A Within Subjects Comparison of Two Antegrade Flushing Regimens in Children

• Sponsor: Nemours Children's Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT02435069
• Collaborator: University of Florida (Other)
• Enrollment: 5
• Location: 1
• Arms: 3
• Actual Duration (Months): 25.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

There is a surgical procedure to help children with intractable fecal incontinence gain continence for stool through construction of a tube that connects the abdominal wall to the colon near or through the appendix. This tube allows easy administration of enema solution into the first part of the colon. Putting enema solution through that tube into the colon is called an antegrade continence enema (ACE) and has been shown to work well in helping some but not all children prevent stool accidents. The purpose of this study is to compare a large volume ACE flush using a salt water solution called normal saline with a small volume ACE flush using liquid glycerin. The aims of this study are to: 1) find the most effective dose and flush frequency of each solution needed to prevent stool accidents; 2) compare which solution given at the best dose has the least side effects and 3) to determine if administration of either of the ACE flushing solutions causes electrolyte abnormalities or affects colon health.

Condition or Disease	Intervention/Treatment	Phase
Fecal Incontinence; Neurogenic Bowel	Drug: Dose Response - NS and USP Glycerin - First Intervention; Drug: Effectiveness - NS and USP Glycerin - Second Intervention	Phase 4

Detailed Description

Fecal incontinence past the time of toilet training is devastating to affected children. Antegrade continence enema (ACE) therapy administered through a catheterizable stoma surgically placed in the cecum has helped children with intractable fecal incontinence attain continence for stool. There are a number of retrospective studies demonstrating the variable effectiveness rates of ACE therapy. This variability may be due to what is used to flush. There are no prospective trials evaluating the effectiveness of different flushing regimens. The catheterizable stoma used for the antegrade administration of enema solution is frequently made by bringing the appendix out through the abdominal wall or by placing a skin-level device (button) in to the cecum. ACE therapy administration through the appendix or into the cecum has the potential to cause colonic dysfunction. The effects of ACE administration on colonic mucosal health has not been investigated. This pilot study will compare a high volume normal saline (NS) flush and a low volume United States Pharmacopeia (USP) glycerin flush. The primary aims of the study are to compare which solution, given at an optimal dose and frequency, is associated with fewer side effects, while promoting the higher degree of fecal continence, and to determine if antegrade enema solution administration through an appendicostomy/cecostomy causes electrolyte abnormalities or affects gut health.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Within Subjects Comparison of Two Antegrade Flushing Regimens in Children
• Actual Study Start Date: Feb 9, 2016
• Actual Primary Completion Date: Mar 28, 2017
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Pre-operative Baseline Phase Baseline data including frequency and severity of fecal soiling and frequency and severity of abdominal pain were collected for a minimum of 2 weeks prior to surgical construction of the ACE stoma. Baseline stool calprotectin and serum electrolytes were collected in the baseline phase prior to initiation of the preoperative bowel prep. Pre-operative data served as the control.
Experimental: Dose Response - NS and USP Glycerin - First Intervention Initial flush used NS or USP Glycerin randomized to treatment sequence. The starting volume and administration frequency for NS was 10mL/kg and glycerin 20 mL administered every other day. The NS dose was titrated in 10 mL increments to achieve continence so as not to exceed 500 mL daily for a child under five years of age and 1000 mL daily for a child over 5 years of age. USP Glycerin was titrated in 5 mL increments so as not to exceed 50 mL daily. For side effects greater than Wong Bailey Faces Pain Rating Scale (WBFPRS) level 4, NS was decreased by 2.5 mL/kg to the lowest dose of 5 mL/kg daily. USP Glycerin was decreased in 5 mL increments to the lowest dose of 5 mL daily. If the maximum dose did not result in continence, if the dose necessary to minimize side effects resulted in fecal soiling, or if there were side effects greater than WBFPRS level 4 at the lowest dose of administration, the child was be trialed on the alternate therapy and then dropped from the study.	Drug: Dose Response - NS and USP Glycerin - First Intervention; This trial used a repeated measures, single subjects alternating treatments A-B-C-B'-C'-B1' withdrawal design in which all subjects were tested under all conditions and each subject acted as his or her own control. The subjects were randomly assigned to either normal saline or USP glycerin to control for order effects. Baseline data A served as the control and was obtained pre-operatively. The B-C arm evaluated dose-response relationship and was used to identify the minimum dosing volume and frequency of ACE administration of NS and USP Glycerin necessary to promote fecal continence. When the optimal dose as identified, the child continued on that dose for 2 weeks to insure treatment stability and effectiveness.; Other Names: 0.9% sodium chloride solution, Glycerol, Glycerin
Experimental: NS and USP Glycerin - Effectiveness - Second Intervention To prevent statistical bias from subject loss due to treatment failure, each child was randomized to a second treatment sequence once they achieved continence on optimal dosing with minimal side effects.This arm evaluated the long term effectiveness of NS and glycerin at optimal dose and administration frequency for 4 weeks and served as comparison between flush solutions. The study concluded with the child being placed back on 2 weeks of the initial flush in the randomized sequence.	Drug: Effectiveness - NS and USP Glycerin - Second Intervention; To prevent statistical bias from subject loss due to treatment failure, each child was randomized to a second treatment sequence once they have achieved continence with minimal side effects on optimal dosing The second phase B'-C'-B1' of the study compared the two regimens at optimal dose and administration frequency. This phase was used to confirm the effectiveness of NS and USP Glycerin at optimal dosing on continence and assess side effects.; Other Names: 0.9% sodium chloride solution, Glycerol, Glycerin

Outcome Measures

Primary Outcome Measures

1. Fecal Soiling - Number of Participants That Gained and Maintained Continence on Each Flushing Regimen [Data collection started following consent and procedural training and was collected daily from day 1 for the duration of the study, an average of 135 days.]

