Studies

Upcoming

PRIMED: Precision Medicine for Improving the Diagnosis of Pediatric Appendicitis in the Emergency Department

Principle Investigator: Dr. Darcy Beer

Accurate, timely diagnosis is important to decrease the risk of serious complications in appendicitis, the most common surgical emergency in children.  However, diagnosis of appendicitis in children is often challenging for health care providers, as currently available investigations such as basic laboratory tests (infection cells, inflammation markers) and imaging studies (ultrasound, computed tomography), suffer from limitations related to accuracy, availability and radiation exposure. 

Recent studies have demonstrated the capacity of precision medicine bio profiling to identify children at risk of serious infection. Using this systems biology approach integrating metabolomics, proteomics and metallomics, we will address the current need for improving the diagnosis of children with appendicitis.

INK: Intranasal versus intravenous ketamine for procedural sedation in children: a randomized controlled non-inferiority Multicenter trial  

Principle Investigator: Dr. Darcy Beer

Orthopedic injuries comprise more than 10% of ED visits in children and 25% to 50% of children will sustain a fracture before age 16 years. Between 20% and 40% of fractures in children require a closed reduction, often necessitating procedural sedation and analgesia. Intravenous (IV) ketamine is the most commonly used sedative agent used to perform a closed reduction. However, children rate IV insertion as the most painful hospital experience, second only to the injury itself. Intranasal (IN) ketamine may provide effective sedation for children undergoing a closed reduction without the distress and pain related to IV insertion. A less painful experience has been found to correlate with child satisfaction which may reduce caregiver anxiety and improve the therapeutic relationship with the health care team. This study is designed to test the hypothesis that intranasal (IN) ketamine is non-inferior to intravenous (IV) ketamine with respect to depth of sedation.                  

DOSE-AGE: Multi-Dose Oral Ondansetron for Pediatric Acute Gastroenteritis

Principle Investigator: Dr. Darcy Beer

To determine if in previously healthy children, who present to an ED with gastroenteritis associated vomiting, is the proportion who develop moderate to severe disease [Modified Vesikari Score (MVS) ≥ 9] following ED evaluation, significantly different in those who receive ondansetron at home compared to those who receive placebo.

Between Life and Death: An Anthropology of the Ventilator in PICU

Principle Investigator: Dr. Louise Chartrand 

Since the 1950’s, when the ability of breathing is compromised the usage of mechanical ventilation has become a standard in western hospitals. The ventilator has revolutionized the way in which medicine is being practiced. Indeed, organ transplantation was made possible because of the ventilator. The brain death concept emerged from the ability of the ventilator to maintain vital biological function within normal limits even when the brain stem is not functional. The ventilator made it possible to adequately anesthetize the recipient of the organ donor. The ventilator has also been the source of social changes.

For instance, Nancy B wanted the right to withdraw the ventilator even if this choice would lead to an inevitable death. Following the Canadian Supreme Court judgement on this case, there has been an increase respect for patient’s choice and autonomy in medical care. Generally speaking, the focus of research in relation to the ventilator has been twofold. On one hand, we find the medical inquiries that focus on making this technology a better tool to ‘save’ lives. On the other hand, we find inquiries that focus on dying with dignity. However, little to no attention has been given to the ventilator itself and how this technology influence practices in hospital settings. Little to no attention has be given to bridging the decision-making process of life saving measures with the dying process. Furthermore, the ventilator is a technology that can be used for various age groups. Indeed, this technology can be used with preterm babies up to late adulthood. A lot has been written in Neonatal population (see Mesman or Anspach) and in adult population (see Chartrand, Castle, Kaufman, Sudnow). But nothing has been done with paediatric or with the children population.

NO-OUCH: Hydromorphone vs. Acetominphen & Ibuprophen

Principle Investigator: Dr. Neil Desai                    

Using a novel preference-informed complementary trial design, we will conduct two simultaneous trials. Caregivers of children presenting to the emergency department (ED) with acute musculoskeletal (MSK) limb injury will decide which trial they wish to participate in: an Opioid trial or a Non-Opioid trial. Our study hypotheses are: 1. A combination of oral ibuprofen and oral acetaminophen will have greater analgesic efficacy than ibuprofen alone, AND 2. A combination of oral ibuprofen and oral hydromorphone will have greater analgesic efficacy than ibuprofen alone OR a combination of oral ibuprofen and oral acetaminophen, as measured by a decrease in self-reported pain using the verbal Numerical Rating Scale (vNRS), at 60 minutes post administration.

Primary Objectives: To determine the effectiveness of a combination of opioid and non-opioid oral analgesic medications (PO ibuprofen+ PO acetaminophen; PO ibuprofen + PO hydromorphone; PO ibuprofen alone) for the pain management of children with an acute MSK limb injury.

Secondary Objectives: 1. To determine the proportion of children with adverse events related to study drug administration (safety), 2. To determine the proportion of children who require additional analgesia at 60 minutes post study drug administration (efficacy), and 3. To determine caregiver reasons for choosing an opioid versus a non-opioid trial (preference).

CoDinos: Newborns with Congenital Diaphragmatic hernia: inhaled Nitric Oxide vs. intravenous Sildenafil

Principle Investigator: Dr. Yasser El-Sayed 

The primary objective of the study is to determine whether the incidence of PH is lower in CDH patients treated with intravenous sildenafil than in patients treated with iNO, defined as the absence of PH on echocardiography on day 14 without pulmonary vasodilator therapy and without treatment failure and/or death within the first 28 days after birth. PH is defined as systolic pulmonary arterial pressure> 2/3 systolic systemic pressure and/or right ventricular (RV) dilatation/septal displacement and RV dysfunction +/- left ventricular dysfunction.

