 cases (4.1%) from two studies.6, 12 The symptoms 
were minor and temporary in all studies.  
2. Posterior anal fissure – reported in two patients (0.8%) from a 
single study13 
3. Rectal prolapse – reported in a single patient (0.4%) from a single 
study13 
 
5.3.2 Risks related to injection  
 
Risks associated with ultrasound scan can be categorised as diagnostic 
errors and biological effects.14 With regards to the risk of diagnostic errors, 
imaging the puborectalis using ultrasonography has been performed 
routinely as part of anorectal physiology studies but only using a transanal 
or perineal approach. The potential of diagnostic error (wrong muscle) 
using the percutaneous infracoccygeal approach is unknown but pilot 
imaging studies on a small number of healthy subjects demonstrate that it 
is easy to locate and obvious in terms of morphology. Further, volitional 
contraction can be used to demonstrate contraction under vision (see 
Figure 2).  
 
Biological effects can be divided into thermal and mechanical effects. The 
National Council on Radiation Protection and Measurements (NCRP) 
report on the use of medical ultrasonography15 concluded that there is no 
evidence to suggest that ultrasound has caused any adverse effects, 
based on human epidemiological studies.    
 
The BTXA injection will be delivered through a narrow-gauge needle as 
used daily for muscle injections by a variety of health professionals 
worldwide. Slight soreness can be associated with injection, but risks of 
infection and bleeding are rare (<1/10,000).16 We will record muscle 
activity (pilot proof of mechanism) using the same needle electrode 
avoiding further discomfort to the patient above that experienced from the 
injection alone.  
 
Subcutaneous local anaesthetic infiltration with 1% lidocaine is routinely 
carried out for minor procedures. The general side-effects of lidocaine are 
stated in the British National Formulary.8 The maximum dosage is 4mg/kg 
(0.4ml/kg of 1% lidocaine) or 30ml, whichever is smaller. The amount 
required for this procedure is 5ml.  
 
5.3.3 Study benefits 
 
Participants will add to the knowledge base for the treatment options for 
patients with dyssynergic defaecation. Though not certain, participants 
may also benefit from improvement in their constipation symptoms.  

 
 
 
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6. Study objectives 
 
 
6.1 Primary objective 
 
The primary objective of this study is to establish the technical feasibility of 
percutaneous infracoccygeal BTXA injection to puborectalis muscle as an 
alternative to transanal puborectalis muscle injection for the treatment of 
dyssynergic defaecation.  
 
6.2 Secondary objective 
 
• 
To assess safety of this technique 
• 
To assess patient acceptability of this technique  
• 
To derive pilot clinical efficacy data to inform future trials 
 
6.3 Primary endpoint 
 
In order to measure technical practicability, the physician delivering the therapy 
will be asked to complete a physician acceptability questionnaire at the end of 
each procedure. The questionnaire subjectively measures the physician’s opinion 
of the procedure difficulty, patient’s discomfort, whether or not the procedure is 
considered successful, and any procedure limitations.  
 
Question/Statement 
Scoring 
1. Patient’s body habitus 
________ kg          ________ cm          ________ BMI  
2. Duration of procedure 
________ minutes 
3. Puborectalis identified by USS 
□ At rest   □ Voluntary contraction    
4. Puborectalis identified by EMG  
□ At rest   □ Voluntary contraction    
6. Difficulty of procedure 
□ Easy   □ Moderate   □ Difficult  
7. Reason for your answer in question 5. 
 
(Free text) 
 
8. Patient was comfortable 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly disagree 
9. Procedure was completed successfully 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly disagree 
10. Procedure limitations  
 
(Free text) 
 
 
Technical practicability will also be measured objectively by the rate of successful 
identification of the puborectalis: 
• Using ultrasound scan at rest and under voluntary contraction 
• Using EMG at rest and under voluntary contraction 
 
6.4 Secondary endpoint 
 

 
 
 
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6.4.1 Safety 
 
Expected adverse event (AE) related to BTXA injection of the puborectalis 
include:  
• 
Bruising at injection site 
• 
Local skin reaction at injection site 
• 
Pain at injection site 
• 
Infection at injection site 
• 
New or worsening faecal incontinence 
 
Following the injection, any adverse event reported by the patients will be 
recorded on the adverse event (AE) form on the patient’s eCRF using 
Research Electronic Data Capture (REDCap). This form will record the 
nature, severity, time of onset of, and treatment required for the AE. 
Patients are encouraged to self-report any adverse events as soon as 
possible by telephone. If no adverse events have been self-reported this 
will be confirmed with the patient at the end of every follow-up 
appointment as part of the follow-up procedure. In addition, at the time of 
first follow-up the injection site will be inspected for any signs of bruising, 
local skin reaction, or infection. At each follow-up, St. Mark’s incontinence 
score will also be measured to allow detection of new or worsening 
incontinence, which is the main procedure specific risk associated with 
this procedure. 
 