   Fecal soiling was defined as non-toilet elimination, which was tracked and documented by the parent/child as direct event recording and tallied as the number of pairs of underwear/protective undergarments soiled with stool per day. The purpose of this outcome measure was to document the number of individuals who gained continence on NS and USP glycerin. Descriptive statistics was limited to percentage of total participants who achieved continence on each flushing regimen. Data was calculated on the last data point in the final phase for both the NS and USP glycerin flush.

2. Fecal Soiling - Quantitative Count Detailing the Number of Episodes of Fecal Incontinence Per Day on NS and USP Glycerin [Data collection began following consent and procedural training and was collected daily from day 1 for the duration of the study, an average of 135 days.]

   Fecal soiling was defined as non-toilet elimination, which was tracked and documented by the parent/child as direct event recording and tallied as the number of pairs of underwear/protective undergarments soiled with stool per day. Descriptive statistics included mean and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05, calculated on the data from the last day of the completed NS and USP Glycerin phases of the study. Power analysis conducted using data from this study with α = 0.5, power of .80, correlation between two means of .598, and effect size of 1.554 estimated a sample size of 11 would be needed to minimize the risk of a Type II error to (20%).

Secondary Outcome Measures

1. NS and USP Glycerin Flush Solution Dosing Frequency Necessary to Achieve Continence [Frequency of administration data was collected as the total number of flushes recieved over the last three days of each dosing phase for both NS and USP Glycerin and recorded as either daily (1), every other day (2), or every third day]

   Flush administration frequency necessary to achieve continence was recorded as a single measure per subject per flush solution obtained as the number of flushes in the last three days of each dosing phase and recorded as either daily (1), every other day (2), or every third day (3). The larger the value, the less frequent the flush, the better the clinical outcome. Dosing frequency was measured using direct observational recording completed by the parent or child. Descriptive analysis included mean, and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Descriptive and inferential statistics were calculated on the data from the last day of the completed NS and USP Glycerin phases of the study.

2. Flush Volume [Data for analysis was collected from the last flush of the NS and USP Glycerin dosing phase of the study]

   Flush volume was measured in mL/flush using a graduated cylinder and recorded by the parent or child with each flush and later calculated in mL/kg. Data derived from the last flush of the completed dosing phase of both NS and USP Glycerin were used to calculate flush volume. Descriptive analysis included mean, median, range, and standard deviation. Reported data excludes subjects who failed to gain and maintain continence on either flushing regimen.

3. Number of Participants With Any Electrolyte Abnormality [Collection dates included a baseline sample (week 1) and at the completion of the dosing trail for both NS and USP glycerin for a total of 3 samples]

   Evaluated impact of NS and USP Glycerin antegrade flush on serum electrolytes using a blood test called a Basic Metabolic Panel. Data analysis limited to percentage of subjects demonstrating any electrolyte abnormality on NS or USP glycerin.

4. Change in Stool Calprotectin Levels Assessed Through Comparing Levels Obtained Following Completion of NS and USP Glycerin Dosing Phases With the Baseline Value For Each Subject [Collection dates included a baseline sample (week 1) and at the completion of the dosing trail for both NS and USP glycerin for a total of 3 samples]

   Stool calprotectin was used to evaluate the impact of NS and USP Glycerin antegrade flush on colonic health. Calprotectin levels were obtained at baseline and following completion of the NS and USP Glycerin dosing phase of the study. Descriptive data analysis included mean and standard deviation for each flush regimen. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Both descriptive and inferential data analysis was calculated on the difference in calprotectin levels between samples obtained at baseline and samples obtained following the completion of the NS and USP Glycerin flush (value at completion of dosing phase - baseline value). The assumption was the length of each dosing phase was sufficient to achieve a credible active washout period and therefore levels obtained at the end of a phase reflected flushing regimen effects colonic health regardless of flush order.

5. Cramping With Flush [Data analysis was completed on data obtained during the last flush in both the NS and USP Glycerin dosing phase]

   Cramping with flush was measured using the Wong Baker Faces Pain Rating Scale (WBFPRS). The WBFPRS has undergone extensive testing and has well established psychometrics in the pediatric population. The scale ranges from 0 (very happy without pain) to 10 (the worse pain imaginable). Each pain level is associated with a facial expression. The child is asked to choose the face that best describes his/her level of discomfort (ordinal data). The parent was instructed to call if the child had flushing regimen-associated discomfort greater than a 4 on the WBFPRS. Documentation of pain severity was completed by the parent and child on a data-collection form at the time of occurrence. Descriptive statistics including mean and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Descriptive and inferential statistics were calculated on the last data point in the dosing phase.

6. Number of Participants Experiencing Vagal Symptoms With Flush [Data collection started with the first flush administered following discharge from the hospital and was collected with every subsequent flush through completion of the study, an average of 115 days.]

   Vagal symptoms including nausea, vomiting, sweating, dizziness, and pallor were noted by the parent. The parent was instructed to call if the child had any vagal symptoms. Documentation of any vagal symptoms was completed by the parent and child on a data-collection form at the time of occurrence. Data was analyzed as a percentage of subjects experiencing vagal symptoms during flush with NS and USP glycerin.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 12 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• This study will involve twelve children ages 3 to 12 years recruited from subspecialty clinics at Nemours Children's Subspecialty Care and the Pediatric Spinal Defects Clinic in Jacksonville, Florida.

• Children will be selected by purposive sampling and will include those who are scheduled to have an ACE stoma and will require regular antegrade enema administration to maintain continence.

Exclusion Criteria:

• Excluded will be children with preexisting electrolyte imbalance, chronic high rectal tone, quadriplegia, renal or cardiac disease, or those who require prophylactic antibiotics, cannot communicate, or have significant cognitive delay that would interfere with their ability to fully participate in the study.

• Parents must have English language competency and be willing and able to participate in administration or oversight of the flushing regimen and data collection for a minimum of 20 consecutive weeks. -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nemours Children's Specialty Clinic	Jacksonville	Florida	United States	32207

Sponsors and Collaborators

• Nemours Children's Clinic
• University of Florida

Investigators

• Principal Investigator: Kimberly S Jarczyk, PhD, Nemours Children's Specialty Care

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 23, 2019

More Information

Publications

• Aksnes G, Diseth TH, Helseth A, Edwin B, Stange M, Aafos G, Emblem R. Appendicostomy for antegrade enema: effects on somatic and psychosocial functioning in children with myelomeningocele. Pediatrics. 2002 Mar;109(3):484-9.
• Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy is followed by increased risk of Crohn's disease. Gastroenterology. 2003 Jan;124(1):40-6.
• Aspirot A, Fernandez S, Di Lorenzo C, Skaggs B, Mousa H. Antegrade enemas for defecation disorders: do they improve the colonic motility? J Pediatr Surg. 2009 Aug;44(8):1575-80. doi: 10.1016/j.jpedsurg.2008.11.061.
• Balter M. Taking stock of the human microbiome and disease. Science. 2012 Jun 8;336(6086):1246-7. doi: 10.1126/science.336.6086.1246. Epub 2012 Jun 6.
• Bani-Hani AH, Cain MP, King S, Rink RC. Tap water irrigation and additives to optimize success with the Malone antegrade continence enema: the Indiana University algorithm. J Urol. 2008 Oct;180(4 Suppl):1757-60; discussion 1760. doi: 10.1016/j.juro.2008.04.074. Epub 2008 Aug 21.
• Bazar KA, Lee PY, Joon Yun A. An "eye" in the gut: the appendix as a sentinel sensory organ of the immune intelligence network. Med Hypotheses. 2004;63(4):752-8.
• Becmeur F, Demarche M, Lacreuse I, Molinaro F, Kauffmann I, Moog R, Donnars F, Rebeuh J. Cecostomy button for antegrade enemas: survey of 29 patients. J Pediatr Surg. 2008 Oct;43(10):1853-7. doi: 10.1016/j.jpedsurg.2008.03.043.
• Biglan A, Ary D, Wagenaar AC. The value of interrupted time-series experiments for community intervention research. Prev Sci. 2000 Mar;1(1):31-49. Review.
• Chertow GM, Brady HR. Hyponatraemia from tap-water enema. Lancet. 1994 Sep 10;344(8924):748.
• Chow, S., & Liu, J. (2014). Design and analysis of clinical trials: Concepts and methodologies (3rd ed.). Hoboken, NJ: John Wiley & Sons.
• Chu DI, Balsara ZR, Routh JC, Ross SS, Wiener JS. Experience with glycerin for antegrade continence enema in patients with neurogenic bowel. J Urol. 2013 Feb;189(2):690-3. doi: 10.1016/j.juro.2012.08.209. Epub 2012 Oct 8.
• Curry JI, Osborne A, Malone PS. The MACE procedure: experience in the United Kingdom. J Pediatr Surg. 1999 Feb;34(2):338-40.
• Dasso JF, Howell MD. Neonatal appendectomy impairs mucosal immunity in rabbits. Cell Immunol. 1997 Nov 25;182(1):29-37.
• Dey R, Ferguson C, Kenny SE, Shankar KR, Coldicutt P, Baillie CT, Lamont GL, Lloyd DA, Losty PD, Turnock RR. After the honeymoon--medium-term outcome of antegrade continence enema procedure. J Pediatr Surg. 2003 Jan;38(1):65-8; discussion 65-8.
• Dolejs SC, Smith JK Jr, Sheplock J, Croffie JM, Rescorla FJ. Contemporary short- and long-term outcomes in patients with unremitting constipation and fecal incontinence treated with an antegrade continence enema. J Pediatr Surg. 2017 Jan;52(1):79-83. doi: 10.1016/j.jpedsurg.2016.10.022. Epub 2016 Oct 27.
• Elder JH. Single subject experimentation for psychiatric nursing. Arch Psychiatr Nurs. 1997 Jun;11(3):133-8. Review.
• Forchielli ML, Walker WA. The role of gut-associated lymphoid tissues and mucosal defence. Br J Nutr. 2005 Apr;93 Suppl 1:S41-8. Review.
• Gast, D.L. (2010). Single subjects research methodology in behavioral sciences. New York, NY: Routledge,Taylor & Francis Group
• Gebbers JO, Laissue JA. Bacterial translocation in the normal human appendix parallels the development of the local immune system. Ann N Y Acad Sci. 2004 Dec;1029:337-43.
• Gomez R, Mousa H, Liem O, Hayes J, Di Lorenzo C. How do antegrade enemas work? Colonic motility in response to administration of normal saline solution into the proximal colon. J Pediatr Gastroenterol Nutr. 2010 Dec;51(6):741-6. doi: 10.1097/MPG.0b013e3181e75d18.
• Hartmann DP, Gottman JM, Jones RR, Gardner W, Kazdin AE, Vaught RS. Interrupted time-series analysis and its application to behavioral data. J Appl Behav Anal. 1980 Winter;13(4):543-59.
• Helikson MA, Parham WA, Tobias JD. Hypocalcemia and hyperphosphatemia after phosphate enema use in a child. J Pediatr Surg. 1997 Aug;32(8):1244-6.
• Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012 Jun 8;336(6086):1268-73. doi: 10.1126/science.1223490. Epub 2012 Jun 6. Review.
• Ismail EA, Al-Mutairi G, Al-Anzy H. A fatal small dose of phosphate enema in a young child with no renal or gastrointestinal abnormality. J Pediatr Gastroenterol Nutr. 2000 Feb;30(2):220-1.
• Janosky, J.E., Leininger, S.L., Hoerger, M.P., & Libkuman, T.M. (2009). Single subjects designs in biomedicine. New York, NY: Springer Science + Business Media.
• Janszky I, Mukamal KJ, Dalman C, Hammar N, Ahnve S. Childhood appendectomy, tonsillectomy, and risk for premature acute myocardial infarction--a nationwide population-based cohort study. Eur Heart J. 2011 Sep;32(18):2290-6. doi: 10.1093/eurheartj/ehr137. Epub 2011 Jun 1.
• Jia W, Li H, Zhao L, Nicholson JK. Gut microbiota: a potential new territory for drug targeting. Nat Rev Drug Discov. 2008 Feb;7(2):123-9. doi: 10.1038/nrd2505. Review.
• Jones, B., & Kenward, M.G. (2003). Design and analysis of cross-over trials (2nd ed.). Boca Raton, FL: Chapman & Hall/CRC.
• Kaugars AS, Silverman A, Kinservik M, Heinze S, Reinemann L, Sander M, Schneider B, Sood M. Families' perspectives on the effect of constipation and fecal incontinence on quality of life. J Pediatr Gastroenterol Nutr. 2010 Dec;51(6):747-52. doi: 10.1097/MPG.0b013e3181de0651.
• Kawanishi H. Immunocompetence of normal human appendiceal lymphoid cells: in vitro studies. Immunology. 1987 Jan;60(1):19-28.
• Kazdin, A.E. (2011). Single-case research designs: Methods for clinical and applied settings (2nd ed.). New York, NY: Oxford University Press.
• King SK, Sutcliffe JR, Southwell BR, Chait PG, Hutson JM. The antegrade continence enema successfully treats idiopathic slow-transit constipation. J Pediatr Surg. 2005 Dec;40(12):1935-40.
• Knox CA, Burkhart PV. Issues related to children participating in clinical research. J Pediatr Nurs. 2007 Aug;22(4):310-8. Review.
• Large T, Szymanski KM, Whittam B, Misseri R, Chan KH, Kaefer M, Rink RC, Cain MP. Ambulatory patients with spina bifida are 50% more likely to be fecally continent than non-ambulatory patients, particularly after a MACE procedure. J Pediatr Urol. 2017 Feb;13(1):60.e1-60.e6. doi: 10.1016/j.jpurol.2016.06.019. Epub 2016 Aug 24.
• Levitt MA, Soffer SZ, Peña A. Continent appendicostomy in the bowel management of fecally incontinent children. J Pediatr Surg. 1997 Nov;32(11):1630-3.
• Ma HH. An alternative method for quantitative synthesis of single-subject researches: percentage of data points exceeding the median. Behav Modif. 2006 Sep;30(5):598-617.
• Marshall J, Hutson JM, Anticich N, Stanton MP. Antegrade continence enemas in the treatment of slow-transit constipation. J Pediatr Surg. 2001 Aug;36(8):1227-30.
• Matsuno D, Yamazaki Y, Shiroyanagi Y, Ueda N, Suzuki M, Nishi M, Hagiwara A, Ichiroku T. The role of the retrograde colonic enema in children with spina bifida: is it inferior to the antegrade continence enema? Pediatr Surg Int. 2010 May;26(5):529-33. doi: 10.1007/s00383-010-2585-6. Epub 2010 Mar 3.
• Nanigian DK, Nguyen T, Tanaka ST, Cambio A, DiGrande A, Kurzrock EA. Development and validation of the fecal incontinence and constipation quality of life measure in children with spina bifida. J Urol. 2008 Oct;180(4 Suppl):1770-3; discussion 1773. doi: 10.1016/j.juro.2008.03.103. Epub 2008 Aug 21.
• National Institutes of Health. (1998). Policy on inclusion of children as research subjects in clinical research. Bethesda, MD: National Institutes of Health.
• Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S. Host-gut microbiota metabolic interactions. Science. 2012 Jun 8;336(6086):1262-7. doi: 10.1126/science.1223813. Epub 2012 Jun 6. Review.
• Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 2004 Dec;12(12):562-8. Review.
• Ok JH, Kurzrock EA. Objective measurement of quality of life changes after ACE Malone using the FICQOL survey. J Pediatr Urol. 2011 Jun;7(3):389-93. doi: 10.1016/j.jpurol.2011.02.012. Epub 2011 Apr 27.
• Peeraully MR, Lopes J, Wright A, Davies BW, Stewart RJ, Singh SS, More BB. Experience of the MACE procedure at a regional pediatric surgical unit: a 15-year retrospective review. Eur J Pediatr Surg. 2014 Feb;24(1):113-6. doi: 10.1055/s-0033-1357502. Epub 2014 Jan 17.
• Penders J, Stobberingh EE, van den Brandt PA, Thijs C. The role of the intestinal microbiota in the development of atopic disorders. Allergy. 2007 Nov;62(11):1223-36. Epub 2007 Aug 17. Review.
• Piantadosi, S. (2005). Clinical trials: A methodologic perspective (2nd ed.). Hoboken, NJ: John Wiley & Sons.
• Pieper P. Ethical perspectives of children's assent for research participation: deontology and on utilitarianism. Pediatr Nurs. 2008 Jul-Aug;34(4):319-23. Review.
• Polit, D.F. (2010). Statistical and data analysis for nursing research (2nd ed.). New York, NY: Pearson.
• Portney, L.G., & Watkins, M.P. (2009). Foundations of clinical research: Applications to practice (3rd ed.). Upper Saddle River, NJ: Pearson Prentice Hall.
• Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol. 2007 Dec 21;249(4):826-31. Epub 2007 Sep 7. Review.
• Randall J, Coyne P, Jaffray B. Follow up of children undergoing antegrade continent enema: experience of over two hundred cases. J Pediatr Surg. 2014 Sep;49(9):1405-8. doi: 10.1016/j.jpedsurg.2014.02.090.
• Rempher, K.J., & Silkman, C. (2007). How to appraise quantitative research articles. American Nurse Today, 2, 26-28.
• Schreiber CK, Stone AR. Fatal hypernatremia associated with the antegrade continence enema procedure. J Urol. 1999 Oct;162(4):1433; discussion 1433-4.
• Senn, S. (2002). Cross-over trials in clinical research (2nd ed.). West Sussex, England: John Wiley & Sons.
• Shuster JJ. Design and analysis of experiments. Methods Mol Biol. 2007;404:235-59. doi: 10.1007/978-1-59745-530-5_12. Review.
• Shuster JJ. Student t-tests for potentially abnormal data. Stat Med. 2009 Jul 20;28(16):2170-84. doi: 10.1002/sim.3581.
• Siddiqui AA, Fishman SJ, Bauer SB, Nurko S. Long-term follow-up of patients after antegrade continence enema procedure. J Pediatr Gastroenterol Nutr. 2011 May;52(5):574-80. doi: 10.1097/MPG.0b013e3181ff6042.
• Sinha CK, Grewal A, Ward HC. Antegrade continence enema (ACE): current practice. Pediatr Surg Int. 2008 Jun;24(6):685-8. doi: 10.1007/s00383-008-2130-z. Epub 2008 Apr 12.
• Smith HF, Fisher RE, Everett ML, Thomas AD, Bollinger RR, Parker W. Comparative anatomy and phylogenetic distribution of the mammalian cecal appendix. J Evol Biol. 2009 Oct;22(10):1984-99. doi: 10.1111/j.1420-9101.2009.01809.x. Epub 2009 Aug 12.
• Stenström P, Granéli C, Salö M, Hagelsteen K, Arnbjörnsson E. Appendicostomy in preschool children with anorectal malformation: successful early bowel management with a high frequency of minor complications. Biomed Res Int. 2013;2013:297084. doi: 10.1155/2013/297084. Epub 2013 Sep 23.
• Thomas JC, Dietrich MS, Trusler L, DeMarco RT, Pope JC 4th, Brock JW 3rd, Adams MC. Continent catheterizable channels and the timing of their complications. J Urol. 2006 Oct;176(4 Pt 2):1816-20; discussion 1820.
• Tiryaki S, Ergun O, Celik A, Ulman I, Avanoglu A. Success of Malone's antegrade continence enema (MACE) from the patients' perspective. Eur J Pediatr Surg. 2010 Nov;20(6):405-7. doi: 10.1055/s-0030-1265156. Epub 2010 Oct 15.
• Tomlinson D, von Baeyer CL, Stinson JN, Sung L. A systematic review of faces scales for the self-report of pain intensity in children. Pediatrics. 2010 Nov;126(5):e1168-98. doi: 10.1542/peds.2010-1609. Epub 2010 Oct 4. Review.
• Vande Velde S, Van Biervliet S, Van Renterghem K, Van Laecke E, Hoebeke P, Van Winckel M. Achieving fecal continence in patients with spina bifida: a descriptive cohort study. J Urol. 2007 Dec;178(6):2640-4; discussion 2644. Epub 2007 Oct 22.
• Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs. 1988 Jan-Feb;14(1):9-17.
• Yardley IE, Pauniaho SL, Baillie CT, Turnock RR, Coldicutt P, Lamont GL, Kenny SE. After the honeymoon comes divorce: long-term use of the antegrade continence enema procedure. J Pediatr Surg. 2009 Jun;44(6):1274-6; discussion 1276-7. doi: 10.1016/j.jpedsurg.2009.02.030.
• Yerkes EB, Rink RC, King S, Cain MP, Kaefer M, Casale AJ. Tap water and the Malone antegrade continence enema: a safe combination? J Urol. 2001 Oct;166(4):1476-8.
• Youssef NN, Barksdale Jr E, Griffiths JM, Flores AF, Di Lorenzo C. Management of intractable constipation with antegrade enemas in neurologically intact children. J Pediatr Gastroenterol Nutr. 2002 Apr;34(4):402-5.

• Responsible Party: Kim Jarczyk, Retired. Non-associate Emeritus, Nemours Children's Clinic
• ClinicalTrials.gov Identifier: NCT02435069
• Other Study ID Numbers: ksj-1
• First Posted: May 6, 2015
• Last Update Posted: Aug 28, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Kim Jarczyk, Retired. Non-associate Emeritus, Nemours Children's Clinic: cecostomy; appendicostomy
• Additional relevant MeSH terms: Fecal Incontinence; Neurogenic Bowel; Flushing; Pharmaceutical Solutions; Glycerol

Study Results

Participant Flow

Recruitment Details	Participants recruited from subspecialty clinics at Nemours Children's Clinic in Jacksonville, Florida between February 2016 and January of 2017
Pre-assignment Detail	9 assessed for eligibility, 4 excluded (3 did not meet inclusion criteria and 1 surgery date significantly delayed), 5 consented and randomized to treatment sequence in dosing phase (3 started on saline followed by USP Glycerin, 2 started on USP glycerin followed by saline).

Arm/Group Title	No Intervention: Pre-operative Baseline Phase	Post-Operative Dose Response: NS Then USP Glycerin	Post-Operative Dose Response: USP Glycerin Then NS	Effectiveness Phase: NS Then USP Glycerin	Effectiveness Phase: USP Glycerin Then NS
Arm/Group Description	Baseline data including frequency and severity of fecal soiling and frequency and severity of abdominal pain were collected for a minimum of 2 weeks prior to surgical construction of the ACE stoma. Baseline stool calprotectin and serum electrolytes were collected in the baseline phase prior to initiation of the preoperative bowel prep. Pre-operative data served as the control.	Subjects randomized to treatment sequence. Arm evaluated dose-response relationship and was used to identify the minimum dosing volume and frequency of ACE administration for NS and USP glycerin necessary to meet outcome criteria. NS started at 10mL/kg administered every other day. Dose titrated to achieve continence so as not to exceed 500 mL NS daily for a child under five years of age, 1000 mL NS daily for a child over 5 years of age. Participant continued on effective dose for 2 weeks to insure treatment stability and effectiveness. If the maximum dose did not result in continence, if the dose necessary to minimize side effects resulted in episodes of fecal soiling, or if there were side effects greater than WBFPRS level 4 at the lowest dose of administration, the child was trialed on the alternate therapy and then dropped from the study.	Subjects randomized to treatment sequence. Arm evaluated dose-response relationship and was used to identify the minimum dosing volume and frequency of ACE administration for USP glycerin and necessary to meet outcome criteria. Glycerin started at 20 mL administered every other day. Dose titrated to achieve continence so as not to exceed 50 mL daily. Participant continued on effective dose for 2 weeks to insure treatment stability and effectiveness. If the maximum dose did not result in continence, if the dose necessary to minimize side effects resulted in episodes of fecal soiling, or if there were side effects greater than WBFPRS level 4 at the lowest dose of administration, the child was trialed on the alternate therapy and then dropped from the study.	To prevent statistical bias from subject loss due to treatment failure, each child who successfully completed the dosing phase was randomized to a second treatment sequence once they have achieved continence on optimal dosing with minimal side effects. This arm evaluated the long term effectiveness of NS at optimal dose and administration frequency for 4 weeks and served as comparison between flush solutions. The study concluded with the child being placed back on 2 weeks of the initial flush in the randomized sequence.	To prevent statistical bias from subject loss due to treatment failure, each child who successfully completed the dosing phase was randomized to a second treatment sequence once they have achieved continence on optimal dosing with minimal side effects. This arm evaluated the long term effectiveness of USP glycerin at optimal dose and administration frequency for 4 weeks and served as comparison between flush solutions. The study concluded with the child being placed back on 2 weeks of the initial flush in the randomized sequence.
Period Title: Preoperative Baseline Phase
STARTED	5	0	0	0	0
COMPLETED	5	0	0	0	0
NOT COMPLETED	0	0	0	0	0
Period Title: Preoperative Baseline Phase
STARTED	0	3	2	0	0
COMPLETED	0	2	1	0	0
NOT COMPLETED	0	1	1	0	0
Period Title: Preoperative Baseline Phase
STARTED	0	0	0	1	1
COMPLETED	0	0	0	1	0
NOT COMPLETED	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	No Intervention: Pre-operative Baseline Phase
Arm/Group Description	Baseline data including frequency and severity of fecal soiling and frequency and severity of abdominal pain were collected for a minimum of 2 weeks prior to surgical construction of the ACE stoma. Baseline stool calprotectin and serum electrolytes were collected in the baseline phase prior to initiation of the preoperative bowel prep. Pre-operative data served as the control.
Overall Participants	5
Age (Count of Participants)
<=18 years	5 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	66.6 (29.3309)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	5 100%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	2 40%
Asian	1 20%
Hispanic	1 20%
African-American	1 20%
Region of Enrollment (participants) [Number]
United States	5 100%
Cause of Neurogenic bowel (participants) [Number]
myelomeningocele	4 80%
Spinal Cord Trauma - MVA	1 20%
Patulent anus (participants) [Number]
Number [participants]	5 100%
Ambulatory (participants) [Number]
Ambulatory	4 80%
Wheel Chair User	1 20%
Presence of Fecal Incontinence at Baseline (Count of Participants)
Count of Participants [Participants]	5 100%

Outcome Measures

1. Primary Outcome

Title	Fecal Soiling - Number of Participants That Gained and Maintained Continence on Each Flushing Regimen
Description	Fecal soiling was defined as non-toilet elimination, which was tracked and documented by the parent/child as direct event recording and tallied as the number of pairs of underwear/protective undergarments soiled with stool per day. The purpose of this outcome measure was to document the number of individuals who gained continence on NS and USP glycerin. Descriptive statistics was limited to percentage of total participants who achieved continence on each flushing regimen. Data was calculated on the last data point in the final phase for both the NS and USP glycerin flush.
Time Frame	Data collection started following consent and procedural training and was collected daily from day 1 for the duration of the study, an average of 135 days.

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Subjects Continent on NS Antegrade Flush	Subjects Continent on USP Glycerin
Arm/Group Description	Number of participants that gained and maintained continence on antegrade enema.	Number of participants that gained and maintained continence on USP Glycerin antegrade enema.
Measure Participants	5	5
Count of Participants [Participants]	1 20%	4 NaN

2. Primary Outcome

Title	Fecal Soiling - Quantitative Count Detailing the Number of Episodes of Fecal Incontinence Per Day on NS and USP Glycerin
Description	Fecal soiling was defined as non-toilet elimination, which was tracked and documented by the parent/child as direct event recording and tallied as the number of pairs of underwear/protective undergarments soiled with stool per day. Descriptive statistics included mean and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05, calculated on the data from the last day of the completed NS and USP Glycerin phases of the study. Power analysis conducted using data from this study with α = 0.5, power of .80, correlation between two means of .598, and effect size of 1.554 estimated a sample size of 11 would be needed to minimize the risk of a Type II error to (20%).
Time Frame	Data collection began following consent and procedural training and was collected daily from day 1 for the duration of the study, an average of 135 days.

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Episodes of Fecal Incontinence on NS Antegrade Flush	Episodes of Fecal Incontinence on USP Glycerin Antegrade Flush
Arm/Group Description	Number of episodes of fecal soiling that occurred daily on NS flushing regimen	Number of episodes of fecal soiling that occurred daily on a USP Glycerin flushing regimen
Measure Participants	5	5
Measure Fecal Soiling	9	1
Mean (Standard Deviation) [underwear soiled/day]	2 (1.87)	0.2 (0.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subjects Continent on NS Antegrade Flush, Subjects Continent on USP Glycerin
	Comments	Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. and calculated on the data from the last day of the completed NS and USP Glycerin phases of the study. Power analysis conducted using data from this study with α = 0.5, power of .80, correlation between two means of .598, and effect size of 1.554 estimated a sample size of 11 would be needed to minimize the risk of a Type II error to (20%).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.069751
	Comments	significance level set at <0.05 a priori
	Method	two-sample pooled variance t-test
	Comments	Two-tailed

3. Secondary Outcome

Title	NS and USP Glycerin Flush Solution Dosing Frequency Necessary to Achieve Continence
Description	Flush administration frequency necessary to achieve continence was recorded as a single measure per subject per flush solution obtained as the number of flushes in the last three days of each dosing phase and recorded as either daily (1), every other day (2), or every third day (3). The larger the value, the less frequent the flush, the better the clinical outcome. Dosing frequency was measured using direct observational recording completed by the parent or child. Descriptive analysis included mean, and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Descriptive and inferential statistics were calculated on the data from the last day of the completed NS and USP Glycerin phases of the study.
Time Frame	Frequency of administration data was collected as the total number of flushes recieved over the last three days of each dosing phase for both NS and USP Glycerin and recorded as either daily (1), every other day (2), or every third day

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Dosing Frequency on NS	Dosing Frequency on USP Glycerin
Arm/Group Description	The minimum frequency with which the NS antegrade flush was administered during the dosing phase of the study necessary to gain and maintain continence. Data includes the maximum frequency of administration trialed in subjects who failed to gain continence on NS antegrade flush.	The minimum frequency with which the USP Glycerin antegrade flush was administered during the dosing phase of the study necessary to gain and maintain continence. Data includes the maximum frequency of administration trialed in subjects who failed to gain continence on USP GLycerin antegrade flush.
Measure Participants	5	5
Mean (Standard Deviation) [Flush administration/day]	1 (0)	1.6 (0.894)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subjects Continent on NS Antegrade Flush, Subjects Continent on USP Glycerin
	Comments	Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. and calculated on the data from the last day of the completed NS and USP Glycerin phases of the study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.172
	Comments
	Method	two-sample pooled variance t-test
	Comments	two tailed

4. Secondary Outcome

Title	Flush Volume
Description	Flush volume was measured in mL/flush using a graduated cylinder and recorded by the parent or child with each flush and later calculated in mL/kg. Data derived from the last flush of the completed dosing phase of both NS and USP Glycerin were used to calculate flush volume. Descriptive analysis included mean, median, range, and standard deviation. Reported data excludes subjects who failed to gain and maintain continence on either flushing regimen.
Time Frame	Data for analysis was collected from the last flush of the NS and USP Glycerin dosing phase of the study

Outcome Measure Data

Analysis Population Description

Subjects limited to those who gained continence (2 saline, 4 USP Glycerin). One subject gained and maintained continence on saline in both the dosing and maintenance phases of the study and one subject who gained continence during the dosing phase of the study but failed to maintain continence on saline during the maintenance phase of the study.

Arm/Group Title	Flush Volume of NS	Flush Volume of USP Glycerin
Arm/Group Description	Volume of flush solution administered during the last NS flush completed in the dosing phase of the study. Data from subjects who failed to gain and maintain continence during the dosing phase of the study on the maximum saline flush volume (500mL for subjects under 5 years of age and 1,000 mL for subjects over 5 years of age) are not included in the data. Data includes one subject who gained and maintained continence on saline in both the dosing and maintenance phases of the study, and one subject who gained continence during the dosing phase of the study but failed to maintain continence on saline during the maintenance phase of the study.	Volume of flush solution administered during the last USP Glycerin flush completed in the dosing phase of the study. Data from subjects who failed to gain and maintain continence on the maximum USP Glycerin flush volume (50mL) are not included in the data.
Measure Participants	2	4
Mean (Standard Deviation) [mL/flush]	39.215 (12.424)	1.475 (0.457)

5. Secondary Outcome

Title	Number of Participants With Any Electrolyte Abnormality
Description	Evaluated impact of NS and USP Glycerin antegrade flush on serum electrolytes using a blood test called a Basic Metabolic Panel. Data analysis limited to percentage of subjects demonstrating any electrolyte abnormality on NS or USP glycerin.
Time Frame	Collection dates included a baseline sample (week 1) and at the completion of the dosing trail for both NS and USP glycerin for a total of 3 samples

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Elelctrolye Abnormalities on NS FLush	Elelctrolye Abnormalities on USP Glycerin FLush
Arm/Group Description	Number of participants who had abnormalities in Basic Metabolic Panel on NS antegrade flush	Number of participants who had abnormalities in Basic Metabolic Panel on USP Glycerin antegrade flush
Measure Participants	5	5
Count of Participants [Participants]	0 0%	0 NaN

6. Secondary Outcome

Title	Change in Stool Calprotectin Levels Assessed Through Comparing Levels Obtained Following Completion of NS and USP Glycerin Dosing Phases With the Baseline Value For Each Subject
Description	Stool calprotectin was used to evaluate the impact of NS and USP Glycerin antegrade flush on colonic health. Calprotectin levels were obtained at baseline and following completion of the NS and USP Glycerin dosing phase of the study. Descriptive data analysis included mean and standard deviation for each flush regimen. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Both descriptive and inferential data analysis was calculated on the difference in calprotectin levels between samples obtained at baseline and samples obtained following the completion of the NS and USP Glycerin flush (value at completion of dosing phase - baseline value). The assumption was the length of each dosing phase was sufficient to achieve a credible active washout period and therefore levels obtained at the end of a phase reflected flushing regimen effects colonic health regardless of flush order.
Time Frame	Collection dates included a baseline sample (week 1) and at the completion of the dosing trail for both NS and USP glycerin for a total of 3 samples

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for NS and 4 participants for USP Glycerin

Arm/Group Title	Calprotectin Levels Following NS FLush	Calprotectin Levels Following USP Glycerin FLush
Arm/Group Description	Calprotectin level from stool sample obtained at completion of the NS dosing phase compared to baseline.	Calprotectin level from stool sample obtained at completion of the USP Glycerin dosing phase compared to baseline.
Measure Participants	5	4
Mean (Standard Deviation) [μg/g]	133.7 (183.359)	108 (113.874)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subjects Continent on NS Antegrade Flush
	Comments	Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. and calculated on the data from the difference in calprotectin levels between samples obtained at baseline and samples obtained following the completion of the NS and USP Glycerin flush in the dosing phase of the study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8028
	Comments
	Method	two-sample pooled variance t-test
	Comments	two-sided

7. Secondary Outcome

Title	Cramping With Flush
Description	Cramping with flush was measured using the Wong Baker Faces Pain Rating Scale (WBFPRS). The WBFPRS has undergone extensive testing and has well established psychometrics in the pediatric population. The scale ranges from 0 (very happy without pain) to 10 (the worse pain imaginable). Each pain level is associated with a facial expression. The child is asked to choose the face that best describes his/her level of discomfort (ordinal data). The parent was instructed to call if the child had flushing regimen-associated discomfort greater than a 4 on the WBFPRS. Documentation of pain severity was completed by the parent and child on a data-collection form at the time of occurrence. Descriptive statistics including mean and standard deviation. Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. Descriptive and inferential statistics were calculated on the last data point in the dosing phase.
Time Frame	Data analysis was completed on data obtained during the last flush in both the NS and USP Glycerin dosing phase

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Pain With NS Antegrade Flush Administration	Pain With USP Glycerin Antegrade Flush Administration
Arm/Group Description	Abdominal pain or cramping associated with NS flush as measured by the WBFPRS	Abdominal pain or cramping associated with USP Glycerin flush as measured by the WBFPRS
Measure Participants	5	5
Mean (Standard Deviation) [units on a scale]	0 (0)	0.4 (0.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Subjects Continent on NS Antegrade Flush, Subjects Continent on USP Glycerin
	Comments	Inferential statistical analysis was accomplished using a two-tailed, two-sample pooled variance t test with a significance level set at 0.05. and calculated on the data from the last day of the completed NS and USP Glycerin phases of the study.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.346594
	Comments
	Method	two-sample pooled variance t test
	Comments	two tailed

8. Secondary Outcome

Title	Number of Participants Experiencing Vagal Symptoms With Flush
Description	Vagal symptoms including nausea, vomiting, sweating, dizziness, and pallor were noted by the parent. The parent was instructed to call if the child had any vagal symptoms. Documentation of any vagal symptoms was completed by the parent and child on a data-collection form at the time of occurrence. Data was analyzed as a percentage of subjects experiencing vagal symptoms during flush with NS and USP glycerin.
Time Frame	Data collection started with the first flush administered following discharge from the hospital and was collected with every subsequent flush through completion of the study, an average of 115 days.

Outcome Measure Data

Analysis Population Description

The data from a total of 5 participants were analyzed for each arm of the study.

Arm/Group Title	Vagal Symptoms With NS FLush	Vagal Symptoms With USP Glycerin Flush
Arm/Group Description	Number of subjects experiencing vagal symptoms with antegrade administration of NS flush solution	Number of subjects experiencing vagal symptoms with antegrade administration of USP GLycerin flush solution
Measure Participants	5	5
Count of Participants [Participants]	0 0%	1 NaN

Adverse Events

Time Frame	1 year 1 month
Arm/Group Title	Vagal Symptoms With NS Flush		Vagal Symptoms With USP Glycerin Flush
Arm/Group Description	Number of subjects experiencing vasovagal symptoms (symptom complex including pallor, diaphoresis, dizziness, weakness, nausea, with or without syncope) with antegrade administration of NS flush solution		Number of subjects experiencing vasovagal symptoms (symptom complex including pallor, diaphoresis, dizziness, weakness, nausea, with or without syncope) with antegrade administration of USP Glycerin flush solution
All Cause Mortality
	Vagal Symptoms With NS Flush		Vagal Symptoms With USP Glycerin Flush
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Vagal Symptoms With NS Flush		Vagal Symptoms With USP Glycerin Flush
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Vagal Symptoms With NS Flush		Vagal Symptoms With USP Glycerin Flush
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		1/5 (20%)
Vascular disorders
Vasovagal Response	0/5 (0%)	0	1/5 (20%)	1

Limitations/Caveats

Titration time to continence, procedural time, quality of life outcomes and microbiome sample analysis not reported due to limited number of subjects completing protocol. Study remained open without additional recruits until P.I. retirement.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.