Probiotic Prophylaxis of Hirschprung's Disease Associated Enterocolitis (HAEC)
Condition: Hirschsprung Disease
MeSH terms: Enterocolitis; Hirschsprung Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Prospective, randomized, controlled trial to test if post-operative administration of
      probiotics in HD patients will lead to a reduction in the occurrence of HAEC.
    

Detailed description: 
      To test the hypothesis that probiotics will decrease the risk of post pull-through
      enterocolitis by randomizing patients to receive either probiotics or placebo for the first 3
      months after surgical treatment for HD.

      E.1. Design: This study will be a prospectively performed, multi-center, double blinded,
      study drug versus placebo controlled study. It will test the hypothesis that post-operative
      administration of probiotics in HD patients will lead to a reduction in the occurrence of
      HAEC E.2. Study medication: VSL#3 (VSL Pharmaceuticals, Inc., Ft. Lauderdale, FL) was
      provided in packets, each of which contained 900 billion viable lyophilized bacteria of 4
      strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus, and L. delbrueckii subsp.
      bulgaricus), 3 strains of Bifidobacterium (B. longum, L. breve, and B. infantis), and 1
      strain of Streptococcus salivarius subsp. thermophilus (designated hereafter as S.
      thermophilus). Maize starch was included as filler. Placebo was provided in identical bags
      containing 3 g of maize starch. VSL#3 and placebo were administered once each night. The
      taste and smell of the active drugs were not readily identifiable.

      E.2.1. Formulation of the study drug: The drug will be delivered to patient's families in
      individual packets. The families will be instructed to administer the probiotic as
      appropriately diluted in 2 ounces of either expressed human milk or formula.

      E.2.2. FDA approval number: VSL#3 is now a "medical food" in the US and does not need FDA
      approval.

      E.2.3. Medication suppliers: VSL Pharmaceuticals, Inc., Ft. Lauderdale, FL E.2.4.Funds for
      medication: It is anticipated that the VSL Pharmaceutical Corporation will donate sufficient
      drug and placebo for the completion of this study. Additional funds for IRB approval and
      costs of dispensing drug/placebo via the Investigational Drug Service are requested from the
      VSL Pharmaceutical Corporation.

      E.2.5. Dosing and frequency: Dosing will be based on patient weight. For those infants
      greater or equal to 5 kg, one gram (360 billion bacteria or 4 sachets) of VSL#3 will be
      administered into 3 ounces of either expressed breast milk or formula daily. For patients
      under 5 kg, 0.5 gm (180 billion bacteria or 2 sachets) daily in the same amount of formula or
      breast milk.

      E.2.6. Time of start of probiotics: Probiotic vs. placebo will begin once the infant has
      reached full oral feeding.

      E.2.7. Duration of the study: Upon initiation of probiotics vs. placebo administration,
      administration will continue for 3 months. Follow up will continue for an additional 3 month
      period after termination of probiotic administration.

      E.3. Study population: Study candidates will include all infants (newborn to 1 year of age)
      who undergo a definitive pullthrough for Hirschsprung disease.

      E.3.1. Study Sites: This study will be conducted in four large pediatric surgery centers
      including:

        -  C.S. Mott Children's Hospital, Ann Arbor, Michigan, USA

        -  Children's Hospital of Buffalo, Buffalo, New York, USA

        -  Hospital for Sick Kids, Toronto, Ontario, Canada

        -  Tanta University, Tanta, Egypt

      And the study will include all pediatric patients diagnosed to have HD and will be subjected
      to definitive pullthrough procedure. Each of these sites contains a quaternary level of
      pediatric surgical care, and treats a large number of patients with HD on a yearly basis. The
      key advantage of Tanta University is that this Hospital group treats three-fold more HD
      patients on a yearly basis than the other Sites, and has a very highly motivated staff with
      research interests in HAEC.

      E.3.2. Method of Patient Recruitment: The study coordinator, co-investigator and collaborator
      at each site will conduct study orientations for the neonatal staff which will include staff
      physicians, training-fellows, house officers and nurses who work in the unit. These
      orientations will help alert the staff as to who are potential candidates for the study. In
      addition, the study coordinator will check each day for new admissions to the neonatal
      intensive care unit for potential candidates. It will be the study coordinator's
      responsibility to consent the parent/guardian and write orders for the study. No preference
      for a specific sex, race or ethnic background will be given.

      E.3.3. Randomization: the study will be double blinded study and the randomization will be
      conducted by the hospital pharmacist whom will be responsible of dispensing the medication to
      the patients after coding it with a special code related to the patient ID and the records is
      kept with the pharmacist till the end of the study. Physicians and other caregivers will be
      blinded as to who is receiving placebo or study drug. Only the pharmacist at the
      Investigational Drug Service (or similar service) will be aware of the assignment. Each
      patient will receive a study number which will identify the patient. The number will allow
      for confidentiality while simultaneously allowing patient identification by the principal
      investigator at each center if it should it be necessary.

      E.3.4.Mechanisms of drug / placebo distribution: The anticipated number of patients to be
      enrolled in this study in each participating center has been calculated according to previous
      records of the center. According to this number, the drug/placebo distribution will be done.
      The responsible group for the blindness of the study and distribution of the drug will be the
      pharmacist in each center and he/she will keep codes for each patient not to be broken except
      at the end of the study. The pharmacist is also responsible for dispensing the drug and
      placebo packets to the patients as monthly supplies and should inform the patient guardian to
      bring the empty packs before receiving the new medication to ensure compliance of the
      patients to the study.

      E.3.5. Removal from protocol after enrollment: Although all patients will be treated as
      intent to treat, physicians may remove infants from the protocol for a number of reasons:
      First, if parent or guardian requests study withdrawal, and this will be honored. Second, if
      it is the opinion of the caring physician that participation in the study protocol may lead
      to undo harm of the child.

      E.3.6. Guidelines for uniformity of patient care: As these studies will be performed at a
      multiple sites, a series of guidelines will need to be followed by each site. Prior to the
      initiation of the study, investigators and their study monitor will meet and discuss
      enrollment criteria, case report forms (CRF, see Appendix I) and review protocols for the
      performance of probiotics administration and monitoring of infants. The treatment
      specifications listed above will serve as an outline for definitive guidelines. Finally, a
      firm agreement on the definition of HAEC will be established.

      E.3.7. Monitoring: Each site will specify a study monitor who will be responsible for data
      collection and monitoring infants for protocol compliance and the development of adverse
      events (AEs, see Appendix II). The study monitor will be responsible for data transmission
      for data collection and analysis. He/she will also be responsible for informing the
      Investigator and the respective IRBs of adverse events. When there is an adverse event which
      is believed to have a relation to the performance of this study or a significant adverse
      event (SAE), they will be responsible for reporting this within 48 hours to both their IRB,
      and all other investigators. In a similar time, a report to the FDA will be done. Yearly
      reporting of all AEs to each IRB and the FDA will be done.

      E.3.8. Safety and Regulatory Issues: Full IRB approval from each participating institution
      will be attained, and IRB will be apprised of the multi-center design as well as names of
      other participating sites.

      E.3.9. Data Obtained:

      E.4.0. Primary Outcome Measure: The primary outcome measure will be the diagnosis of
      Hirschsprung-associated enterocolitis (HAEC).

      The severity of clinical episodes of HAEC will be stratified into three grades according to
      established clinical grading system as follows (11):

      Grade I: mild explosive diarrhea, mild to moderate abdominal distension, no significant
      systemic manifestations (fever, anorexia, weight loss, tachycardia).

      Grade II: moderate explosive diarrhea, moderate to sever abdominal distension associated with
      mild to moderate systemic manifestations.

      Grade III: explosive diarrhea, marked abdominal distension, shock, or impending shock.

      E.4.1. Secondary Outcome Measures: Secondary outcome measures will be to measure the
      expression of MUC-2 and MUC-3 expressed proteins in the stools of study patients.

      Mucins will be detected by using a modified Western immunoblot technique of stool specimens
      as previously described.

      Finally, we will attempt to correlate if there are additional clinical benefits of probiotics
      in HD, by examining the number of un-scheduled clinic visits or emergency visits, the
      stooling pattern, and the growth curve in probiotic treated group versus the placebo group.
    

Intervention name(s): VSL#3; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Dosing will be based on patient weight. For those infants greater or equal to 5 kg, one gram (360 billion bacteria or 4 sachets) of VSL#3 will be administered into 3 ounces of either expressed breast milk or formula daily. For patients under 5 kg, 0.5 gm (180 billion bacteria or 2 sachets) daily in the same amount of formula or breast milk.
E.2.6. Time of start of probiotics: Probiotic vs. placebo will begin once the infant has reached full oral feeding.; Dosing will be based on patient weight. For those infants greater or equal to 5 kg, one gram (4 sachets) of placebo will be administered into 3 ounces of either expressed breast milk or formula daily. For patients under 5 kg, 0.5 gm (2 sachets) daily in the same amount of formula or breast milk Initiation: within one week of pullthrough Duration: 3 months
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Hirschsprung disease; enterocolitis; probiotics