The severity of any adverse events will be classified according to the 
Clavien-Dindo classification18 of surgical complications: 
• 
Grade 1 – any deviation from normal post-operative course without 
need for pharmacological (antiemetics, antipyretics, analgesics, 
diuretics, and electrolytes are permitted), surgical, endoscopy, or 
radiological interventions  
• 
Grade 2 – requiring pharmacological treatment other than those 
permitted in 1 (including blood transfusion and total parenteral 
nutrition) 
• 
Grade 3 – requiring surgical, endoscopic, or radiological 
intervention 
o Grade 3a – not under general anaesthetic 
o Grade 3b – under general anaesthetic 
• 
Grade 4 – life-threatening complication requiring intensive care 
management 
o Grade 4a – single organ dysfunction, including dialysis 
o Grade 4b – multi-organ dysfunction 
• 
Grade 5 – death  
 
Serious adverse events (SAE) will be recorded as above and will also be 
reported as described in the safety reporting section (see Section 16). 
6.4.2 Treatment acceptability 
 
Treatment acceptability will be measured objectively by the recruitment 
rate and subjectively using a patient acceptability questionnaire, which will 
be completed by the participant at the end of the procedure. The 
questionnaire measures patient’s overall opinion of the procedure, level of 

 
 
 
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pain during treatment, satisfaction with the duration of the procedure, and 
willingness to undergo the procedure again.  
 
Question/Statement 
Scoring 
1. The procedure was painful. 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly 
disagree 
2. The procedure was embarrassing. 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly 
disagree 
3. The procedure was comfortable 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly 
disagree 
4. The procedure duration was too 
long. 
□ Strongly agree   □ Agree   □ Neutral   □ Disagree   □ Strongly 
disagree 
5. What score corresponds best with 
your opinion of the treatment 
procedure? 
(10 = acceptable, 0 = unacceptable) 
0         1         2         3         4         5         6         7         8         9       
10 
 
Unacceptable                                     Neutral                              
Acceptable 
6. Reason for your answer in 
question 5. 
(Free text) 
7. Would you be willing to undergo 
this procedure again? 
□ Yes 
□ No 
 
6.4.3 Clinical efficacy 
 
Subjectively improvement will be measured using the Cleveland Clinic 
Constipation Score (CCCS)19 and Measure Yourself Medical Outcome 
Profile (MyMop)20 assessment pre- and post- intervention. 
 
As part of NHS follow-up care, the patients will undergo repeat anorectal 
physiology studies (anorectal manometry) to assess the need for further 
treatment. The post-procedure findings will be compared with pre-
procedure findings to identify any changes.   
 
This information will be helpful to make an estimate of the sample size 
and follow-up rate for future studies.  
 
7. Study population 
 
Patients will be recruited from referrals to the pelvic floor multidisciplinary team 
(MDT) meeting and those who fulfil the inclusion criteria will be invited to participate 
in the study. The duration for participation is 12 months. 
 
7.1 Inclusion criteria 
 
• 
Adult patients (age 18 – 80 years) 
• 
Diagnosis of dyssynergic defaecation using ROME IV criteria17.  
- The patient must satisfy diagnostic criteria for functional constipation 
and/or irritable bowel syndrome (IBS) with constipation 
- The IBS criteria includes recurrent abdominal pain, on average at least 
1 day per week in the last 3 months, associated with 2 or more of the 
following: related to defaecation, associated with a change in 

 
 
 
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frequency of stools, or associated with a change in form (appearance) 
of stool.  
- In IBS with predominant constipation (IBS-C) more than 25% of bowel 
movements are of Bristol stool form scale (BSFS) type 1 or 2 
consistency, and less than 25% are of types 6 or 7.  
- The functional constipation diagnostic criteria applies to those who do 
not meet the criteria for irritable bowel syndrome, whose stools are 
rarely loose without the use of laxatives, and must include 2 or more of 
the following: straining*, lumpy or hard stools (BSFS 1-2)*, sensation of 
incomplete evacuation*, sensation of anorectal obstruction/blockage*, 
manual manoeuvres to facilitate defaecation*, fewer than 3 
spontaneous bowel movements per week 
- During repeated attempts to defaecate, there must be features of 
impaired evacuation, as demonstrated by 1 of the following 2 tests: 
abnormal balloon expulsion test or impaired rectal evacuation by 
imaging** 
- Inappropriate contraction of the pelvic floor as measured with anal 
surface EMG or manometry with adequate propulsive forces during 
attempted defaecation (as defined by age- and sex-appropriate normal 
values) 
- Criteria fulfilled for the last 3 months with symptom onset at least 6 
months before diagnosis. 
• 
Ability to understand written and spoken English. 
• 
Ability and willingness to give informed consent. 
 
