Implantation of BioSphincter TM for Treatment of Severe Passive Fecal Incontinence

This is a two-center first-in-human prospective Phase I study of the immediate and long-term safety of an implanted internal anal sphincter (IAS) bioengineered from autologous cells to treat subjects with severe passive FI who have failed standard treatments. The data will be analyzed to assess the safety of the treatment and the potential initial efficacy of the implanted BioSphincter(TM) in decreasing the number of episodes of incontinence in subjects with severe FI.

After being informed of the risks, informed consent patients will undergo a biopsy procedure to collect tissue samples and will then undergo an implantation surgery of the bioengineered BioSphincter(TM). Patients will be followed for 36 months, post implantation.

Inclusion criteria

Patients are eligible to be included in the study only if all of the following criteria apply:

• Males and females aged 18 years old and over at the time of signing the IRB approved informed consent.
• Have the ability to understand the requirements of the study and are willing to comply with all study procedures.
• In the opinion of the investigator, able to participate in the study.
• Experience four or more FI episodes per 2-week period for the past 12 months. For purposes of this study, FI is defined as the loss of control sufficient to have stool in the subject's undergarments or require the changing of the undergarments. FI does not include the presence of a minimal amount of fecal material on the subject's undergarments and does not require the changing of the undergarments.
• Failed standard medical and surgical therapies for FI as defined below:

• Failure of standard medical therapy is defined as

• Bulking agents such as Citrucel or Metamucil fail to decrease the frequency of FI episodes to 4 or fewer episodes per two-week period after 4 weeks of treatment. Treatment failure is defined as a lack of response to the intervention after 4 weeks of treatment. Upon initiation of fiber, patients should see a change in stool consistency within 24-48 hours. Additional time for fiber treatment is needed to titrate the dose to optimize stool consistency and minimize side effects of bloating and increased flatus. Four weeks allows time to change stool consistency and measure changes in FI with a stable fiber regimen.
• Antidiarrheal agents such as Imodium or Lomotil may decrease FI or produce constipation but fail to decrease the frequency of FI episodes to 4 or fewer episodes per two-week period after 4 weeks of treatment. Treatment failure is defined as a lack of response to the intervention after 4 weeks of treatment. Upon initiation of Imodium or Lomotil, the patient should see a change in stool frequency within 24-48 hours. Additional time on Imodium/Lomotil treatment is needed to titrate the dose to optimize stool frequency and minimize side effects of bloating. Four weeks allows time to change stool frequency and measure changes in FI on a stable Imodium/Lomotil regimen.
• Failure of biofeedback training to reduce the frequency of FI episodes to 4 or fewer episodes per two-week period after 4 weeks of treatment. Treatment failure is defined as a lack of response to the intervention after 3 months of treatment. Three months of physical therapy is needed to allow strengthening of pelvic floor musculature and improvement in pelvic floor coordination.
• Failure of standard surgical therapy is defined as

• Sacral nerve stimulation (SNS) fails to decrease the frequency of FI episodes to 4 or fewer episodes per two-week period after 2 months or more of treatment. SNS requires a two week period for two surgeries, trial implantation and then permanent implantation. During the two week period, patients can see a change in FI symptoms secondary to SNS implantation that informs the decision to proceed with permanent implantation. After permanent implantation, the settings of the SNS can be manipulated to optimize fecal control and minimize patient side effects. Two months allows time for the two surgeries to occur and SNS setting changes to ensure optimization of FI. Failure of SNS treatment will also include patients who have SNS explantation due to complications or side effects. Finally, SNS failure will also include patients who fail test stimulation and do not undergo chronic implantation. Patients can be considered to have SNS failure if after informed consent for the procedure, they elect to not undergo SNS trial or implantation.
• Sphincteroplasty failure will have occurred if the FI episode frequency is four or more episodes per two-week period, 12 months or more after surgical repair. After sphincteroplasty, patients may initially see an improvement in FI. However, over time, there has been a measured degradation in response to this surgical despite intact sphincter repair. Therefore, after 12 months, if a patient has undergone sphincteroplasty but fails to have improvement in FI, OR redevelops FI after initial improvement in FI, the patient will be eligible for potential trial enrollment.
• Patients with severe passive fecal incontinence are eligible for the trial if they have failed all medical and surgical therapy for fecal incontinence and are being considered for a colostomy.
• Anorectal manometry (ARM) testing history of ARM while at the discretion of the Physician/Surgeon. ARM must show low IAS pressure and presence of the Recto Anal Inhibitory Reflex (RAIR). Low IAS pressure is defined as ≤ 60 mmHg during the anorectal motility exam performed with a high-resolution catheter. Normal IAS pressure range is > 60 mm Hg.
• Pre-surgery, vital signs must be within the following parameters: SBP (mmHg) >100 or < 140; DBP (mmHg) >60 or <90; HR >60 or <100 bpm; afebrile, RR< 20 or >12 bpm; Pulse ox >95% on room air.
• Women of childbearing potential must use acceptable contraceptives during this study. Acceptable contraceptives include oral contraceptives and IUDs. Females of childbearing potential will have a urine pregnancy test on the day of trial enrollment.
• Women not using hormonal contraception or hormonal replacement therapy (HRT) must have confirmation of a postmenopausal state. A high follicle stimulating hormone (>40 IU/L) level in the postmenopausal range may be used; however, in the absence of 12 months of amenorrhea, confirmation with more than one FSH measurement is required.
• Men of childbearing potential should use a medically accepted contraceptive during this study. Acceptable contraceptives include total abstinence and condoms + spermicide.
• Colonoscopy performed within the past 5 years that excludes malignancy, inflammation, or infection.
• Willingness to return for all follow-up visits through 36 months post-treatment.

