Trial design, setting, and explanation for choice of comparators.

The study is a phase 3 open label, pre- and post-, single center clinical trial in pediatric subjects with SBS, aged 2–18 years who have been dependent on PN for at least six months. Treatment will be the use of the RELiZORB enzyme cartridge with the administration of EN daily for a total of 90 days. This study will be open label; all patients receive the study treatment. Allocation will be known by the subjects, Principal Investigator and their medical staff. Participants will be enrolled and followed at Boston Children’s Hospital.

Based on the study design, each subject will be compared to themselves utilizing pre-treatment baseline measurements; effectively each patient serves as their own control. This type of study design is beneficial in rare diseases, such as pediatric SBS, characterized by extensive heterogeneity between patients [3]. Given this approach and to reduce bias, patients need to demonstrate stability on key outcomes prior to enrollment, including PN dependence and EN requirements, as outlined below.

Eligibility criteria.

The following are the inclusion criteria required for eligibility:

1. Male or female patients, aged 2–18 years, inclusive.
2. Diagnosed with SBS, as determined by medical history and PN dependence (i.e. need for PN for >60 days after intestinal resection or a bowel length <25% of expected).
3. Congenital or acquired gastrointestinal disease requiring surgical intervention that has occurred at least three months prior to screening.
4. Patient is on parenteral lipid and at least 30% of daily caloric and fluid intake has been provided by PN for at least six months prior to screening.
5. Stable PN nutrition requirement, determined by less than 5% reduction in PN nutrition for at least one month prior to screening, or at the discretion of the investigator.
6. The patient has a CVC at the time of study inclusion.
7. Screening direct bilirubin that is in the normal range for age or is not determined to be clinically significant by the investigator.
8. The patient has an existing feeding tube, receiving EN via an enteral feeding pump at a rate>10ml/hr but <120ml/hr, and is able to tolerate at least 10 ml/kg/day EN with which the RELiZORB cartridge can be used.
9. Stable EN requirement with no change in formula composition or rate for at least one month prior to screening.
10. The patient or a parent or legal guardian of the patient is able to read, understand, and is willing to provide informed consent (or assent, if applicable) for the patient.
11. The patient (if assent is applicable) or a parent or legal guardian is able to understand the requirements of the study and is willing to bring the patient to all clinic visits and complete all study related procedures (as determined by the investigator).
12. A parent or legal guardian is willing to provide written authorization for the use and disclosure of protected health information.

Patients will be excluded from the study if any of the following apply:

1. Other causes of chronic liver disease other than SBS (i.e. hepatitis C, cystic fibrosis, biliary atresia, alpha 1 anti-trypsin deficiency, and Alagille syndrome).
2. The patient has had a bowel lengthening procedure, including but not limited to, a STEP procedure.
3. Any serum triglyceride concentration >400 mg/dL at screening.
4. Pancreatic insufficiency as defined as the use of pancreatic enzymes within 30 days prior to screening.
5. Evidence of untreated intestinal obstruction or active stenosis, as determined by the investigator.
6. Unstable absorption due to cystic fibrosis or known DNA abnormalities (i.e., familial adenomatous polyposis, Fanconi syndrome) as determined by the investigator.
7. History of microvillus inclusion disease, as determined by medical history.
8. Severe known dysmotility syndrome (i.e., pseudo-obstruction, gastroschisis-related motility disorders), as determined by the investigator.
9. Initiation of teduglutide or other GLP-2 analogues within six months of screening
10. Use of growth hormone, or supplemental glutamine within three months prior to screening.
11. Use of cisapride within 30 days prior to screening.
12. Active clinically significant pancreatic or biliary disease, as determined by the investigator.
13. Receiving EN via any formula that is not compatible with the RELiZORB cartridge (for example, insoluble fiber-containing formulas).
14. Determined by the investigator to be unsuitable for participation in this trial for any reason.

Interventions.