*  
More than 25% of defaecations. 
** In our unit, imaging of rectal evacuation is performed using 
defaecography, and the assessment of pelvic floor contraction is 
assessed by evaluating the propulsive force, anorectal angle, and 
relaxation of the anal canal.  
 
7.2 Exclusion criteria 
 
• 
Paediatric patients (age under 18 years) 
• 
Diagnosis of defined structural or metabolic diseases that could cause 
constipation, such as Hirschsprung’s disease, Parkinson’s disease, 
multiple sclerosis, hypothyroidism (untreated), diabetic neuropathy, 
muscular dystrophy, motor neurone diseases, spinal injury leading to 
paraplegia, cauda equina syndrome 
• 
Psychiatric or physical inability to comply with the study protocol 
(including e-diary assessments) at investigator discretion. 
• 
Contra-indications to BTXA such as allergies, pregnancy (or intention to 
become pregnant during study period), breastfeeding, generalised 
disorders of muscle activity, myasthenia gravis 
• 
Contra-indications to infracoccygeal injection at injection site such as 
infection or pressure sore, spina bifida, pilonidal disease, bleeding 
disorders (including therapeutic anticoagulation) 
• 
Morbid obesity (BMI ≥ 40) 
• 
Defunctioning loop or end stoma in situ 
• 
External rectal prolapse 
 

 
 
 
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8. Study design 
 
The overall design is of a single-centre, prospective, uncontrolled, open-label 
observational study. Patients diagnosed with dyssynergic defaecation, using Rome 
IV criteria, will be identified from weekly pelvic floor MDT and current waiting list for 
biofeedback therapy and invited to participate. BTXA injection is not offered as an 
alternative to biofeedback and does not preclude patients from receiving biofeedback 
therapy as per standard treatment as this is not a study of treatment efficacy. 
 
All participants will undergo BTXA injection within 12 weeks of recruitment. 
 
Data collection: 
• 
Baseline data collection from patient’s initial symptoms questionnaire and 
anorectal physiology report (pre-procedure). 
• 
MYMOP questionnaire (pre-procedure and at final follow-up) 
• 
Patient and physician procedural questionnaire to be completed at the end of 
the BTXA injection procedure (see Section 5.3 and 5.4). 
• 
Cleveland clinic constipation score and St. Mark’s incontinence score to be 
completed by the patient at each follow-up.  
• 
Anorectal physiology report (post-procedure) for anorectal manometry results 
at first follow-up. 
• 
Any adverse events reported by the patient will be recorded on an adverse 
event form (see Section 5.4).  
 
Data analysis: 
• 
Feasibility and efficacy outcomes will be extracted from the questionnaires and 
reports and recorded onto Research Electronic Data Capture (REDCap). 
• 
Anonymised summary data will be exported to Excel and descriptive statistics 
(e.g. mean, confidence intervals of effect) used to present data for publication.  
9. Study procedures 
 
Recruitment 
 
Patients diagnosed with dyssynergic defaecation, using Rome IV criteria, will be 
identified from the weekly pelvic floor MDT and current waiting list for biofeedback 
therapy. These patients will be screened against the inclusion and exclusion criteria. 
Patients will be continually recruited until 10 patients have undergone the procedure, 
including re-recruitment for drop-outs.  
 
Visit 1: initial discussion 
 
Eligible patients will be contacted by a member of the clinical team by telephone and 
invited to have a discussion about participating in the study. Following the initial 
discussion about the study with a member of the research team by phone, an 
information leaflet will be sent out. A minimum of 24 hours will be provided to allow 
the patient to consider the given information. 
 
Visit 2: consent and baseline data 
 
A second appointment will be arranged to obtain consent should the patient wish to 
participate in the study, which may be undertaken by an appropriately trained 

 
 
 
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member of the clinical or research team. Patient’s original symptom questionnaire 
and anorectal physiology reports will be obtained to extract baseline data (CCCS, 
evacuation time and completeness, quality of expulsive force, opening of the 
anorectal angle, relaxation of the anal canal, as well as squeeze and push 
pressures). The patient will then complete CCCS, SMIS, and MyMop questionnaires. 
 
