Background
Evidence of SNM efficacy
Evidence of SNM mechanism
Methods/design
Overall study aim
Objectives
Primary clinical objectives
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Hypothesis: SNM reduces frequency of total FI episodes by a mean of 30% compared to SHAM stimulation in the third month of chronic stimulation
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Hypothesis: sub-sensory SNM leads to significant and clinically-beneficial changes in a range of established and novel innovative outcome measures in the third month of chronic stimulation
Secondary clinical objectives
Mechanistic objectives
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Hypotheses: (1) SNM but not SHAM increases frequencies of fasting and fed perceived and unperceived transient anal sphincter relaxations (TASR) (based on prolonged high-resolution anorectal manometry recordings) to levels observed in healthy individuals; (2) SNM but not SHAM increases conscious sensation of defaecatory urge based on symptom reporting and objective measures of anorectal sensory function
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Hypothesis: SNM leads to brain plasticity (based on magnetoencephalography (MEG)) in motor and non-motor cortical and sub-cortical regions
Eligibility criteria
Inclusion criteria
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Adults aged 18–75 years
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Meet Rome III and ICI definitions of FI (recurrent involuntary loss of faecal material that is a social or hygienic problem and not a consequence of an acute diarrhoeal illness)
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Failure of non-surgical treatments to meet the NICE standard*
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Minimum severity criteria of eight FI episodes in a 4-week screening period (this is important to exclude patients who might thence have zero FI episodes during baseline evaluations)
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Ability to understand written and spoken English or relevant language in European centres (due to questionnaire validity)
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Ability and willingness to give informed consent
Exclusion criteria
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Known communication between the anal and vaginal tracts
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Prior diagnosis of congenital anorectal malformations
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Previous rectal surgery (rectopexy / resection) performed < 12 months ago (24 months for cancer)
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Present evidence of full-thickness rectal prolapse
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Prior diagnosis of chronic inflammatory bowel diseases
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Symptoms of chronic constipation with over-flow incontinence
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Structural abnormality of the pelvic floor leading to clear evidence of obstructed defaecation based on examination and/or imaging
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Symptoms of significant evacuatory dysfunction based on Obstructive Defecation Syndrome Score ≥ 8
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Presence of active perianal sepsis (including pilonidal sinus)
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Defunctioning loop or end stoma in situ
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Diagnosed with neurological diseases, such as diabetic neuropathy, multiple sclerosis and Parkinson’s disease
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Current or future need for MR imaging based on clinical history
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Complete or partial spinal cord injury
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Bleeding disorders, e.g. haemophilia, warfarin therapy
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Pregnancy or intention to become pregnant during the study period
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Not fit for preferred method of anaesthesia
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Anatomical limitations that would prevent successful placement of an electrode including congenital abnormalities
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Psychiatric or physical inability to comply with the study protocol (including e-diary assessments) at the investigator’s discretion
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Is required to drive for long periods of time, e.g. lorry drivers, taxi drivers and delivery drivers
Trial design
Randomised, double-blind crossover design overview
Cohort study: 12-month outcomes
Study procedures
Recruitment and consent procedures
Randomisation procedures
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Group 1 (45): SNM/SHAM
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Group 2 (45): SHAM/SNM
Blinding procedures
Planned interventions
Sacral neuromodulation (SNM) (Medtronic Interstim®)
SHAM stimulation
Procedures for mechanistic studies (subgroup of patients)
Anocortical studies
Study visits
Visit 0: Screening
Screening and baseline visits
Visit 0: Screening
Visit 1: Baseline
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Demographics, standardised medical/surgical history taken including history of incontinence symptoms, gynaecological history and pregnancy test (women of childbearing potential)
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Clinical examination of perineum, anus and rectum (if not documented previously within 6 months)
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Baseline outcome assessments: St Mark’s continence score, Deferment time, Longo Score, OAB-Q Short Form, International Consultation on Incontinence Bowel (SF-ICIQ-B) questionnaire, Faecal Incontinence Quality of Life (FI QoL) score and EQ-5D-5 L/Visual Analogue Scale (VAS)
Surgical intervention visits
Visit 2a: Test stimulation
Visit 2b: Mechanistic study enrolment
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MRI head
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MEG to electrical anal stimulation, anal squeeze, sacral-root suprasensory stimulation, median nerve stimulation
Visit 3a: Permanent device implantation (SNM implant)
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Group 1 will the initially receive sacral neuromodulation and
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Group 2 will initially receive SHAM stimulation
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Lead position – radiological side and foramen level. Number of electrodes in foramina
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Motor thresholds for each of the four electrodes on the quadripolar lead
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Physiological motor (± sensory) response for the chosen foramen for lead implantation
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Other intraoperative data: length of op, type of anaesthesia (including use of any paralyzing agent), blood loss, any other complications
Visit 3b: Initial programming (T0)
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Group 1: the sub-sensory amplitude will be recorded along with the electrode configuration used.
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Group 2: the sub-sensory amplitude will be recorded along with the electrode configuration used before returning the amplitude to 0 V
Crossover phases T0 to T32
Visit 4: 6-week reprogramming visit (T + 6)
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Group 1: patient assessed for sub-optimal efficacy or unwanted effects of stimulation. In the presence of sub-optimal efficacy or adverse effects the electrode configuration can be changed as per reprogramming algorithm. The sensory threshold is once again recorded and device returned to the sub-sensory setting
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Group 2: the sensory threshold is recorded and the electrode configuration can be changed if the site of stimulation appears to be sub-optimal (aim for anal stimulation) before returning device to 0 V
Visit 5: Assessment (T + 12 to + 16)
Visit 6: Crossover visit (T + 16)
Visit 7: 6-week reprogramming visit (T + 22)
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Group 1: the sensory threshold is recorded and the electrode configuration can be changed if the site of stimulation appears to be sub-optimal (aim for anal stimulation) before returning device to 0 V
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Group 2: patient assessed for sub-optimal efficacy or unwanted effects of stimulation. In the presence of sub-optimal efficacy or adverse effects the electrode configuration can be changed as per reprogramming algorithm. The sensory threshold is once again recorded and the device returned to the sub-sensory setting
Visit 8: Assessments (T + 28 to + 32)
Open-label cohort follow-up T32–58
Visit 9: End of crossover (T + 32)
Visit 10: Final assessment (T + 54 to + 58)
Concomitant care and interventions
Discontinuation criteria (participants and study)
Withdrawal criteria
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Electively withdraw from treatment
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Are not fit for surgery
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Become pregnant or intend to become pregnant
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Are unable to participate due to an concurrent severe illness
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Develop an acute psychological illness causing concerns
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Choose to withdraw from treatment and follow-up data collection
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Become lost to follow-up (after at least three attempts at contact by research/clinical staff using at least two different methods)
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Die or become severely incapacitated so follow-up data collection is impossible
Criteria for early termination
Outcomes
Primary clinical outcome
Secondary clinical outcomes
Mechanistic outcomes
Anorectal sensorimotor function
Anocortical function
Statistical considerations
Sample size
Method of analysis
Mechanism studies
Confidentiality
Access to data and archiving
Adverse events (AEs)
Expected events
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Bleeding
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Pain
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Wound infection
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Worsening of, or de novo urinary incontinence
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Worsening faecal incontinence
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Unwanted/undesirable stimulation effects
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Numbness at neurotransmitter site
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Technical device issues including lead migration and fracture
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Infection of lead or implantable pulse generator (IPG) necessitating removal or admission for intravenously administered antibiotics
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Unwanted stimulation effects necessitating device removal
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Lack/loss of efficacy necessitating device removal
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Revision of IPG placement due to discomfort or displacement
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Revision or removal of IPG due to technical device failure (including fractured lead or failure of impedance check on all four leads)
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Unrelated hospitalisation; e.g. elective surgical procedures or injury or acute medical problems