BPD LUS: Early identification of preterm infants with evolving Bronchopulmonary dysplasia: utility of Lung Ultrasound severity score

Principle Investigator: Dr. Yasser El-Sayed 

Preterm infants (GA ≤ 28+6 weeks) are at high risk for BPD and other complications of extreme prematurity. Certainly, additional therapeutic and preventive measures are very much needed to prevent or reduce the risk of BPD in this vulnerable population. LUS score has the potential of early prediction of infants at risk of developing BPD and this in turn can lead to an early intervention.

The primary objective of this study is to assess if LUS score can be utilized to predict the development of BPD in infants born at ≤ 28+6 weeks, early in their postnatal course, when the disease is likely to be most amenable to preventative/curative treatment.

Canadian Neonatal Network Plus

Principle Investigator: Dr. Michael Helewa 

The CPTBN team will collect maternal and infant data for Canadian preterm infants and will use the data to perform research projects in 3 integrated research clusters: 1) evidence- based quality improvement, 2) association of maternal, perinatal and neonatal care with outcomes and 3) economics, resource use and surveillance of preterm birth. The CPTBN research program is designed to be flexible and to allow for new projects, project modification, collaborations and partnerships. The 3 research clusters will function as a platform for ongoing integrated comparative effectiveness research, randomized controlled trials, translational studies, proof-of concept studies, health services evaluation and programmatic evaluations. The CPTBN will be governed by a steering committee, a director and 4 advisory boards.

CanCORPS: Female Fetal Abdominal Cysts

Principle Investigator: Dr. Richard Keijzer 

Study Objectives

  • To report the natural history of female fetal abdominal cysts.
  • To report the incidence of fetal ovarian cysts among all female fetal abdominal cysts.
  • To report the spontaneous resolution rate of fetal ovarian cysts.
  • To produce evidence-based recommendations for the surveillance and indications for intervention for fetal ovarian cysts.

The main research question is the following: What constitutes a safe period of observation for patients with prenatally diagnosed ovarian cysts?

Hypotheses

  • Greater than 90% of abdominal cysts diagnosed between 22 weeks gestation and 3 months postpartum in females are of ovarian origin.
  • Cyst resolution occurs in the majority (greater than 50%) of asymptomatic fetal ovarian cysts by the age of 6 months if they are managed conservatively (if they are not electively surgically removed), independent of any cyst characteristics or other clinical variables.
  • Complete ovarian loss will result in the majority (greater than 50%) of cases of complex fetal ovarian cysts.

CARRA: Observational Study of Pediatric Rheumatic Disease and CAPRI: The Canadian Alliance of Pediatric Rheumatology Investigators National Juvenile Idiopathic Arthritis Registry

Principle Investigator: Dr. Lily Lim 

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) based is a non-profit research network of pediatric rheumatologists and related investigators whose mission is to improve the health, well-being and outcomes of children and adolescents with rheumatic diseases.  Its Data Coordinating Center is located at the Duke Clinical Research Institute in North Carolina.

The purpose of this study is to collect information on disease course, outcomes and medication adverse events to create and maintain a registry, which is a database (a searchable collection of information) about children, adolescents and young adults with pediatric onset of rheumatic diseases. 

This data may help: 

  1. Provide answers about expected disease outcomes. 
  2. Evaluate the safety and benefit of medications that are prescribed to patients with rheumatic diseases.
  3. Provide new insights about rheumatic diseases, their treatments, and potential preventions and cures.
  4. Compare outcomes and treatments across centres to help improve the healthcare provided to children with rheumatic diseases.
  5. Allow researchers to answer their own research questions about rheumatic diseases.
  6. Identify patients who may be eligible for future studies. 

UCAN CANDU

Principle Investigator: Dr. Lily Lim 

One of the challenges when it comes to treating childhood arthritis is identifying the right children to receive the right treatment at the right time and knowing when to stop the treatment. We have promising preliminary data to address these questions. We will combine multiple data types – clinical and biologic data – to identify biomarkers that can provide diagnostic and prognostic information to caregivers at the bedside. We will develop separate profiles of biomarkers to predict disease course, treatment response and risk of disease relapse.

Indo: Pharmacokinestics and pharmacodynamics of indomethacin in neonates < 27 weeks gestational age

Principle Investigator: Dr. Deepak Louis 

Primary objective:  To evaluate the pharmacokinetics of indomethacin used for PDA treatment in extremely preterm neonates <27 weeks’ gestational age.

Secondary objective: To establish the pharmacodynamics of indomethacin in this patient group with a focus on therapeutic outcomes (PDA closure, intraventricular hemorrhage), clinical course (days of mechanical ventilation) and adverse effects (acute kidney injury, gastrointestinal complications including spontaneous intestinal perforation, necrotizing enterocolitis) 

Parent-EPIQ: MiCare substudy: SPOR CHILD-BRIGHT Project 1.2: Parent integrated Evidence- based Practice to Improve Quality -AIM #2 

Principle Investigator: Dr. Diane Moddemann  

Research Questions: 

  1. What early childhood outcome measures are meaningful to parents of children born very preterm?
  2. Using existing resources, can the Parent Integrated Evidence based Practice to Improve quality (Parent-EPIQ) approach be used to implement interventions known to improve cognitive and/or language abilities in children born preterm at less than 29 weeks gestational age?
  3. Will neurodevelopmental outcomes improve more in Parent-EPIQ intervention sites than non-intervention sites during the study duration? 