Visit 3: BTXA injection 
 
The BTXA injection will be scheduled by the radiology department within 12 weeks. 
The patient and radiologist carrying out the injection will complete a procedure-
related questionnaire after the procedure. Ultrasound and EMG report on each 
patient will be obtained following the procedure. The patient will be asked to report 
any adverse events following the BTXA injection as soon as possible by phone or at 
follow-up.  
 
Visit 4: first follow-up 
 
The patient will attend first follow-up 4-6 weeks after the injection and complete the 
Cleveland Clinic constipation scoring (CCCS) as well as St. Mark’s incontinence 
scoring (SMIS). They also undergo a repeat anorectal physiology tests. 
 
Visit 5: second follow-up 
 
The patient will be given the option of telephone, face-to-face, or electronic follow-up 
at 3 months following the injection and will complete the CCCS and SMIS. They will 
also be asked if they have experienced any adverse events. 
 
Visit 6: final follow-up 
 
This will take place at 6 months following the injection and will be similar to the 
second follow-up but the patient will also be asked to complete a MYMOP follow-up 
questionnaire, and to rank their level of satisfaction with the treatment using a 
satisfaction thermometer.  
 
Visit 
Study Stage 
Data 
Week 
Carried out by 
Setting 
0 
Recruitment  
N/A 
0 
Research team 
Pelvic Floor MDT 
1 
Initial discussion 
N/A 
1-4 
Clinical/research team 
Phone 
2 
Consent and 
baseline data 
CCCS 
SMIS 
Anorectal physiology 
MYMOP 
5-6 
Clinical/research team 
Outpatient clinic 
3 
BTXA injection 
Patient questionnaire  
Physician questionnaire 
Adverse events reporting 
18 
Radiologist 
Outpatient 
Ultrasound 
4 
First follow-up 
 
CCCS 
SMIS 
Anorectal physiology 
22-24 
Clinical/research team 
GI physiology 
5 
Second follow-up 
CCCS 
SMIS 
30 
Clinical/research team 
Outpatient clinic/ 
phone/ online form 
6 
Final follow-up 
CCCS 
SMIS 
MYMOP follow-up 
Satisfaction thermometer 
42 
Clinical/research team 
Outpatient clinic/ 
phone/ online form 
 
 
 
 

 
 
 
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Study intervention (at visit 3):  
 
Botulinum toxin type A injection (BTXA) – The intervention is an injection of 200 units 
of Botulinum toxin type A in to the puborectalis muscle under ultrasound guidance.  
• 
In the prone position, the puborectalis muscle will be identified below the 
coccyx using ultrasound.  
• 
After skin preparation using 70% Isopropyl Alcohol Pad, up to 5ml of local 
anaesthetic (1% lidocaine) an electromyography (EMG) needle will be inserted 
and the puborectalis muscle stimulated using a current to confirm correct 
needle position. Figure 3 demonstrates an example EMG trace on a healthy 
volunteer at rest (a) and under voluntary contraction (b) 
• 
200 units of BTXA (Botox, Allergan, Ireland) prepared in 2 ml of saline solution 
and drawn up using a 2ml syringe. 
• 
1ml (100 units) of BTXA solution is injected through the EMG needle into the 
puborectalis muscle to each side of the midline, achieving a total of 200 units.  
• 
The needle is withdrawn, and the procedure is complete. 
 
At the end of the procedure, the patient and physician both complete post-procedure 
questionnaires.  
 
At any stage of the study, expected adverse events will be recorded on the patient’s 
eCRF. If no adverse events have been self-reported this will be confirmed with the 
patient at the end of every follow-up appointment as part of the follow-up procedure. 
Serious or unexpected adverse events will be recorded and also reported according 
to research governance framework guidelines (see Section 14).  
 
Patients can withdraw at any point in the study without the requirement to provide a 
reason. The data collected from the point of consent to the point of withdrawal will be 
kept for analysis of retention and follow-up rate, as well as incidents of adverse 
events depending on the stage at withdrawal. Such patients will return to routine 
care.  
 