Subjects are initially evaluated in a screening visit (Day -3) during which they will be screened for eligibility, including baseline clinical and physical assessments (Fig 1). At screening, the investigator or designee will review the subject’s medical history to determine eligibility, explain the study to the subject and the subject’s parent or legal guardian, and if eligible, obtain informed consent (S3 File). Informed consent and assent will be obtained from study investigators and authorized personnel and the discussion will be documented in the patient’s electronic medical record. If consent is given and the subject is deemed eligible based on the results of the screening visit, they will be enrolled in the study and pre-baseline assessments will be performed, which will include physical examination, nutritional assessment, vital signs, and laboratory evaluations (Fig 1). The subject’s parent or guardian will also receive education from a registered dietitian on recording caloric intake and composition in oral and enteral feeds, and PN. As part of this education, the dietitian will review how to record daily oral and enteral intake via paper dairy or with a HIPAA-compliant nutrition/food tracking phone application. If the latter, the subject’s parent or guardian will receive access to a nutrition/food tracking phone application.

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Fig 1. Schedule of enrolment, interventions, and assessments.

I/E criteria = Inclusion and exclusion criteria. FAs = fatty acids. PN = Parenteral nutrition. a. Record known bowel length/type from last surgical resection or other measurement. b. Blood pressure, pulse rate, respiratory rate and temperature. c. Includes height or length, head circumference (for subjects < 36 months), and weight. If a physical examination or nutrition assessment was performed during the 3-day screening period, it will be used for the baseline assessment when available. d. Includes chemistry (including fat-soluble Vitamins A, D, E, and K), hematology, coagulation and C-reactive protein (CRP). Clinical laboratory evaluations obtained at time of screening will serve as the baseline assessment. e. 72-hour fecal collection will occur in the 72 hours preceding treatment day 1 and the final clinic visit day 90. f. Samples of the lipid profile will include cholesterol, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL). Results of samples obtained at time of screening will be analyzed during enrollment period, prior to participant receiving device. g. Samples of total plasma fatty acids will include total saturated, total monosaturated, total polyunsaturated, total Omega-3, total Omega 6, total fatty acids, a-linolenic Acid, linoleic acid, oleic acid, EPA, arachidonic acid, mead acid, DHA, and triene:tetraene ratio. h. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum gamma-glutamyl transpeptidase (GGT). i. 24-hour nutritional intake/composition (PO and enteral dietary intake and PN volume) will be recorded using a phone-based application or paper diary. This will be especially important during the 72-hour stool collection periods for calculation of the coefficient of fat absorption. j. Adverse events will be recorded daily in an electronic or paper format by the subject’s parent or guardian, and by study staff during clinic visits. Monitoring of these events will also occur through a daily phone call from a study coordinator. If any AEs or concerns are noted by the family, the study coordinator will alert the study team by email. PI or other delegated investigators will determine next steps.

https://doi.org/10.1371/journal.pone.0282248.g001

The subject’s parent or guardian will then be asked to collect all stool for 72-hours over Day -3 to Day -1 and to record caloric intake and composition in oral and enteral feeds, and PN during that time. The collected stool will be submitted to the Boston Children’s clinical laboratory for total fat quantification. To evaluate the degree of fat malabsorption, the intake data and stool fat quantification will be used to measure the baseline CFA, as previously described [15].

Treatment will be administered on study Day 1, followed by daily use of the RELiZORB enzyme cartridge whenever EN is administered, for a total of 90 days. During the treatment period, all EN will be administered through the RELiZORB enzyme cartridge. Nutritional intake (24-hour enteral dietary and PN volume intake), stool consistency/amount/frequency (if applicable) or ostomy (if applicable) output, study device use, and incidence of symptom changes will be recorded daily, in an electronic or paper diary, by the subject’s parent or guardian. Access to the nutrition/food tracking phone application along with a daily phone call from a study coordinator will be used to ensure accurate recording and completion of these tasks.

Subjects will return to the clinic on Days 7, 14, 28, 60, and 90 of the treatment period (Fig 1). The final clinic visit will be preceded by a repeat 72-hour stool collection and measurement of CFA to determine the change (if any) in intestinal fat absorption. During the clinic visits, staff will review the information in the subject’s diary, review compliance with the use of the study device and discuss relevant observations with the subject during the visit. Upon review, information contained in the diary will be entered in the electronic database. In addition to a daily study coordinator phone call, the study staff will have weekly telephone contact with families during interim weeks after the day 14 visit. Prior to these visits, subjects will be weighed at home by their parent or guardian using a standardized weight scale. At the in-person clinic and weekly telephone visits, study staff will monitor safety, diaries, weight data, stool composition (Bristol scale) and output, changes in caloric intake, changes in urine output, and will make adjustments to PN and enteral feeding accordingly (Fig 2). Adjustments will be based on the subject’s nutritional needs, weekly weights, height, hydration status and investigator’s medical judgement. If necessary, unscheduled visits can be arranged in place of the telephone contacts.