Exclusion criteria

A patient is not eligible for inclusion in the study if any of the following criteria apply:

• Symptomatic anorectal disease including hemorrhoid disease, anal fissure, or fistula causing symptoms such as bleeding, swelling, pain, or drainage.
• Pre-existing anorectal pain of any cause.
• Incontinence of flatus only.
• Chronic watery diarrhea unmanaged by medical therapy and which is the primary cause for FI.
• Greater than 60 degrees of either external anal sphincter disruption or both (>60° IAS and EAS). Patients with severe (>60 degree) disruption of the EAS ± IAS are likely to have a component of both urge (EAS) and passive (IAS) fecal incontinence. Due to a combined etiology of FI, patients with a large EAS ± IAS disruption are unlikely to have a significant improvement in FI from BioSphincter treatment.
• Acute or chronic anorectal infections (including proctitis, recurrent abscesses, or fistulae).
• Presence of anorectal tumors.
• Active proctitis.
• Uncontrolled inflammatory bowel disease (IBD) characterized by one or more of the following: CRP 10 mg/L, fecal calprotectin > 200 mg/L, new or uncontrolled symptoms of IBD, endoscopic disease, evidence of inflammation on MR Imaging.
• Any illness or disease requiring chemotherapy or any malignant disease within 5 years of enrollment.
• History of organ transplantation requiring immunosuppressive medications.
• History of a bleeding disorder diagnosed and treated by a hematologist, or patient with a diagnosed bleeding disorder currently being treated by a hematologist. If patient is on anticoagulation therapy which can be temporarily halted with permission from the prescribing provider for elective surgery, the patient will be eligible for the trial.
• History of pelvic radiation, rectal prolapse, anorectal malformations, anorectal surgery within the previous 12 months or current colostomy..
• Neurologic disease characterized by significant peripheral neuropathy or spinal cord dysfunction.
• Mobility impairment requiring the use of assistive devices (e.g., wheelchair).
• Current pregnancy, breastfeeding, or childbirth within previous 12 months.
• History of unstable cardiac function (New York Heart Association Functional Classification III or IV).
• History of unstable pulmonary function requiring home oxygen.
• History of abnormal kidney function (Cr >1.5 mg/dl or on dialysis).
• Any clinically important abnormal laboratory tests, including but not limited to:

• Hemoglobin <10g.
• ALT and AST >2 times the upper limit of normal).
• Bilirubin >1.5mg/dl. For criteria a, b, and c, the test can be repeated one time at the discretion of the Investigator. If this option is used, the last obtained reading will be used for determination of eligibility. Averages will not be used.
• Active untreated gynecological or urologic infection.
• Documented history of or positive test results for human immunodeficiency virus (HIV)-1/HIV-2 Antibodies (Abs), Hepatitis B surface Antigen (HBsAg), or Hepatitis C Antibody (HCVAb) and evidence of a chronic active infection.
• Presence of significant comorbidities that may be an underlying cause of FI (e.g., uncontrolled diabetes (>7.5 HgA1C), severe spinal stenosis).
• History of alcohol or substance abuse within past 12 months.
• Concurrent participation in any other clinical investigation during the period of this investigation. Patients who have been treated with any other investigational drug or participated in any investigational study within 30 days prior to enrollment in this study.
• Inability to participate in all necessary study activities due to physical or mental limitations.
• Inability or unwillingness to return for all required follow-up visits.
• Inability or unwillingness to sign informed consent.
• Any circumstance in which the investigator deems that participation in the study is not in the subject's best interest.
• Presence of increased surgical risk associated with jejunal or IAS biopsy (e.g., multiple previous surgeries with potential for adhesions, ventral hernia). Subjects also may be excluded during the biopsy procedure (i.e., an intraoperative exclusion) if the investigator observes any conditions that in the investigator's opinion would generate increased risk. Should this occur, biopsy will not be performed, and the subject will be classified as an intraoperative screen failure.
• Previous history of anorectal surgery or disease which would prevent or increase the difficulty of surgical dissection of the intersphincteric space.
• Allergy to Marcaine, epinephrine, betadine, Dermabond dressing, Prolene (polypropylene) suture, Polydioxanone suture (PDS) and Monocryl suture.