Figure 3a. EMG of puborectalis demonstrating tonic activity at rest 
 
 
 
Figure 3b. EMG of puborectalis demonstrating voluntary contraction 
 
 
 

 
 
 
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10. Assessment and management of risk 
 
Risk to the participants: 
• 
The potential side-effects and expected AE’s from Botulinum toxin type A 
injection are discussed in section 5.3.1 and 6.4.1, respectively. The potential 
risks to patients associated with the injection and routine NHS investigations 
are discussed in section 5.3.2 and 5.3.3, respectively. Any side-effects or 
AE’s experienced by the participants will be assessed and treated by the 
clinical team and reported in accordance with the procedure outline in section 
16 of this protocol.  
• 
The questionnaires used in this study, in addition to routine care, are 
validated symptoms questionnaires (Cleveland Clinic constipation score, St. 
Marks Incontinence score, and MyMOP), a satisfaction thermometer, and a 
short post-procedure questionnaire. None of these contain any questions 
which are expected to cause mental or emotional harm.  
• 
No financial loss for participants is anticipated as they will be compensated 
for travel expenses of up to £20 for each face-to-face appointment.  
 
Risk to the clinician: 
• 
There is no increased risk of needle stick injuries associated with this 
procedure in comparison with the current standard technique of BTXA 
injection (through the anal canal), which carries a higher risk of needle stick 
injury as it is guided by the administrator’s finger and is not under direct 
vision. 
11. Statistical considerations 
 
This is a prospective, uncontrolled, open-label, observational study. Descriptive 
statistics are appropriate to present data. Data analysis on this basis will be 
supervised by the chief investigator.   
 
11.1 Sample size 
 
The sample size of 10 is a convenience sample (achievable in 12 months) and is 
not based on a priori calculations of statistical power. In the event of pre-
procedure patient withdrawal, further recruitment will take place to achieve a 
total of 10 patients.  
 
 
11.2 
Method of analysis  
 
Statistical analysis will not use hypothesis testing. Descriptive statistics will be 
used to summarise technical feasibility and other outcomes, including the 
proportion of patients who undergo successful BTXA injection where the 
puborectalis muscle was identified on ultrasound and on EMG before BTXA 
injection.  
 
Qualitative summary of technical difficulties, patient satisfaction and reported 
adverse events will also be documented. 

 
 
 
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12. Ethics 
 
This study is a non-CTIMP study using BTXA injection, which is an established 
treatment for dyssynergic defaecation, and will adhere to the Research Governance 
Framework for Health & Social Care (2005), the World Medical Association 
Declaration of Helsinki (1996), ICH Good Clinical Practice Guidelines (1996), current 
applicable local regulatory requirements, and REC conditions of approval.  
 
Patients with dyssynergic defaecation on the waiting list for biofeedback therapy are 
offered BTXA injection using a novel approach, avoiding the need for general 
anaesthetic. It is not offered as an alternative to biofeedback and does not preclude 
patients from receiving biofeedback therapy as per standard treatment, as the aim of 
the study is not to assess efficacy of this treatment in isolation but to ascertain its 
acceptability to patients and physician. The additional symptom questionnaire and 
anorectal physiology tests performed at follow-up will assess the need for further 
treatment, which may be biofeedback therapy or repeat injection with BTXA, as part 
of ongoing NHS care. 
 
 
12.1 
Annual Safety Reporting  
 
The CI will complete the Annual Progress Report (APR) to the REC and the 
sponsor using the HRA template at the end of the study.  
 
13. Public Involvement 
 
Prior to the commencement of this study, with Bowel Research UK through the 
Patient and Research Together (PaRT) initiation, public opinion on patient facing 
documents (information leaflet and consent) to develop informative and 
comprehensive patient literature for the study was sought. Public involvement 
remains the key focus of this study as its primary focus is on patients’ opinion on this 
new treatment modality.    
14. Data handling and record keeping 
 
14.1 Data management 
 
Data will be handled in accordance with the Data Protection Act 2018 and Barts 
Health NHS Trust Information Governance policy. This study is performed on a 
single site.  
 
Source data are kept in the original format. Electronic data (clinic letters, 
radiology and anorectal physiology reports, pregnancy test) are logged directly 
on the patient’s electronic record. Original copies of physical data 
(questionnaires, case report forms, and consent forms) are kept in the site file, 
which is stored in a locked cupboard. Electronic case report forms are generated 

 
 
 
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electronically from the source data using REDCap and can be verified with the 
original records.  
 