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Fig 2. Nutritional support adjustments based on weight changes.

Additional considerations include other growth parameters, laboratory evaluations (if available), overall clinical status, intake/output ratio, and enteral tolerance. Figure created with Biorender.com.

https://doi.org/10.1371/journal.pone.0282248.g002

At each clinic visit, vital signs, physical examination, clinical evaluations, AEs, concomitant medications, medical/surgical procedures, and blood tests to determine the levels of liver enzymes will also be performed. Blood samples will be collected to analyze lipid profiles. All AEs post-baseline that occur will be recorded. Participants will meet with a study dietitian during each visit to assess nutritional needs and address issues or concerns.

Subject discontinuation.

Subjects may voluntarily withdraw consent from the trial at any time. The investigators will provide a written explanation of the reason for discontinuation in a source document which will be captured and summarized in the data management system. A subject may also be removed from the study in the event of an AE, which in the judgement of the investigator, investigational product manufacturer, or the DSMB presents an unacceptable consequence or risk to the subject. Subjects may also be removed if, in the judgement of the investigator, an intercurrent illness or complication occurs that prevents the continued adherence to the protocol requirements. Noncompliance to the protocol requirements and/or refusal of investigational product administration are reasons for involuntary subject withdrawal. Reasonable efforts will be made to monitor such subjects for AEs and to complete follow-up assessments after discontinuation.

Adherence and related strategies.

Subjects and their families will receive initial training and education on the use of RELiZORB with their enteral feeds during the screening (Day -3) and Day 1 visits. Educational pamphlets and printed instructions will complement these educational sessions. The daily coordinator phone call is incorporated into the protocol to monitor for continued adherence regarding the use of the device with each enteral feed and promote participant retention/follow-up. Any issues noted during these calls will be addressed promptly. Subjects will be considered to have complied with study treatment if ≥80% of the planned EN was administered using the RELiZORB device. The frequency and percentage of subjects who were compliant will be presented.

Concomitant care.

Clinical care will be continued as per the discretion of the Center for Advanced Intestinal Rehabilitation (CAIR) program at Boston Children’s Hospital. Concomitant medications will be logged and tracked during each study visit in the appropriate case reporting form (CRF). As the lipase enzyme is covalently bound to beads in the device, it remains in the cartridge and is not ingested. Therefore, there is no potential for drug interactions with other medications the participant may be taking. In the event of a hospitalization, subjects will be instructed to bring their consent forms and study devices to avoid interruption in treatment. The research team will work with the clinical teams in such an event to ensure continued protocol adherence.

Post-trial care.

Families will have the option to work with the CAIR program coordinators at our institution on obtaining insurance approval for long-term coverage of RELiZORB following the end of the study. In the event of injury harm directly results from taking part of this research, we will ensure that the required care is provided. Participants are not eligible for compensation in the event of an injury, and this is mentioned in the informed consent form.

Outcomes.

The primary outcome of this study is the change from baseline in PN calories, assessed weekly throughout the study. The secondary outcome is the change from baseline in body weight (weight-for-age adjusted Z-score), also assessed weekly throughout the study.

Safety outcomes include the following:

1. The incidence of adverse events, grade 2 or higher. All AEs will be reported by study participants including changes in stool consistency (Bristol stool scale)/amount/frequency (if applicable), increased ostomy output (if applicable, defined as >2.5mL/kg/hour), the need to decrease enteral feeds, changes in urine color assessed by the Urine Dehydration Color scale, and discontinuation from the study treatment, assessed over the entire study.
2. The incidence of abnormalities in vital signs (blood pressure, pulse rate, respiratory rate, temperature) assessed at baseline, Days 7, 14, 28, 60, and 90.
3. The incidence of abnormalities in hematology and biochemistry parameters. based on hospital reference ranges, assessed at baseline, Days 7, 14, 28, 60, and 90.

