Translumbosacral Neuromodulation for FI (TNT)

Translumbosacral Neuromodulation Therapy For Fecal Incontinence: Randomized Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Fecal Incontinence
• Intervention / Treatment: Device: Translumbosacral Neuromodulation Therapy (TNT); Other: Sham TNT Therapy

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.

• Study Type: Interventional
• Enrollment (Anticipated): 132
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Augusta, Georgia, United States, 30912-4810
      • Recruiting
      • Augusta University
      • Contact: Tennekoon Karunaratne, MD,PhD; Phone Number: +1-706-721-1968; Email: tkarunaratne@augusta.edu
      • Sub-Investigator: Amol Sharma, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Ahmad Samad; Phone Number: 617-726-2132; Email: ASAMAD1@mgh.harvard.edu
      • Contact: Kyle Staller, MD; Phone Number: +1-617-724-6038; Email: KSTALLER@mgh.harvard.edu
      • Principal Investigator: Braden Kuo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1 Hz 2400 TNT Treatment; Intervention: TNT treatment intervention with 2400 total stimulations with the magnetic coil..	Device: Translumbosacral Neuromodulation Therapy (TNT); A probe with 2 pairs of bipolar steel ring electrodes, will be placed in the rectum. At each site a mapping procedure is performed with single stimulus coil to assess the motor threshold intensity, defined as the minimum level of magnetic stimulation intensity required to achieve an anal and rectal MEP response of 10 microvolts and an anterior tibialis MEP of 20 microvolts with 50% of trials.The intensity for TNT at each site is capped at a maximum of 150% above this threshold to comply with safety guidelines. Thus, intensity of magnetic stimulations will be individualized. Bilateral lumbar stimulations (rTLMS) are administered at L2/L3 disc space, and sacral stimulations (rTSMS) at S2/S3 level. Next a 70 mm double air film self-cooling coil is positioned randomly over one of the 4 sites, held in place by a coil fixator and 300 or 450 stimulations are delivered. After a 5 min rest the cycle is repeated (Total =600-900/site).The coil is moved to the opposite side and it is repeated.
Active Comparator: 1 Hz 3600 TNT Treatment; Intervention: TNT treatment intervention with 3600 total stimulations with the magnetic coil.	Device: Translumbosacral Neuromodulation Therapy (TNT); A probe with 2 pairs of bipolar steel ring electrodes, will be placed in the rectum. At each site a mapping procedure is performed with single stimulus coil to assess the motor threshold intensity, defined as the minimum level of magnetic stimulation intensity required to achieve an anal and rectal MEP response of 10 microvolts and an anterior tibialis MEP of 20 microvolts with 50% of trials.The intensity for TNT at each site is capped at a maximum of 150% above this threshold to comply with safety guidelines. Thus, intensity of magnetic stimulations will be individualized. Bilateral lumbar stimulations (rTLMS) are administered at L2/L3 disc space, and sacral stimulations (rTSMS) at S2/S3 level. Next a 70 mm double air film self-cooling coil is positioned randomly over one of the 4 sites, held in place by a coil fixator and 300 or 450 stimulations are delivered. After a 5 min rest the cycle is repeated (Total =600-900/site).The coil is moved to the opposite side and it is repeated.
Sham Comparator: Sham TNT Treatment; This arm will have the sham treatment session. First we will assess the motor threshold intensity described above. Next, a sham coil is placed on each of 4 regions (2 lumbar & 2 sacral), and 600 stimulations will be given at each site in 2 trains, with a 5 minutes rest period between each site and 3 minutes between trains.	Other: Sham TNT Therapy; This is the sham TNT treatment as mentioned in the different ARMs using the fake coil with no magnetic stimulations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	A responder will be defined as a patient who shows at least 50% reduction in FI episodes/week when compared to baseline.	6 weeks (short term)
AIM 2: Latencies for lumbo-anal Magnetic Evoked Potentials (MEP) responses compared to baseline	The bilateral latencies, amplitudes and area under the curve (AUC) for the lumbo-anal MEP responses will be measured.	6 weeks
AIM 2: Latencies for sacro-anal MEP responses compared to baseline	The bilateral latencies, amplitudes and area under the curve (AUC) for the sacro-anal MEP responses will be measured.	6 weeks
AIM 2: Latencies for the ano-cortical Cortical Evoked Potentials (CEP) responsecompared to baseline.	The bilateral latencies, amplitudes and area under the curve (AUC) for the anal CEPs will be averaged to measure the latency of each component, P1, N2, etc, and mean group data.	6 weeks
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.	A responder will be defined as a patient who shows > 50% reduction in FI episodes/week at the end of 48 weeks compared to baseline	48 weeks (long term)
AIM 3: Latencies for lumbo-anal MEP responses	The bilateral latencies, amplitudes and area under the curve (AUC) for the lumbo-anal MEP responses will be measured.	48 weeks
AIM 3: Latencies for sacro-anal MEP responses	The bilateral latencies, amplitudes and area under the curve (AUC) for the sacro-anal MEP responses will be measured.	48 weeks
AIM 3: Latencies for the ano-cortical CEP response .	The bilateral latencies, amplitudes and area under the curve (AUC) for the anal CEPs will be averaged to measure the latency of each component, P1, N2, etc, and mean group data	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stool Frequency	Stool frequency-how often subjects have a bowel movement.	6 weeks, 48 weeks