14.2 Source data 
 
Study Assessment 
Source 
Data Transfer 
Screening and eligibility checklist 
Pelvic floor MDT 
Electronic medical 
records 
eCRF 
Informed consent 
Copy in site file and 
patient’s notes 
None 
Patient questionnaires (including bowel 
symptoms questionnaire, CCCS, SMIS, 
MYMOP, post-procedure questionnaire, 
and satisfaction thermometer) 
Patient  
eCRF 
Physician questionnaires 
Physician 
eCRF 
Radiology report 
Patient electronic 
records 
eCRF 
Anorectal physiology report 
Patient electronic 
records 
eCRF 
 
14.3 Confidentiality 
 
Information related to participants will be kept confidential and managed in 
accordance with the Data Protection Act (2018), the General Data Protection 
Regulation (GDPR), NHS Caldecott Principles, the UK Policy Framework for 
Health and Social Care Research, the ICH Good Clinical Practice Guidelines 
(1996) and the conditions of Research Ethics Committee favourable opinion.  
 
Patient identifiable information to be collected from the participants include: 
• 
Full name 
• 
Date of birth 
• 
Hospital number  
• 
Contact details 
These will be used to contact the participants only and will not leave the study 
site without prior consent. All case report forms will be anonymised, and 
participants will not be identifiable in any future publications relating to this study.  
 
Study data will be available to qualified members of the research team, auditors, 
the REC and any regulatory authorities as required by law.  
 
14.4 Record Retention and Archiving 
 
The UK Policy Framework for Health and Social Care Research requires that 
research records are kept for 25 years after the project has completed. This single 
site study involve Barts Health NHS Trust patients, is undertaken by Barts Health 
NHS Trust staff. All research documentation (including consent forms and 
questionnaires) will be archived at the approved repository for long-term storage of 
local records, the Trust Corporate Records Centre. 
 

 
 
 
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15.  Interventions and tools  
 
15.1 Techniques and interventions 
 
The injection technique is described in section 9 under study intervention (at visit 
3). There is no patent on this technique. 
 
15.2 Tools 
 
The post-procedure questionnaire is included in section 6.4.2. Other validated 
questionnaires used in this study includes the Cleveland Clinic constipation 
score, St. Marks Incontinence score, MyMOP questionnaire, and a satisfaction 
thermometer.  
 
15.3 Medicinal product  
 
Botulinum toxin type A (Botox, Allergan, Ireland) 
• 
Indication: focal muscular spasm (of the puborectalis in dyssynergic 
defaecation) 
• 
Licensing status: PL 00426/0119 
• 
Dosing schedule: injection of 200 units once 
• 
Route of administration: intramuscular injection (to puborectalis muscle) 
• 
Source of Medicinal Product: Royal London Hospital pharmacy 
• 
Storage and dispensing: product will be dispensed on the day of the 
procedure and stored in a refrigerator before use 
• 
Contraindications: 
o Known hypersensitivity to BTXA, human albumin, sodium chloride 
o Presence of infection at the proposed injection site 
• 
Side-effects: 
o Common or very common8: alopecia; asthenia; autonomic 
dysreflexia; bladder diverticulum; constipation; dizziness; 
drowsiness; dry eye; dry mouth; dysphagia (most common after 
injection into sternocleidomastoid muscle and salivary gland); 
ecchymosis (minimised by applying gentle pressure at injection 
site immediately after injection); eye discomfort; eye disorders; 
eye inflammation; fall; fever; gait abnormal; haematuria; 
headaches; hot flush; increased risk of infection; influenza like 
illness; insomnia; joint disorders; leukocyturia; malaise; muscle 
complaints; muscle weakness; musculoskeletal stiffness; nausea; 
neuromuscular dysfunction; oedema; pain; paresis; sensation 
abnormal; skin reactions; subcutaneous nodule; urinary disorders; 
vision disorders 
o Uncommon8: anxiety; coordination abnormal; depression; 
dysphonia; dyspnoea; facial paralysis; memory loss; oral 
paraesthesia; photosensitivity reaction; postural hypotension; 
speech impairment; taste altered; vertigo 
o Frequency not known8: abdominal pain; angioedema; angle 
closure glaucoma; appetite decreased; arrhythmia; diarrhoea; 
hearing impairment; hypersensitivity; myocardial infarction; 

 
 
 
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myopathy; nerve disorders; respiratory disorders; seizure; 
syncope; tinnitus; vomiting 
o Procedure specific: 
▪ 
Temporary incontinence – faecal incontinence occurred in 
17 cases (6.9%) from three studies10-12 and flatus 
incontinence occurred in 10 cases (4.1%) from two 
studies.6, 12 The symptoms were minor and temporary in all 
studies.  
▪ 
Posterior anal fissure – reported in two patients (0.8%) 
from a single study13 
▪ 
Rectal prolapse – reported in a single patient (0.4%) from 
a single study13 
16. Safety reporting  
 
All adverse events (AE) related to or thought to be related to the procedure will be 
recorded in the patient’s eCRF using an adverse event form. This form will record the 
nature, severity, time of onset of, and treatment required for the AE. Severity of the 
AE is graded according to the Clavien-Dindo classification18 (see Section 5.4) 
 
16.1 Adverse Events (AEs) 
 
An AE is any untoward medical occurrence in a participant to whom an 
intervention has been administered, including occurrences which are not 
necessarily caused by or related to that intervention. An AE can therefore be any 
unfavourable or unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with study activities. 
 
16.2 Adverse Reaction (ARs)  
 
An AR is any untoward and unintended response in a participant to an 
intervention.  All adverse events judged by either the reporting investigator or the 
sponsor as having a reasonable causal relationship to the intervention qualify as 
adverse reactions. The expression ‘reasonable causal relationship’ means in 
general that there is evidence or an argument to suggest a causal relationship. 
 
16.3 Notification and reporting of Adverse Events and Reactions 
 
If the AE is not defined as serious, the AE will be recorded in the study 
documents and the participant followed up by the research team. The AE will be 
documented in the participants’ source documents, the Case Report Form 
(CRF), and, where appropriate, medical records. 
 
16.4 Serious Adverse Events (SAEs) or reactions 
 
A serious adverse event (SAE) is defined as an untoward occurrence that: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires hospitalisation or prolongation of existing hospitalisation, 
• 
Results in persistent or significant disability or incapacity, 

 
 
 
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• 
Consists of a congenital anomaly or birth defect, or 
• 
Is otherwise considered medically significant by the investigator. 
 
SARs will be reported to the REC where in the opinion of the CI the event was 
serious and: 
• 
Related (it may have resulted from administration of any of the research 
interventions), and 
• 
Unexpected (the type of event is not listed in the protocol or other 
Reference Safety Information as an expected occurrence). 
 
16.5 Notification and reporting of Serious Adverse Events  
 
Serious Adverse Events (SAEs) that are considered to be ‘related’ and 
‘unexpected’ will be reported to the sponsor within 24 hours of learning of the 
event, and to the REC within 15 days in line with the required timeframe.  
 
16.6 Urgent Safety Measures 
 
The CI will take urgent safety measures if necessary to ensure the safety and 
protection of the clinical study participant from immediate hazards to their health 
and safety. The measures will be taken immediately. The approval of the REC 
prior to implementing urgent safety measures is not required. However, the CI 
will inform the sponsor and REC (via telephone) of this event immediately.  
 
The CI will inform the REC in writing within 3 days, in the form of a substantial 
amendment. The sponsor (Joint Research Management Office (JRMO)) will be 
sent a copy of the correspondence with regards to this matter.  
 
16.7 Annual Safety Reporting 
 
The CI will send the Annual Progress Report to the REC using the HRA template 
(the anniversary date is the date on the REC “favourable opinion” letter) and to 
the sponsor.  
 
 
16.8 Overview of the Safety Reporting responsibilities 
 
The CI is the medical assessor on behalf on the sponsor and will review all 
events reported. The CI will ensure that safety monitoring and reporting is 
conducted in accordance with the sponsor’s requirements.  
 
 
17. Monitoring and auditing 
 
The sponsor or delegate retains the right to audit any study, study site, or central 
facility. Any part of the study may be audited by the funders, where applicable. 
 
On-site monitoring is not required given the small study size and being conducted on 
a single site.  
 

 
 
 
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18. Trial committees 
 
A small study management group (SMG) will be responsible for the delivery of the 
study, and will consist of: 
 
• 
The trial CI: Prof. Charles Knowles (BHT/NBRC)  
• 
Co applicant: Dr Mark Scott (BHT/NBRC) 
• 
Clinical research fellow: Pam Chaichanavichkij (BHT/NBRC) 
• 
Radiologist: Dr Niall Power (BHT) 
• 
Neurophysiologist: Dr Abir Sanyal (BHT) 
• 
Trial co-ordinator: N/A 
• 
Data manager: N/A 
 
19. Finance and funding 
 
This study will utilise departmental funding as the procedure is a part of standard 
clinical care. Additional equipment specific to this technique (EMG needle), patient 
travel expenses, and cost of research staff is provided by Bowel Research UK small 
grant for the 12-months period of the study.  
 