Several exploratory outcomes will also be examined:

1. The change from baseline in 72-hour fecal fat and CFA, assessed at baseline (Days -3 to -1) and prior to the end of the study (Days 87–89).
2. The change from baseline in plasma fatty acid composition and fat-soluble vitamins (A, D, E, and K), assessed at Day 7, 14, 28, 60, and 90.
3. Change in growth height (assessed by height-for-age Z-score) and head circumference (assessed by head-circumference-for-age Z-score) [in subjects < 36 months]) from baseline, assessed at Day 7, Day 14, Day 28, Day 60, and Day 90.
4. The change in BMI-for-age Z-score assessed at Day 7, 14, 28, 60, and 90.
5. The change from baseline in PN volume, assessed weekly.
6. The change from baseline in total enteral calories and total enteral volume, assessed weekly.
7. The change from baseline in total oral calories and total oral volume, assessed weekly.
8. The ability to wean from PN, assessed over the entire study from baseline until Day 90.

Participant timeline.

The detailed participant timeline for this protocol can be found in Fig 1.

Sample size.

Precision-based power calculations were determined using nQuery Advisor 7.0 (GraphPad Software DBA Statistical Solutions, San Diego, CA). The primary outcome is the change in PN calories from baseline, assessed weekly at 13 assessments (study days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 90) using a baseline-adjusted time-weighted average (AUC_7-90). In adults receiving teduglutide intended to improve enteral absorption in PN dependent patients with intestinal failure, an aim of 20% reduction was used to assess efficacy [9]. When adapted for a pediatric intestinal failure population, a ≥10% reduction was considered a valid pharmacodynamics (PD) marker of increased intestinal absorptive capacity. Based on the design of the teduglutide studies it was felt that the data provide similar support for a ≥10% reduction at Day 90 as a predictor of pharmacodynamic effect with the use of the RELiZORB device.

A reliable estimate for the standard deviation (SD) of AUC_7-90 for the primary outcome in this patient population is unavailable. Unpublished data for seven patients are available, but at least four of these would not meet the eligibility criteria for this study (ages 1–10; one had a STEP procedure; three have pancreatic involvement). Nevertheless, the mean ± SD reduction (AUC_7-90) for these seven patients was 0.81±0.14, representing a 19% decrease over 90 days. Using this SD with a sample size of n = 32, a 20% observed reduction in outcome would provide a 95% confidence interval (CI) = (0.75, 0.85), ruling out a true mean population reduction smaller than 15%. Conservatively, if the SD was doubled (SD = 0.28), the 95% CI = (0.7, 0.9), excluding a true mean population reduction smaller than 10%, our target threshold. In general, for any continuous outcome, a sample size of n = 32 with two-side alpha = 0.05 will provide 80% power to detect an effect size (mean/SD) as small as 0.51, considered a medium-sized effect [16].

Recruitment and retention.

Historical review of patients followed by the CAIR program suggests that an average of eight patients per year can be expected to meet the eligibility criteria, for a total of 32 subjects over four years. Patients who follow with the CAIR program will be screened for initial eligibility. Subjects who meet the eligibility criteria will then be approached during their regular short bowel clinic visits which typically occur every two months. If interested, the study coordinators will then schedule the initial screening and enrollment study visits. All study subjects will receive all of their care through CAIR so retention is expected to be high with minimal loss to follow up.

Data collection methods.

Paper CRFs will be used to capture study assessments and data. The study coordinator or other delegated study personnel will enter data from source documents into the CRFs and then into the electronic database. InForm (Oracle Health Sciences, Redwood Shores, CA), an FDA Part 11 compliant electronic data capture (EDC) system, will be used for this study. The investigator will review and sign off on appropriate CRFs prior to filing. Study documents related to consent, eligibility, unanticipated adverse device effects (UADESs), and device accountability will be reviewed by the study monitor during periodic site visits. This can include consent forms, CRFs, study logs and source documents. Copies of the CRFs used in this study are available upon reasonable request.

Data training and management.

Training will be provided to authorized study personnel for the use of InForm. All clinical trial personnel using the EDC system must have the necessary education, training, and experience or any combination of these. The investigators will be responsible for documenting employee education, training, and previous experience that pertain to the EDC system for all site personnel.

The investigators will maintain adequate security of the EDC system, including documentation that all users have been trained on the appropriate standard operating procedure and a list of authorized users. To ensure all data entries can be tracked, all personnel responsible for data entry must obtain InForm training certificates before any data can be entered in the database. The EDC system is configured to track all user entries and edits to the data. Authorized study personnel will be assigned a unique password after receiving database training. The sponsor-investigator (MP) will ensure that the electronic data systems are validated, and that data are backed up.

Confidentiality and data access.

