Clinical trial NCT03899181: Translumbosacral Neuromodulation for FI
Official title: Translumbosacral Neuromodulation Therapy For Fecal Incontinence: Randomized Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Fecal Incontinence
Lead sponsor: Augusta University
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Massachusetts General Hospital
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2019-04-02
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Fecal Incontinence (FI) affects 40 million Americans, predominantly women and elderly. It is a major health care burden, significantly impairs quality of life and psychosocial function. FI is characterized by multifactorial dysfunction including lumbosacral neuropathy, anorectal sensori-motor dysfunction, and abnormal pelvic floor-brain innervation. A critical barrier to progress in the treatment of FI is the lack of RCTs, absence of mechanistically based non-invasive therapies that modify disease, and a lack of understanding on how treatments affect pathophysiology of FI. Consequently, most current remedies remain ineffective. Our long-term goal is to address the problem of lack of effective treatments for FI by investigating treatments that modulate neuronal perturbations and thereby improve sensory and motor control, and to understand the neurobiologic basis of these treatments. Our central hypothesis is that a novel, non-invasive treatment consisting of Translumbosacral Neuromodulation Therapy (TNT), using repetitive magnetic stimulation, will significantly improve FI in the short-term and long-term, by enhancing neural excitability and inducing neuroplasticity. Our approach is based on compelling pilot study which showed that TNT at 1 Hz frequency, significantly improved FI, by enhancing bidirectional gut- brain signaling, anal sphincter strength and rectal sensation compared to 5 or 15 Hz. Our objectives are to 1) investigate the efficacy, safety and optimal dose of a new treatment, TNT, in a sham controlled, randomized dose-dependent study in 132 FI patients; 2) determine the mechanistic basis for TNT by assessing the efferent and afferent pelvic floor-brain signaling, and sensori-motor function; 3) identify the durability of treatment response and effects of TNT, and whether reinforcement TNT provides augmented improvement, by performing a long-term, sham controlled randomized trial. Our expected outcomes include the demonstration of TNT as a durable, efficacious, safe, mechanistically based, non-invasive, and low risk treatment for FI. The impact of our project includes a novel, disease modifying, non-invasive treatment, a scientific basis for this treatment, and improved understanding of the pathophysiology of FI and how TNT modifies bidirectional gut and brain axes and anorectal function. Ultimately, the knowledge generated by this project will provide new avenues for the development of innovative, evidence-based therapies for FI.

Detailed description: Fecal incontinence (FI), defined as the involuntary passage of either formed or liquid stool, affects 8-15% of ambulatory Americans, mostly women and elderly and 45% of nursing home residents. It occurs at least weekly in 3% of adults, and in 37% of patients attending primary care clinics. FI has a major impact on quality of life, causes significant distress including anxiety and depression, and carries a considerable health care burden. FI is characterized by multifactorial dysfunctions that include lumbosacral neuropathy, anorectal sensori-motor dysfunction, and decreased rectosigmoid reservoir capacity and maladaptive pelvic floor-brain innervation. Consequently, treatments that help a single dysfunction, for example, anal dextranomer injection or anal sphincteroplasty could improve FI by reinforcing the anal barrier, but unlikely to improve the multidimensional problem of FI. Also, anal sphincteroplasty felt to be effective initially, was disappointing long-term with only 30% remaining continent at 10 years. An-other surgical procedure, sacral nerve stimulation (SNS) has been shown to be useful in 54% of FI patients, but has significant complications (33%) and a failure rate of 15%, its mechanism of action is unknown, and lacks rigorous sham-controlled trial. Furthermore, a comparative assessment of the effectiveness of current treatments has not been performed, and none of the current therapies have been shown to improve the multifactorial pathophysiological dysfunction(s) in FI.

A critical barrier to progress in the treatment of FI is the lack of RCTs, and absence of mechanistically based non-invasive therapies that modify the pathophysiology of FI. Consequently, most current remedies have remained ineffective. These findings were highlighted by experts at a recent NIDDK workshop focused on research in FI. Our long-term goal is to address the problem of lack of effective treatments for FI by investigating therapies that modulate peripheral and central neuronal perturbations, and to understand the neurobiologic basis of these treatments. Translumbosacral Neuromodulation Therapy (TNT) is a novel, non-invasive technique that involves the focal delivery of magnetic energy through an insulated coil to the lumbo-sacral nerves that regulate anorectal function. The pulses generated are of the same strength as clin-ical MRI machines. It builds on the concept of neuromodulation therapies such as repetitive transcranial magnetic stimulation (rTMS) that uses a computerized electromechanical medical device to deliver brief pulses of magnetic energy and has been shown to be effective in major depression , refractory auditory hallucinations (AH), and visceral pain, and our studies in post-stroke dysphagia. Our central hypothesis is that TNT will significantly improve FI, both in the short-term and long-term, by enhancing neural excitability and inducing neuroplasticity, and thereby will provide a multidimensional thera-peutic benefit- improve neuropathy, enhance anal strength, improve rectal perception and capacity.