 
20. Indemnity 
 
The insurance that Queen Mary University of London has in place provides cover for 
the design and management of the study as well as "No Fault Compensation" for 
participants, which provides an indemnity to participants for negligent and non-
negligent harm. 
 
 
21. Dissemination of research findings 
 
Findings will be subjected to oral presentation in a specialist research meeting, 
reporting in an appropriate peer reviewed journal, and will also be disseminated 
through the Bowel Research UK website. It will also form part of the research fellow’s 
PhD thesis.  
 
22. References 
 
1. 
Rao SS, Bharucha AE, Chiarioni G, et al. Functional Anorectal Disorders. 
Gastroenterology 2016. 
2. 
Woodward S, Norton C, Chiarelli P. Biofeedback for treatment of chronic 
idiopathic constipation in adults. Cochrane Database Syst Rev 
2014:Cd008486. 
3. 
Emile SH, Elfeki HA, Elbanna HG, et al. Efficacy and safety of botulinum 
toxin in treatment of anismus: A systematic review. World J Gastrointest 
Pharmacol Ther 2016;7:453-62. 
4. 
Shafik A, El-Sibai O. Botulin toxin in the treatment of nonrelaxing 
puborectalis syndrome. Dig Surg 1998;15:347-51. 

 
 
 
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5. 
Maria G, Brisinda G, Bentivoglio AR, et al. Botulinum toxin in the 
treatment of outlet obstruction constipation caused by puborectalis 
syndrome. Dis Colon Rectum 2000;43:376-80. 
6. 
Maria G, Cadeddu F, Brandara F, et al. Experience with type A botulinum 
toxin for treatment of outlet-type constipation. Am J Gastroenterol 
2006;101:2570-5. 
7. 
Excellence NIfHaC. Surgical site infections: prevention and treatment 
(NG125). Volume 2019. NG125 ed, 2019. 
8. 
Formulary TBN. Botulinum Toxin Type A. Volume 2019: 
MedicinesComplete, 2019. 
9. 
Han TI, Kim IO, Kim WS, et al. US identification of the anal sphincter 
complex and levator ani muscle in neonates: infracoccygeal approach. 
Radiology 2000;217:392-4. 
10. 
Zhang Y, Wang ZN, He L, et al. Botulinum toxin type-A injection to treat 
patients with intractable anismus unresponsive to simple biofeedback 
training. World J Gastroenterol 2014;20:12602-7. 
11. 
Hompes R, Harmston C, Wijffels N, et al. Excellent response rate of 
anismus to botulinum toxin if rectal prolapse misdiagnosed as anismus 
('pseudoanismus') is excluded. Colorectal Dis 2012;14:224-30. 
12. 
You Y-TW, Jen-Yi; ChangChien, Chung-Rong; Chen, Jinn-Shiun; Hsu, 
Kuan-Cheng; Tang, Reiping; Yeh, Chien-Yuh. The Treatment of Outlet 
Obstruction Constipation. Farmosan Journal of Surgery 2001;34:3-10. 
13. 
Ron Y, Avni Y, Lukovetski A, et al. Botulinum toxin type-A in therapy of 
patients with anismus. Dis Colon Rectum 2001;44:1821-6. 
14. 
Abramowicz JS. Benefits and risks of ultrasound in pregnancy. Semin 
Perinatol 2013;37:295-300. 
15. 
Measurements NCoRPa. Exposure Criteria for Medical Diagnostic 
Ultrasound: II Criteria Based on All Known Mechanisms. In: Nyborg WL, 
ed, 2002. 
16. 
Gechev A, Kane NM, Koltzenburg M, et al. Potential risks of iatrogenic 
complications of nerve conduction studies (NCS) and electromyography 
(EMG). Clin Neurophysiol Pract 2016;1:62-66. 
17. 
Lacy BE, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology 
2016. 
18. 
Dindo D, Demartines N, Clavien PA. Classification of surgical 
complications: a new proposal with evaluation in a cohort of 6336 patients 
and results of a survey. Ann Surg 2004;240:205-13. 
19.  
Agachan F, Chen T, Pfeifer J, et al. A constipation scoring system to 
simplify evaluation and management of constipated patients. Dis Colon 
Rectum 1996;39:681-5. 
20. 
Paterson C. Measuring outcomes in primary care: a patient generated 
measure, MYMOP, compared with the SF-36 health survey. Bmj 
1996;312:1016-20. 
 
This protocol is based on JRMO Protocol template for Interventional Studies; 
v3.0 01.03.2021