The anonymity and privacy of participating subjects is of the outmost importance. Subjects will be identified by an assigned subject number on CRFs and other documents retrieved from the site or sent to the study monitor, regulatory agencies, central laboratories, or blinded reviewers. Documents that identify the subject (e.g., the signed informed consent form) will be maintained in strict confidence by the investigator, except to the extent necessary to allow auditing by the appropriate regulatory authority, or the study monitor. The investigators will keep all data confidential about the nature of the proposed investigation provided by the study monitor to the investigator (with the exception of information required by law or regulations to be disclosed to the IRB, the subject, or the appropriate regulatory authority).

Upon study completion, the investigators will retain control of the data. Even though the final dataset will lack identifiers, we believe that there remains the possibility of deductive disclosure of subjects given the limited number of enrolled subjects as well as the rarity of SBS. Therefore, we will make the data and associated documentation available to users only under a data-sharing agreement that provides for: 1) a commitment to using data only for research purposes and not to identify any individual participant; 2) a commitment to securing the data using appropriate computer technology; and 3) a commitment to destroying or returning the data after analyses are completed.

Statistical methods: Outcomes evaluation.

Data will be summarized in tables listing the number of subjects, mean, standard deviation, standard error, 95% confidence interval (CI), median, interquartile range (IQR), minimum, and maximum for continuous data and number of subjects, frequency and percentage for categorical data. Summaries will be presented by subject and visit, as well as in aggregate when appropriate. Outcomes will be presented in their native units (i.e. as collected), in addition to transformed units when necessary (for example logarithmic). Anthropometry outcomes (weight, height, head circumference, body mass index) will be examined as Z-scores using the Centers for Disease Control growth charts. All outcomes will be explored visually using various graphing methods, including (but not limited to) box-whisker, profile, and bar plots. All statistical analyses will be performed with SAS version 9.4 or later (Cary, NC).

Continuous outcomes, which include all outcomes except the incidence of AEs and incidence of weaning from PN, will be described as indicated in the general overview above using summary measures at each visit. Incidence of ever weaning from PN will be summarized by frequency count and percentage.

Assessment of change in continuous outcomes will be made using the area under the curve between study day 7 and 90 (AUC_7-90), adjusted for baseline (Day 1), calculated over all relevant assessment timepoints (5 and 13 post-baseline weekly assessments for measurements obtained in clinic and at home, respectively). Measurements obtained in clinic will be assessed at study days 7, 14, 28, 60 and 90, while those obtained at home will be assessed on study days 21, 35, 42, 49, 56, 63, 70, 77, 84.

Adjustment for baseline will be made by dividing the outcome value at each assessment by the baseline value, leading to interpretation of AUC_7-90 as a mean relative percent increase or decrease in outcome depending on whether AUC_7-90 is greater or less than unity (1), respectively. AUC_7-90 will be calculated as a time-weighted average, given by the equation: Where t_i denotes the assessment day as described above, and r_i = y_i/y₁ denotes the outcome at assessment day t_i divided by the baseline (day 1) value.

The assumption of normality will be assessed for AUC_7-90 for each continuous outcome using quantile-quantile (Q-Q) plots and the Shapiro-Wilk test. Outcomes determined to be skewed will be normalized using an appropriate transformation (e.g. logarithm; normal scores based on ranks). AUC_7-90 for each outcome will be summarized as described above.

Statistical methods: Safety analysis.

Safety analysis will be performed on all subjects enrolled in the study with a follow-up safety assessment. Adverse event data will be listed individually and summarized by system organ class and preferred terms within a system organ class. The number and percentage of subjects with AEs, serious adverse events (SAEs), AEs that lead to discontinuation, study device-related AEs (determined by the investigator), and AEs that lead to death will be summarized. Only AEs grade 2 or higher will be presented. When calculating the incidence of AEs, each adverse event will be counted only once for a given subject. If the same AE occurs on multiple occasions in a subject, the occurrence with the highest severity and relationship to study device will be reported. If two or more adverse events are reported as a unit, the individual terms will be reported as separate events. AEs will also be summarized with regards to severity and relation to study drug. Additionally, the frequency of each AE within-subject will be calculated and summarized across all subjects in order to rank the commonality of each particular AE.

Vital signs, hematology, and clinical chemistry parameters from baseline to the end of the study will be presented as outlined above for continuous outcomes and reported to the Data Safety Monitoring Board (DSMB) at the regularly scheduled meetings. Incidence of changes in laboratory parameters from normal to abnormal, based on Boston Children’s Hospital reference ranges, will be identified and lab values listed by subject.

Statistical methods: Additional considerations.

The primary population analyzed for efficacy will be the full-analysis population (often referred to as intention-to-treat), defined as all subjects enrolled in the study. This population will include all enrolled subjects regardless of protocol deviations, compliance, or number of visits completed. A per-protocol population will be used for sensitivity analysis where results will be compared to the full-analysis population. The per-protocol population will exclude subjects with substantial deviations from the protocol (as determined by the investigator prior to database lock), <80% compliance, intercurrent illness for >20% of follow-up, or insufficient study visits (as determined by the investigator prior to database lock). The safety population will include a subset of the full-analysis population who received at least one treatment with RELiZORB and who have at least one adverse event grade 2 or higher.

The default method for calculating area under the curve when either the first follow-up visit (Day 7), last follow-up visit (Day 90), or both first and last follow-up visits are missing will be to evaluate from the first available follow-up visit to the last available follow-up visit. That is, AUC_F-L (area under the curve from first available until last available) will be calculated with no change in outcome indicated by AUC_F-L = 1. Sensitivity of the area under the curve to unknown data will be investigated using a best- and worse-case scenario method, as detailed in the study protocol (S2 File).

Study coordination and execution.

The daily operations of this project will be managed by study coordinators and project managers. Study staff will also include a dedicated dietitian, pharmacist, postdoctoral research fellow, biostatistician, and research assistants. The principal and associated investigators will oversee all study operations. Weekly team meetings will discuss study progress, enrollment, any necessary protocol amendments, AE status and classification, and address any issues as they occur. Details regarding study documentation are available in the complete study protocol (S2 File).

Data monitoring.

The DSMB will be a board comprised of three clinicians who are subject experts, and one biostatistician not participating in this study–all independent of the study investigators and sponsors. One of the clinicians will be appointed as chairman of the DSMB. The DSMB is responsible for safeguarding the interests of study participants, assessing the safety and efficacy of study procedures, and for monitoring the overall conduct of the study. The first meeting will occur prior to the first participant’s enrollment. The DSMB will then convene once the first participant has enrolled into the study, followed by every six months to review limited cohort safety data with additional meetings scheduled as needed. Specific details about the DSMB composition, responsibilities, organization and meeting frequency can be found in the DSMB Charter (S4 File).

No interim analysis or early stopping rules are planned given the sample size and protocol design. However, the DSMB will have the right to recommend stopping the trial early if safety concerns arise. Additionally, an independent site monitor will perform periodic visits to review consent, eligibility and unanticipated adverse device effects (UADEs) for all enrolled subjects, as well as device accountability documents.

Adverse events and related procedures.

Any adverse events that occur after the use of RELiZORB enzyme cartridge will be recorded and tracked in a dedicated AE log. AEs will be defined, graded, and classified according to the Common Terminology Criteria for Adverse Events, v.5.0 [17]. The subject will receive appropriate treatment and medical supervision for any AE that occurs. Subjects with anaphylactic or allergic reactions will not continue to receive the study device. All AEs judged to be clinically significant, including clinically significant laboratory abnormalities, will be followed until resolution. All AEs will be summarized in the annual report or more frequently if requested by the regulatory agency.

For the purposes of this trial, any AE that is results in death, is life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life operations, or other medically important events will be considered a SAE. Any SAE occurring after use of the study device must be reported to the IRB and the Data and Safety Monitoring Board (DSMB) by phone or in person within 72 hours of the time the investigator becomes aware of the SAE, or within 24 hours if the event is fatal or life threatening.

Auditing.

This study will be monitored through an independent monitoring program at our institution. This monitoring program follows established auditing procedures as outlined in the FDA Guidelines for the Monitoring of Clinical Investigations, as well as the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices. After enrollment of the first subject, an in-person monitoring visit will occur every three months for the duration of the study. During these visits, patient records specifically related to consent, eligibility, device accountability, and unanticipated adverse device effects will be reviewed for accuracy and completeness. Based on these reviews, reports will document the findings, if any, and any actions that need to be taken to correct any issues. The study team will be responsible for reviewing each report and ensuring that the proper follow-up actions occur as deemed necessary. A final monitoring visit will occur at the end of the study to ensure that all study-related documentation is present and complete.