Stool consistency	Stool consistency (Bristol Stool scale, 1-7). 1-very hard stool, 4-normal, smooth stool, and 7-watery stool	6 weeks, 48 weeks
Bowel Urgency	Severity of Bowel urgency-Unable to postpone BM for more than 15 Minutes? YES/NO	6 weeks, 48 weeks
Reduction of Fecal Incontinence (FI) episodes	Percentage of subjects with 100% and 75% reduction in FI episodes compared to baseline	6 weeks, 48 weeks
Stool Leakage Characteristics	Leakage characteristics-amount 0. None; Mild; Moderate; Excessive	6 weeks, 48 weeks
Global Assessment of bowel satisfaction	using 7 point Likert scale (1. Considerably relieved; 7-considerably worse)	6 weeks,, 48 weeks
Global Assessment of bowel satisfaction-Visual Analog Scale	0 (absent)-10 (very severe) point visual analog scale (VAS)	6 weeks, 48 weeks
FI severity-Fecal Incontinence Severity Index (FISI)	Fecal Incontinence Severity Index (FISI)-assessed on characteristics of accidental bowel leakage: 1: 2 or More times a day and 6: Never any symptom	6 weeks,4 8 weeks
FI severity-Fecal Incontinence Severity Score (FISS):	Fecal Incontinence Severity Score (FISS): 5 questions asking about severity of their fecal incontinence. Not a scale.	6 weeks, 48 weeks
FI severity-International Consultation on Incontinence Questionnaire (IC-IQB):	International Consultation on Incontinence Questionnaire (IC-IQB): Questionnaire asking several questions about bowel symptoms. There are scales within each question: 0: never-4:always. How much does this (symptom) bother you? 0 (not at all) and 10 (a great deal).	6 weeks, 48 weeks
Change in FI Quality of Life (FI-QOL)	A 4 question questionnaire that assesses the quality of life with FI symptoms. 2 questions have scaled questions: 1 (most of the time) 4 (none of the time) and 1(strongly agree) 4 (Strongly disagree)	6 weeks, 48 weeks
Psychological Function PROMIS anxiety Questionnaire	Questionnaire that assesses anxiety symptoms. Asks questions on a scale of 1 (never) and 5 (always).	6 weeks, 48 weeks
Psychological Function PROMIS Depression Questionnaire	Questionnaire that assesses Depression symptoms. Asks questions on a scale of 1 (never) and 5 (always).	6 weeks, 48 weeks
Psychological Function PROMIS Efficacy Questionnaire	Questionnaire that assesses self-efficacy for managing symptoms. Asks questions on a scale of 1 (I am not at all confident) and 5 (I am very confident).	6 weeks, 48 weeks
Amplitudes (Milivolts of the nerve) for lumbo-rectal MEP compared to baseline	of the lumbo-rectal MEP responses.	6 weeks, 48 weeks
Amplitudes (Milivolts of the nerve) for sacro-rectal MEP	Milivolts of the nerve for the sacral-rectal MEP compared to baseline.	6 weeks, 48 weeks
Amplitudes (Milivolts of the nerve) for recto-cortical CEP responses	Milivolts of the nerve for the recto-cortical CEP responses compared to baseline.	6 weeks, 48 weeks
MEP Index The area under the curve of the MEP response	The area under the curve of the MEP response compared to baseline	6 weeks, 48 weeks
Anal Sphincter Function-Sustained Squeeze Pressure	Anal sustained squeeze pressure (mm Hg) measure from Anal rectal manometry study compared to baseline.	6 weeks, 48 weeks
Anal Sphincter Function-Anal Resting Pressure	Anal resting pressure (mm Hg) measure from Anal rectal manometry study compared to baseline.	6 weeks, 48 weeks
Anal Sphincter Function-Squeeze Pressure	Anal squeeze pressure (mm Hg) measure from Anal rectal manometry study.	6 weeks, 48 weeks
Rectal Sensation-First Sensation (volume of air)	During anal manometry test, subject tells investigator when they feel a first sensation of the balloon inside their rectum. (measure in mL of air).	6 weeks, 48 weeks
Rectal Sensation- Desire to defecate	During anal manometry test, subject tells investigator when they feel a desire to defecate from the balloon that is blown up inside their rectum. (measure in mL of air).	6 weeks, 48 weeks
Rectal Sensation-Urgency to Defecate	During anal manometry test, subject tells investigator when they feel an urgency to defecate from the balloon that is blown up inside their rectum. (measure in mL of air).	6 weeks, 48 weeks
Rectal Sensation-Maximum tolerable volume	During anal manometry test, subject tells investigator when they feel have a maximum tolerable volume (as much as they can handle) from the balloon that is blown up inside their rectum. (measure in mL of air).	6 weeks, 48 weeks
Rectal Compliance	Assessed by dv/dp	6 weeks, 48 weeks
Symptoms correlation	Correlate bowel symptoms (FI episodes), severity and physiological changes with MEP and CEP latency.	6 weeks, 48 weeks

Collaborators and Investigators

• Sponsor: Augusta University
• Collaborators: Massachusetts General Hospital; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Study Director: Satish Rao, MD,PhD, Augusta University

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2019
• Primary Completion (Anticipated): February 1, 2024
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: February 20, 2019
• First Submitted That Met QC Criteria: March 29, 2019
• First Posted (Actual): April 2, 2019

Study Record Updates

• Last Update Posted (Actual): July 21, 2022
• Last Update Submitted That Met QC Criteria: July 19, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Fecal Incontinence
• Other Study ID Numbers: 1303352; R01DK121003 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No