Eligibility criteria: Inclusion Criteria:

* Recurrent episodes of FI for 6 months;
* No mucosal disease (colonoscopy + biopsy); and
* On a 2-week stool diary patients reported at least one episode of solid or liquid FI/week.

Exclusion Criteria:

* severe diarrhea (\>6 liquid stools/day, Bristol scale \>6);
* on opioids,);
* active depression;
* severe cardiac disease, chronic renal failure or previous GI surgery except cholecystectomy and appendectomy;
* neurologic diseases (e.g. head injury, epilepsy, multiple sclerosis, strokes, spinal cord injury) and increased intracranial pressure;
* metal implants (within 30 cm of magnetic coil placement), pacemakers;
* previous pelvic surgery/radiation, radical hysterectomy;
* Ulcerative and Crohn's colitis;
* rectal prolapse;
* active anal fissure, anal abscess, congenital anorectal malformation, fistulae or inflamed hemorrhoids;
* pregnant women

Primary outcomes:
measure: AIM 1 Primary Outcome measure is the proportion of patients achieving >50% of reduction in fecal incontinence episodes/weeks at the end of 6 weeks compared to baseline.
timeFrame: 6 weeks (short term)
measure: AIM 2: Latencies for lumbo-anal Magnetic Evoked Potentials (MEP) responses compared to baseline
timeFrame: 6 weeks
measure: AIM 2: Latencies for sacro-anal MEP responses compared to baseline
timeFrame: 6 weeks
measure: AIM 2: Latencies for the ano-cortical Cortical Evoked Potentials (CEP) responsecompared to baseline.
timeFrame: 6 weeks
measure: AIM 3:Primary Outcome measure is the proportion of patients achieving >50% of reduction in fecal incontinence episodes/weeks at the end of 48 weeks compared to baseline.
timeFrame: 48 weeks (long term)
measure: AIM 3: Latencies for lumbo-anal MEP responses
timeFrame: 48 weeks
measure: AIM 3: Latencies for sacro-anal MEP responses
timeFrame: 48 weeks
measure: AIM 3: Latencies for the ano-cortical CEP response .
timeFrame: 48 weeks
Secondary outcomes:
measure: Stool Frequency
timeFrame: 6 weeks, 48 weeks
measure: Stool consistency
timeFrame: 6 weeks, 48 weeks
measure: Bowel Urgency
timeFrame: 6 weeks, 48 weeks
measure: Reduction of Fecal Incontinence (FI) episodes
timeFrame: 6 weeks, 48 weeks
measure: Stool Leakage Characteristics
timeFrame: 6 weeks, 48 weeks
measure: Global Assessment of bowel satisfaction
timeFrame: 6 weeks,, 48 weeks
measure: Global Assessment of bowel satisfaction-Visual Analog Scale
timeFrame: 6 weeks, 48 weeks
measure: FI severity-Fecal Incontinence Severity Index (FISI)
timeFrame: 6 weeks,4 8 weeks
measure: FI severity-Fecal Incontinence Severity Score (FISS):
timeFrame: 6 weeks, 48 weeks
measure: FI severity-International Consultation on Incontinence Questionnaire (IC-IQB):
timeFrame: 6 weeks, 48 weeks
measure: Change in FI Quality of Life (FI-QOL)
timeFrame: 6 weeks, 48 weeks
measure: Psychological Function PROMIS anxiety Questionnaire
timeFrame: 6 weeks, 48 weeks
measure: Psychological Function PROMIS Depression Questionnaire
timeFrame: 6 weeks, 48 weeks
measure: Psychological Function PROMIS Efficacy Questionnaire
timeFrame: 6 weeks, 48 weeks
measure: Amplitudes (Milivolts of the nerve) for lumbo-rectal MEP compared to baseline
timeFrame: 6 weeks, 48 weeks
measure: Amplitudes (Milivolts of the nerve) for sacro-rectal MEP
timeFrame: 6 weeks, 48 weeks
measure: Amplitudes (Milivolts of the nerve) for recto-cortical CEP responses
timeFrame: 6 weeks, 48 weeks
measure: MEP Index The area under the curve of the MEP response
timeFrame: 6 weeks, 48 weeks
measure: Anal Sphincter Function-Sustained Squeeze Pressure
timeFrame: 6 weeks, 48 weeks
measure: Anal Sphincter Function-Anal Resting Pressure
timeFrame: 6 weeks, 48 weeks
measure: Anal Sphincter Function-Squeeze Pressure
timeFrame: 6 weeks, 48 weeks
measure: Rectal Sensation-First Sensation (volume of air)
timeFrame: 6 weeks, 48 weeks
measure: Rectal Sensation- Desire to defecate
timeFrame: 6 weeks, 48 weeks
measure: Rectal Sensation-Urgency to Defecate
timeFrame: 6 weeks, 48 weeks
measure: Rectal Sensation-Maximum tolerable volume
timeFrame: 6 weeks, 48 weeks
measure: Rectal Compliance
timeFrame: 6 weeks, 48 weeks
measure: Symptoms correlation
timeFrame: 6 weeks, 48 weeks
Other outcomes:
Locations:
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Augusta University
name: Satish Rao, MD,PhD
role: STUDY_DIRECTOR
References: