HIP Trial

Principal Investigator: Stephen Fenton
Keywords: Hernia , Repair , Neurodevelopmental , Outcomes , Comparative Effectiveness Research , Inguinal Department: PEDIATRIC SURGERY DEVELOPMENT
IRB Number: 00080548 Co Investigator: Bradley Yoder
Specialty: Pediatric Neurology, Pediatric Surgery
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Austin Stevens
austin.stevens@hsc.utah.edu
(801) 662-2969

Brief Summary

Statement of Problem

The problem we are addressing in the HIP Trial is the lack of knowledge regarding whether IH repair in premature infants who are diagnosed while in the NICU is more safely performed, for the majority of infants, prior to discharge (early repair) or ~5 months after NICU discharge (late repair).  Additionally, the timing (and duration) of general anesthesia is believed to be an important determinant of neurodevelopmental outcomes beyond infancy.  The HIP trial will also compare neurodevelopmental outcomes, as assessed by the Bayley Scales of Infant Development, 3rd edition (BSIDIII), at 2 years corrected age, for infants in the early versus late IH repair groups.

 

Hypotheses

Primary:  Late IH repair (5 months after NICU discharge, ~ 55-60 weeks post-menstrual age [PMA]) in premature neonates with an IH will result in a 10% absolute reduction in the proportion of infants with > 1 SAE compared to early IH repair (prior to NICU discharge, ~ 38 weeks PMA).

 

Secondary:

  • Late IH repair will be associated with a 0.4 SD increase in mean scores on the BSIDIII Cognitive Composite score (6 points absolute difference) compared to early IH repair.
  • Despite an overall treatment effect favoring late IH repair, the actual treatment effect will vary for pre-defined and specified patient subgroups.
  • Successful conduct of this RCT, as defined by >60% randomization and achievement of required sample size, will further establish the Ped SRC as an entity that will promote further conduct of prospective clinical trials within pediatric surgery and foster successful grant submissions by junior and established pediatric surgeons.

 

 

Specific Aims

Primary Aim:   Compare the overall safety of early and late IH repair with respect to significant adverse events (SAEs) and total hospital days in the 10 months after randomization.  

 

The primary outcome measure is the proportion of infants with >1 SAE, measured from enrollment through 10 months after enrollment.  Final determination of SAE will be by an independent adjudication committee, masked to treatment group assignment, consisting of an experienced pediatric surgeon, a neonatologist, and others, at their discretion.

 

Secondary outcome measures will include the number of hospital days from enrollment through 10 months beyond enrollment.  This measure was chosen because it is easily measured, objective, and is a direct measure of the impact of underlying SAEs.  With regard to this outcome, we hypothesize that late IH repair will be associated with a 3 day reduction in the median total number of hospital days during this period (18 hospital days for early IH repair versus 15 for early IH repair). Additionally, participants will be asked to return to Vanderbilt’s neurodevelopmental clinic for a neurodevelopmental follow-up exam when they are 22-26 months corrected age (chronological age - # weeks/months premature). A standard neurological exam and the Bayley Scales of Infant Development, 3rd Edition (BSIDIII), will be administered by a trained examiner at this follow-up visit. The BSIDIII is a standardized assessment and was chosen for its validity, reliability, ease of administration, and widespread use for the targeted age group across facilities.

 

Secondary Aims:

  1. Compare the overall safety of early and late IH repair with respect to neurodevelopmental outcome at 22-26 months corrected age (at selected sites with well-established follow up programs).  
  2. Using Bayesian and frequentist analyses, evaluate specific hypotheses about patient characteristics that may influence the relative safety of early and late IH repair.
  3. To conduct the HIP Trial in an exemplary manner and thereby promote the newly established pediatric Surgery Research Collaborative as an ongoing research network.  

Detailed Description

Very few commonly used neonatal surgical therapies have been evaluated to determine their safety. Premature infants are especially vulnerable to unrecognized treatment hazards. Inguinal hernia (IH) repair is the most commonly performed major operation in premature infants, is associated with a 30-40% morbidity rate, and it is unknown whether the operation should occur prior to neonatal intensive care unit (NICU) discharge or be delayed. Early IH repair likely increases anesthesia and cardiorespiratory serious adverse events (SAEs), whereas delayed IH repair likely increases hernia-related adverse events. A growing concern is the possibility that early anesthesia exposure impairs neurodevelopment. The randomized clinical trial (RCT) proposed will be the first trial to evaluate the effect of timing and duration of anesthesia exposure on neurodevelopmental outcomes. Our objective is to conduct a multicenter RCT to determine whether early inguinal hernia repair (prior to NICU discharge) or late inguinal hernia repair (~5 months after NICU discharge) is the safer surgical approach for premature infants who are diagnosed with an inguinal hernia while in the NICU. Assuming a 60% randomization rate, which is supported from a feasibility pilot RCT, 615 infants will be randomly assigned to early or late IH repair over a 2.5-year period. The primary hypothesis is that late IH repair is safer as defined by a 10% absolute reduction in the proportion of infants with >1 SAE (relative risk = 0.66; number needed to harm of 10 for early repair) within 10 months after enrollment. The primary outcome, as adjudicated by a committee masked to treatment group assignment, is the proportion of infants with >1 SAE during the study period. Secondary outcome measures include the number of hospital days during the study period (hypothesis: median 3 days less with late IH repair) and, in selected centers (n=200 infants), neurodevelopmental testing with the Bayley Scales of Infant Development (BSID), 3rd edition, at 2 years corrected age (hypothesis: 0.4SD higher Cognitive Composite score with late IH repair). The potential differences in treatment effect according to prespecified patient characteristics (at enrollment) will be examined by frequentist and conservative Bayesian methods and a method to predict the relative safety of early and late IH report for individual infants will be developed and tested. The trial is utilizing the Pediatric Surgery Research Collaborative (PedSRC), a recently established cooperative group committed to performing prospective clinical studies in pediatric surgery. Successful completion of the RCT proposed will stimulate future studies within pediatric surgery.

Inclusion Criteria

Inclusion Criteria:  1) GA < 37 wks, 0 days; 2) In a NICU / other nursery, at participating sites; 3) Diagnosed with an IH per the pediatric surgeon; and 4) Parental consent and providers willing to randomize the infant.

Exclusion Criteria

Exclusion Criteria:  1) Infant is undergoing another operative procedure and IH repair is planned as a secondary procedure (e.g. fundoplication or gastrostomy tube is planned, and IH repair is considered a secondary procedure); 2) Known major congenital anomaly or chromosomal abnormality; and 3) Family unable / unwilling to return for follow up and late IH repair; or likely unable to monitor IH as outpatient (e.g. maternal incarceration or moving away from the area).