The overall aim of this study is to engage parents to co-create definitions of NDI and guide EPIQ initiatives to improve developmental outcomes within the Follow-Up Program infrastructure.

Specific aims are:

  1. To define outcomes that are meaningful to parents of very preterm children (< 29 weeks GA) at CNFUN visits at 18-21 CA.
  2. To implement Parent EPIQ interventions to improve cognitive and language abilities in a preterm population at 12 intervention sites.
  3. Evaluate whether CNFUN measured outcomes across Canada are improving using annual benchmarked reports for Parent-EPIQ intervention and non-intervention sites.

Hypothesis 1: Parent identified meaningful outcomes will differ from definitions of NDI and sNDI in Table 1.

Hypothesis 2: At least 75 % of the audits, performed as part of a Parent-EPIQ cycle, will successfully meet or surpass the identified target.

Hypothesis 3: Cognitive and language abilities, as measured by Bayley-III composite scores at 18-21 months CA will improve more from study baseline to study end at Parent EPIQ intervention sites than non-intervention sites.

CBAR: The Canadian Biliary Atresia Registry: Establishing Best Practices for the Assessment, Management, and Outcome of Biliary Atresia in Canada

Principle Investigator: Dr. Melanie Morris  

The aim of this study is to create a national biliary atresia registry to: 

  1. Follow prospectively the current assessment, management and outcome of biliary atresia in Canadian children.
  2. To collect epidemiologic data of BA in Canada in a uniform fashion
  3. To standardize the surgical Kasai Procedure and the post Kasai management for BA in Canadian children. 
  4. To provide a framework to assess the feasibility and cost effectiveness of novel diagnostic or therapeutic strategies in Canadian children with biliary atresia 
  5. To promote education and research for Canadian children with BA through knowledge translation with local and national foundation and agencies 

In Canada, recent retrospective studies have identified a problem of late referral and delay in the optimal timing of the KP, a lack of uniform management for Canadian children with BA and less than optimal outcomes in terms of native liver survival compared with other European countries.  The establishment of a national BA registry will afford opportunity to prospectively evaluate the assessment and outcome of BA in Canada. It will also allow for the development of uniform protocols, the introduction of novel strategies and the capacity for knowledge translation to optimize the current outcomes of Canadian children with BA.

CGD: Effects of an Exclusive Human Milk Diet on Enteral Feeding Outcomes of Neonates with Congenital Gastrointestinal Disorders

Principle Investigator: Dr. Michael Narvey 

Specific Aims

  1. To compare the time to full enteral feeds and days on PN in neonates with CGD who receive an EHMD, compared with those receiving partial and non-human milk diets, while hospitalized in the NICU. 
  2. To compare peak conjugated bilirubin levels, episodes of sepsis, feeding tolerance, feeding interruptions, episodes of NEC, LOS, and death between CGD neonates who receive EHMD versus partial and formula feeding, while hospitalized in the NICU.

Our goal is to identify whether an EHMD would improve outcomes in CGD patients by facilitating an earlier transition off PN when compared to the current standard of a partial HM or exclusive formula diets.

SIL02 (Silo): Safety of Sildenafil in Premature Infants at Risk of Bronchopulmonary Dysplasia

Principle Investigator: Dr. Michael Narvey 

Primary objective: Describe the safety of sildenafil in premature infants at risk of BPD. 

Secondary objective: Preliminary effectiveness and pharmacokinetics (PK) of sildenafil.

RETT: A translational clinical study: Targeting the mental health and life of children with Rett syndrome

Principle Investigator: Dr. Mubeen Rafay 

Rett syndrome (RTT) is a severe neurological disorder and a leading cause affecting mental health in young females. RTT patients appear normal at birth, but by 6-18 months of age exhibit developmental

Regression, mainly loss of speech and purposeful hand movements along with autistic behaviors. For over a decade, our team has worked on MeCP2-associated diseases, and published widely on the molecular effects of MeCP2 in mouse models of RTT 4-9. More recently, we were successful in establishing a national cohort of human RTT brain tissues in Manitoba to advance our understanding of the pathophysiologic mechanisms of MeCP2 in RTT patients. Using RTT mouse models and cellular systems, solid evidence exists in the literature (and our lab) for impaired glucose and cholesterol metabolism in RTT and hence potential for the development of therapeutic strategies targeting this pathway in patients with RTT, utilizing safe and cheap FDA-approved drugs, such as metformin and statins. These drugs have minimal side effects, and are already commonly used for diabetes and high blood cholesterol control. However, in parallel to the completion of our pre-clinical studies in RTT mouse (currently funded by ORSA) and prior to initiation of any phase 2 clinical trial, we need to demonstrate whether RTT patients have impairments of blood sugar or cholesterol metabolism. Our primary objective is to confirm the in vitro and in vivo research data indicating impairments in glucose and cholesterol metabolism in patients with RTT. We, propose initiation of a clinical study in RTT patients in Winnipeg, to address these unanswered questions:

  1. Do RTT patients have obesity, glucose tolerance issues, high blood sugar, and/or high
  2. Cholesterol?
  3. Do the parents and siblings of RTT patients show obesity glucose tolerance issues, high blood
  4. Sugar, and/or high cholesterol? And if no, could this be solely explained by the presence of MeCP2
  5. Mutation in RTT patients?
  6. To understand how MeCP2 mutation could be the cause for impaired glucose and cholesterol
  7. Metabolism

MiCARE: Maternal Infant Care (EPIQ 3)

Principle Investigator: Dr. Molly Seisha 

Preterm birth is the most important cause of perinatal mortality and long-term neurodevelopmental morbidity. It complicates 76 of every 1000 births in Canada, and its incidence has risen over 30% during the past 2 decades. The costs of preterm birth are estimated to exceed $1 billion annually in Canada and include NICU care, which is expensive and often prolonged. A major weakness in our health research enterprise is the inability to effectively, efficiently and rapidly translate knowledge into improved quality of care, better patient outcomes and reduced costs.  For instance, 25 years after Liggins et al1 and others2,3 first reported that antenatal corticosteroid treatment of women expected to give birth preterm significantly reduced the incidence of respiratory distress syndrome and mortality among newborn infants, Chien et al4 found only 59% of eligible preterm infants admitted to Canadian neonatal intensive care units (NICUs) received antenatal corticosteroid treatment. Furthermore, it was estimated that increased use of antenatal corticosteroid treatment for preterm births could reduce neonatal mortality in Canada by 10%. Lee et al 5 found significant variation in outcomes among Canadian NICUs and others have reported that variations in outcomes may be attributable to differences in practice.6, 7, 8,9 These studies demonstrate current mechanisms for knowledge translation are slow, uneven and ineffective. More importantly, improved translation of knowledge into practices and policies could potentially improve patient outcomes and reduce costs of health care.

This research program is designed to improve outcomes and reduce costs through a better understanding of how different practices and risks affect short and long-term outcomes of preterm infants, and how improved methods of knowledge translation can enhance quality of care. The proposal is modelled through the PARIHS framework. The PARIHS model is a guide for implementing evidence-based practice change and is based on three components: Evidence, Context and Facilitation. Maximizing the quality of these variables will ensure successful implementation of practice change.

To carry out this program of research, we will use the Canadian Neonatal Network database and infrastructure and establish a national neonatal follow-up database using standardized assessments of all infants born at less than 29 weeks gestation. Then, the follow-up database will be linked to existing databases that collect standardized information on sociodemographic factors, outcomes, practice and resource use data for all high risk pregnancies, infants admitted to any tertiary NICU in Canada, selected NICU infants needing surgery, and infant pain evaluation and management to form a single, novel, integrated Maternal-Infant Care (MICare) Database.

We will generate high quality Evidence by meeting two objectives. First, the MICare Database will be used to study how biological, sociodemographic, environmental and treatment risks during pregnancy, childbirth and infancy interact to affect short and long-term infant outcomes. Then, variations in outcomes will be used to identify practices associated with good or poor long-term neurodevelopmental outcomes as part of the MiCare project 3 (separate REB approval), for design of potential practice change interventions to improve quality of care.

Our second aim is to improve NICU and developmental outcomes within the Follow-Up Program infrastructure, with the quality improvement process EPIQ (Evidence based Practice to Improve Quality). Outcomes will be monitored using annual benchmarked reports for CNN and CNFUN knowledge translation to improve care for preterm infants by conducting 5 projects that link evidence with context and facilitation. We will create a novel national population-based database that links the entire period from pregnancy to childbirth to infancy for research. The 5 innovative projects will use this database to generate new knowledge about the risk determinants of preterm birth, create new models for knowledge translation and quality of care improvement, develop new measurement and monitoring systems, and provide better tools for family counseling and decision making. We will leverage strengths from across Canada by including 18 carefully selected clinical, health services and population health researchers from 7 universities, and building upon four well-established national neonatal-perinatal research networks involving 30 hospitals across Canada. We will actively facilitate training of new leaders in research and leverage 3 CIHR funded STIRH training programs. Our team will add value and provide a novel database platform that will generate new knowledge for improving care for pregnant women and their infants. Over the next 5 years, our team will transform the face of preterm pregnancy and infant care in Canada and internationally.

I-PASS: Implementation of a standardized handover in Pediatric Surgery

Principle Investigator: Dr. Anna Shawyer 

With the new era of shorter work hours for health care providers, including trainees, there are more times when the team must “handover” to the next team. This creates the need for efficient and comprehensive handover to ensure that all pertinent information is transmitted in a timely fashion.

Historically, handovers were fit into the end of the day, fraught with many distractions, and were not standardized but rather a narrative review of the patients. Thus, the patient information available for the next team is often patchy and out-of-date.

Standardized handover is becoming the standard to improve patient safety and has been shown to reduce medical errors, and to improve communication among health care providers. i-PASS was developed for use in pediatric medical specialties to assist with handover; however it has not been evaluated in pediatric surgery.

This study is prospective observational intervention study. Participants are eligible while part of the pediatric surgery team at the Winnipeg Children’s Hospital.

The prospective nature permits meaningful and complete date gathering through the prospective implementation of the I-PASS handover tool, and permit prospective evaluation of the tool.

BITS: PK and PD of Budesonide Intratracheal Surfactant – Preterm 

Principle Investigator: Dr. Geert ‘t Jong

Primary Objective: To understand the pharmacokinetics (PK) of budesonide in BITS administration in preterm infants <29 weeks GA, who are intubated and require treatment with surfactant for respiratory distress syndrome. 

Secondary Objective: To establish the pharmacodynamics (PD) of budesonide in BITS in this patient group using pulmonary parameters, inflammatory markers, and any adverse drug events.

Ongoing

PROLACTA: Human-Derived Human Milk Fortifiers (H2MF) on Gut Microbiota PMI

Principle Investigator: Dr. Meghan Azad

Characterizing the effect of H2MF on gut microbiome development and oxidative stress in preterm neonates will advance knowledge of these critical physiological processes, and provide new information about the biological basis for the clinical benefits of H2MF.  A better understanding of these biological mechanisms will inform future efforts to enhance H2MF products, optimize feeding protocols and improve health outcomes for preterm neonates.

Primary objective:  To evaluate the effect of H2MF vs. HMF on gut microbiota composition in premature infants <1250 gr

Secondary objective: To evaluate the effect of H2MF vs. HMF on fecal and urinary biomarkers of oxidative stress in premature infants <1250 gr

Family Needs Survey

Principle Investigator: Dr. Darcy Beer 

Primary Objective: To determine families’ (parent and child) perceived emotional, practical, and general informational needs related to their current PED visit. 

Secondary Objectives: A comparison of child versus parent-reported needs (b) a comparison of child versus parental satisfaction with their experiences during the PED visit, (c) a description of the health literacy of a population of parents who use PEDs across Canada, (d) association of reported needs and satisfaction (parent and child) to parent health literacy, (e) association of reported needs and satisfaction (parent and child) with demographic and visit characteristics and (f) an assessment of the variation in needs, by site and season.

STEC: Risk Factors for the Hemolytic Uremic Syndrome in Children with STEC Infection

Principle Investigator: Dr. Darcy Beer 

Hemolytic uremic syndrome (HUS) occurs in approximately 15% of patients infected with

Shiga-­toxin producing E. coli (STEC). Oligoanuric renal failure (OARF) occurs in approximately 65% of patients with HUS and almost always results in significant immediate (e.g. dialysis) and long-­term (e.g. chronic renal failure) sequelae. HUS without OARF has also been implicated in long-term renal complications such as proteinuria and hypertension. To date, HUS caused by STEC infection is the most common cause of acute renal failure in children. Risk factors for the development of HUS and OARF in children with STEC are inadequately characterized and there appears to be a wide variation in management of these patients.

Aim 1: Describe host phenotypes and patient and provider patterns for patients with STEC infections across a large network of hospitals.

Aim 2: Identify host phenotypes and patient and provider care data (e.g. IV fluid hydration, antibiotic pharmacotherapy) that are associated with development of HUS and OARF in patients with STEC infections.

POSITIVE:  CNTRP Paediatric Outcomes in Transplant: Personalising Immunosuppression to Improve Efficacy (linked to Transplant Biobank Registry: H2011:321, expiry Sept 26, 2019)

Principle Investigator: Dr. Patricia Birk 

Adequate control of immunosuppression is essential to prevent graft failure after transplantation and to avoid life-threatening viral and malignant complications. Children undergo periods of rapid change from birth to young adulthood as their bodies change with growth and maturation- this makes achieving optimal immunosuppression in children difficult.

Knowledge gained from the POSITIVE study will help to tailor post-transplant management to the unique needs of growing children and young adults with the goal of prolonging graft survival, delaying re-transplantation and ultimately improving the long-term quality of life of patients post transplant.

This includes how post-transplant immunosuppression can be adjusted to meet the unique needs of child, reduce the risk of developing viral and malignant complications, and way to improve adherence with medicines after transplant.

PROBE: Pediatric Renal Transplant Optimization with Biomarkers 

Principal Investigators: Dr. Tom Blydt-Hansen, Dr. Juliet and Tom How

The primary goal of this program is to improve the long-term kidney function and survival of children with end-stage kidney disease after kidney transplantation by greatly enhancing our ability to detect kidney allograft injury. Such injury is common and may remain undetected (subclinical injury), with devastating impact on kidney allograft survival. This grant proposal will support prospective noninvasive monitoring of incident pediatric kidney transplant recipients to: 1) characterize silent (subclinical) and clinically apparent acute allograft injury phenotypes including, but not limited to, cell-mediated rejection; and 2) establish the correlation of urine biomarkers of subclinical allograft injury with functional, histological and immunological outcomes. 

Kidney transplantation greatly improves health and survival of children afflicted with end-stage kidney disease. This is tempered by an unacceptably high rate of accrued allograft injury that results in premature graft loss and reduced patient survival. This risk is substantially higher in children who experience higher rates of rejection and allograft failure compared with adults, despite increased intensity of immunosuppressive treatment. Children are also more likely to experience important allograft injury like rejection without clinically detectable changes in allograft function. The main clinical challenge in managing children after kidney transplantation remains to balance the need for timely diagnosis and treatment of serious allograft injury, against the damage associated with invasive testing or over-immunosuppression.

There are no validated biomarkers to detect rejection in children and measures of renal function are insensitive forcing reliance on invasive surveillance kidney biopsy to diagnose renal injury. Acute change in glomerular filtration rate (GFR) does not indicate the nature of underlying injury and by contrast, less fulminant injury is masked by compensatory hyperfiltration of remaining glomeruli. Such injury is termed subclinical but has nonetheless major consequences for allograft damage and survival. There is therefore need for reliable and noninvasive testing for serial allograft injury surveillance and to guide treatment.

SQUEEZE: Septic Shock Reversal – Fluid-Sparing Strategy vs. Usual Care

Principal Investigators: Dr. Jeff Burzynski

Primary Objective SQUEEZE Trial: To determine whether time to shock-reversal is quicker in pediatric patients with septic shock treated with a Fluid Sparing resuscitation strategy vs. Usual Care.

Secondary Objectives SQUEEZE Trial: To determine whether a Fluid Sparing strategy impacts:

  1. Clinical outcomes
  2. Adverse events potentially attributable to fluid overload or inotrope/vasopressor use
  3. Clinical course, resource use, and procedures
  4. Health services outcomes

Pfizer: MENACWY-TT-04: GSK/Pfizer- C0921003

Principal Investigators: Dr. David Connor

Current data from clinical studies with the MenACWY-TT vaccine suggest that a single dose in toddlers provides sufficient protection. However, data on the possible advantage of administrating two vaccine doses are not available for toddlers around 12 months of age at the time of vaccination. The European Medicines Agency (EMA) requested GSK to conduct a study to evaluate the immediate and longer term antibody titres elicited by one or two doses of MenACWY-TT administered in children aged 12-23 months. This study was therefore designed to evaluate the immunogenicity of one and two doses of MenACWY-TT administered to unprimed toddlers during their second year of life. Several European countries recommend a booster dose of a pneumococcal conjugate vaccine between 11 and 15 months of age. This study will also be conducted to demonstrate that coadministration of meningococcal vaccine MenACWY-TT with the booster dose of pneumococcal conjugate vaccine Prevenar 13 does not adversely impact the immunogenicity of either of the vaccines. The safety profile of both vaccines will also be evaluated.

iCARE: Improving Renal Complications in Adolescents with T2D through Research

Principal Investigators: Dr. Allison Dart

Type 2 diabetes (T2D) is increasing among youth, and is associated with extremely high rates of complications. Amongst the youth followed in Manitoba, 30% with T2D develop albuminuria within 4 years of diagnosis, and ≥ 50% progress to end-stage kidney disease before age 30. Current clinical practice focuses entirely on conventional biological risk factors, however preliminary data from the iCARE cohort study suggests that biological factors only explain a portion of the risk for renal pathology, and that psychological factors play an equally important, but underappreciated role. We found that both biological and psychological factors were independent important predictors of albuminuria in youth with T2D and that elevated inflammatory cytokines may be a common pathway through which these factors lead to renal injury. A prospective, multi-site cohort is needed to determine the temporal nature of these observations and confirm their external validity in a more ethnically diverse population.

CKiD: Chronic Disease in Children

Principal Investigators: Dr. Allison Dart

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in collaboration with the National Institute of Child Health and Human Development (NICHD) and the National Heart, Lung and Blood Institute (NHLBI) funded a cooperative agreement including two Clinical Coordinating Centers, a Data Coordinating Center and Central Biochemistry Laboratory to conduct a prospective epidemiological study of children with chronic kidney disease (CKD). The primary goals of this study are to determine the risk factors for decline in kidney function and to define how a progressive decline in kidney function impacts neurocognitive function and behavior; the risk factors for cardiovascular disease; and growth failure and its associated morbidity.

CHILDNEPH: The Canadian Childhood Nephrotic Syndrome Project

Principal Investigators: Dr. Allison Dart

Nephrotic syndrome, a common acquired kidney disease in children, causes severe swelling of the body due to protein leak (proteinuria) from blood into urine.1   Many affected children will have recurrent episodes (or relapses) which may lead to life-threatening complications including severe infections and thromboembolism.  The goals of treatment are to induce remission of proteinuria, reduce relapse rates, minimize toxicity of treatments and delay kidney damage.  Nephrotic syndrome can be effectively treated with steroids in most children.2,3 Various other non-steroid drugs are often used in the course of the illness to decrease frequency of relapses and to avoid side effects of prolonged steroid use (which include obesity, growth retardation, hypertension, cataracts, poor bone health, and cosmetic effects).3-14  Therefore, minimizing relapse rates and steroid exposure are the most important outcomes for children with nephrotic syndrome.

The current approach for treatment of childhood nephrotic syndrome is based on several seminal studies.2,15,16 However, management of childhood nephrotic syndrome is also known to be highly variable among physicians and care centres.17,18   We conducted a national survey of pediatric nephrologists and found striking variation in treatments. Variation was particularly high in steroid prescriptions for first presentation and relapses of nephrotic syndrome.  One potential reason for high variability in care is uncertainty in the literature regarding the most difficult challenge in the treatment of childhood nephrotic syndrome: balancing optimal duration of steroid therapy to reduce relapse rates while minimizing toxicity due to steroids.  

Recently, best available evidence for effective treatments for nephrotic syndrome were synthesized and published in an international Clinical Practice Guideline.19  We found evidence-practice gaps (gaps between reported practice according to our survey of nephrologists and best evidence as synthesized in this Guideline) in the treatment of childhood nephrotic syndrome, and specifically the duration of steroid therapy.20   The impact of these evidence-practice gaps and variations in steroid protocols on outcomes of children with nephrotic syndrome are unknown.  Recognizing the limitations of survey methods to accurately assess clinical practice, we identified a need to define the extent of variation in steroid treatments, to identify factors driving variation and to assess the impact of variation on patient outcomes.  By documenting practice variation, evaluating determinants of practice variation and related patient outcomes, we will improve use of best evidence in practice and ultimately improve patient outcomes. To address these issues, we will conduct a national prospective longitudinal observational cohort study of children with nephrotic syndrome. We will use a web based data collection system to obtain data regarding variability in treatments and patient outcomes.  We will identify critical knowledge gaps in the management of nephrotic syndrome and ultimately, create a best practice approach for treatment.  This study will also facilitate the design of randomized controlled clinical trials to generate new knowledge required to improve care and outcomes of patients in the future (see adjacent figure). Our specific objectives are as follows: 

Study 1: Prospective cohort (quantitative) study Among children with nephrotic syndrome, 

a) to determine the association between centre- , physician-, patient-level characteristics and i) cumulative steroid exposure (primary outcome), and ii) length of steroid treatment (secondary outcome); and b) to determine the association of cumulative steroid exposure and time to first relapse (secondary outcome)   

Study 2: Qualitative study 

To identify rationales for practice variation in steroid dose and duration of treatment between pediatric nephrology care providers and centres for children with nephrotic syndrome

IDEA: Origins of Childhood-onset T2DM Impact of Diet & Exercise Activity

Principal Investigator: Dr. Vern Dolinsky

Research Aims: Aim #1: Determine how diabetes during pregnancy affects DNA methylation of genetic loci associated with obesity and obesity-related complications in children. Using the NGS platform, we will perform large-scale biomarker discovery (i.e. epigenetic DNA methylation profiling) and validation using biological samples from the NextGen and iCARE cohorts. Results will identify candidate epigenetic biomarkers for increased risk of childhood obesity and obesity-related complications that will be examined in the general population-based Gen3G, CHILD and IDEA cohorts to determine associations between methylation profiles of these genes and phenotyping of obesity/T2D risk as well as prioritize loci analysis in subsequent aims.

Aim #2: Determine tissue-level mechanisms that explain programming of metabolic disease. In rodent offspring exposed to diabetes during pregnancy, we will perform an unbiased screen of DNA methylation patterns in metabolic tissues and perform a detailed phenotypic analysis using NGS, imaging and metabolic core facilities. Using tissues and cells from male and female rodent offspring, we will perform functional studies to examine the direct impact of altered DNA methylation on the function of tissues.

Aim #3: Develop novel early-life interventions that prevent obesity and obesity-related diseases in children. We will test whether interventions delivered in early life (i.e.- maternal exercise, breastfeeding etc.) modify epigenetic biomarkers and reduce the risk of pediatric obesity and its complications due to the early life environmental exposure to maternal diabetes during pregnancy.

Significance: This program of research will address the major clinical problem of obesity and obesity-related complications in children, through the translational identification of novel epigenetic signatures. Ultimately, this research aims to achieve a shift in clinical practice that leads to better treatments for overweight and obese children and pregnant women

(NOTE: REB letter has Dr. Shen as PI)
Cost (See MOU)

Principal Investigator: Dr. Wael El-Matary

CIDDSCAN: Child IBD Network

Principal Investigator:  Dr. Wael El-Matary

Inflammatory bowel diseases (IBD) denote a heterogeneous group of disorders characterized by chronic intestinal inflammation with or without extra-intestinal manifestations and classified hitherto based on clinical, endoscopic and histologic features into two major phenotypes: Crohn’s disease (CD) and ulcerative colitis (UC) 1. 

IBD manifests during childhood or adolescence in up to 25% of patients. The phenotypic spectrum of childhood-onset IBD is different from that of adult-onset IBD. IBD developing prior to age 8-10 years affects the colon predominantly: i.e. either “UC” or “colonic CD” or colitis of undetermined type (“IBD-U)”. In comparison to UC in adults, childhood onset UC is typically more extensive, and hence associated with a greater likelihood of severe exacerbations, which are frequently medically refractory. CD occurring prior to puberty affects a preponderance of males 2. In comparison to adult-onset CD, where macroscopic location of disease is relatively stable over time, disease extent may be more likely to evolve in young children. Unique to children is the potential for linear growth impairment and associated pubertal delay as a consequence of chronic inflammation, particularly in CD. Overall, the burden of illness imposed by IBD on affected children and their families is considerable. 

Systematic review of international epidemiologic studies by Benchimol.

The overall objective of the Childhood Inflammatory Bowel Disease network, as facilitated by this C.H.I.L.D./CIHR partnership grant, is to establish the necessary infrastructures for clinical and biomedical research which can be leveraged, respectively i) to systematically examine and continually improve patient outcomes via optimization of assessment tools and treatment algorithms and ii) to unravel the etiopathogenesis of paediatric inflammatory bowel disease.

MALPID: Manitoba Ambi-directional Longitudinal Pediatric IBD Cohort Study

Principal Investigator: Dr. Wael El-Matary

The overall objective of this long-term study is to systematically examine and longitudinally characterize children with IBD through creating a pediatric IBD registry and database.

The epidemiology, demographics, pathogenesis, disease extent, distribution, course and characteristics, markers, diagnosis, and outcomes for all children with IBD (0-17 years) in Manitoba from January 2012 onwards will be documented.

These data will be ultimately utilized to provide better understand the disease process and eventually achieving sustained steroid-free deep remission with normal growth and development of children with IBD.

SLEEP study (see MOU)

Principal Investigator:  Dr. Wael El-Matary

CAPE: Interventional Registry – Humira (Adalimumab) – Active Crohn’s Disease 

Principal Investigator: Dr. Wael El-Matary

The primary objective of this Registry is to evaluate long-term safety of Humirain pediatric patients (between the ages of 6 and 17 years inclusive at the time of enrollment) with moderately to severely active CD who are prescribed and treated in accordance with the approved local Humira product label under the conditions of routine clinical setting.  Patients being prescribed and treated with conventional immunosuppressant therapy with no concurrent biologic use will also be enrolled as a reference group. The secondary objective of this Registry is to evaluate the long-term effectiveness of Humirain pediatric patients (between the ages of 6 and 17 years inclusive at the time of enrollment) with moderately to severely active CD who are prescribed and treated in accordance with the approved local Humiraproduct label under the conditions of routine clinical setting.  In addition, the impact of treatment interruptions on the safety and effectiveness of Humirawill be evaluated.  Patients being prescribed and treated with conventional immunosuppressant therapy with no concurrent biologic use will be considered a reference group.

IEHS: Integrated Evaluation of Hemodynamics Service on Outcomes

Principal Investigator: Dr. Yasser El-Sayed

IMPACT: Canadian Rotavirus Surveillance through the Immunization Monitoring Program Active: Assessment of Hospitalizations and Emergency Department Visits – the Impact of Publicly Funded Vaccine Programs in Canada

Principal Investigator: Dr. Joanne Embree

The Primary Objective  

  1. To determine changes in rotavirus hospitalization rates in 12 pediatric hospitals in Canada pre- and post rotavirus vaccine implementation 2005 to 2014.  

Secondary Objectives  

  1. To determine the number of hospital acquired rotavirus infections in children and compare pre- and post immunization burden across the network.
  2. To determine the most common rotavirus genotypes 2012 to 2014 for both hospitalized patients and those seen in the Emergency Departments.
  3. To estimate the impact of rotavirus vaccine uptake over time on the burden of ED visits for gastroenteritis seen at pediatric tertiary care centers.

JIA-Uveitis: Co-existent Uveitis and Arthritis in Children

Principal Investigator: Dr. Kerstin Gerhold

This research aims to explain the association of juvenile idiopathic arthritis (JIA) and eye inflammation (a condition called uveitis) in children, a distinct pediatric clinical entity having potentially lifelong devastating consequences.  Arthritis is among the most common chronic childhood diseases afflicting 24,000 Canadian children. JIA denotes a group of painful and potentially disabling forms of chronic childhood arthritis that burden patients, their families, and health care systems.  Chronic, non-granulomatous anterior uveitis is among the most common and potentially debilitating extra-articular JIA manifestation. One in eight children with JIA (an estimated 3,000 Canadian children) also will have uveitis and, despite intensive and often distressing therapies (for example, administration of eye drops to young children many times a day), up to one-third of affected children develop profound, permanent vision loss.  Prompt recognition of at-risk children and expeditious treatment can contribute to improving outcomes8.  As a young adult who has endured childhood onset arthritis and uveitis stated: “Arthritis and uveitis are independently life altering; together they can have devastating consequences.  Lack of mobility or loss of sight can quickly strip the innocence of childhood.”

Informed by results of our previous animal and human studies we expect to show that JIA-associated uveitis results from immune reactivity to collagen-related arthritogenic and uveitogenic peptides in joints and eyes in genetically vulnerable children. A thorough understanding of molecular interactions and immune targets that drive the relationship between joint and eye inflammation will help guide evidence-based strategies to predict, diagnose, monitor, treat, and prevent JIA-uveitis. By identifying immunopathogenic mechanisms that mediate the JIA-uveitis association we envision compiling a panel of  affordable and accessible clinical and biomarker attributes to serve as a composite tool to predict JIA-uveitis occurrence, flare, and outcome; inspire new management strategies; predict treatment response; and help identify etiologic triggers. 

The etiology and pathogenesis mediating the enigmatic association of joint and eye inflammation is poorly understood. Consequently, treatment, while improving, cannot be as rationally conceived, effective, or as safe as desired and prevention and cure remain elusive. Understanding the biologic basis of JIA-uveitis should help optimize management of both arthritis and uveitis. 

The constellation of risk factors typifying JIA-uveitis include female sex, young onset age, oligoarthritis, and a positive antinuclear antibody (ANA) test. However, even when all these factors are present they lack precision in predicting JIA-uveitis onset, course, treatment response, and outcome.  With this project we expect to show that coincident JIA and uveitis is mediated by immune reactions to collagen-derived pathogenic peptides activated by inflammatory mediators. Furthermore, the elements of this proposal will clarify the association with young onset age, female predilection, ANA positivity, and genetic vulnerability among children with JIA-uveitis.

Our recent pre-clinical animal and proof-of-concept human studies support this proposal’s unifying hypothesis. This project exemplifies the value of transdisciplinary, multi-centred collaborations for rapidly mobilizing and translating animal research to human applications.

Chronic Pain Network: First Steps in Establishment of a Service for Pediatric Patients with Chronic Pain Conditions: Education and Networking

Principal Investigator: Dr. Kerstin Gerhold

LOM-FABRY: Lucerastat Oral Monotherapy in Adults – Fabry Disease

Principal Investigator: Dr. Cheryl Greenberg

CNDR: Canadian Neuromuscular Disease Registry

Principal Investigator: Dr. Ed Leung

The lack of epidemiologic data on NMDs in Canada, combined with the recognition that small, single-centre clinical studies provide inadequate sample sizes to study NMDs, and the growing international interest in NMD registries suggest that a new, more comprehensive approach is needed in Canada. This requires a national NMD registry to facilitate collaborative research that will result in a greater understanding of the societal and healthcare burden of NMDs and, in combination with basic laboratory scientific advances, will result in enhanced opportunity to perform multi-centered clinical research. 

The CNDR will create a national framework to provide mutual accessibility between patients and medical scientists to facilitate clinical studies on a national level while providing access to patients from all across Canada including those in remote areas with limited access to specialized neurologic care.

Primary Objective:

  • Improve the future for NMD patients through the enablement and support of research into potential treatments

Secondary Objectives:

  • Enhancing the understanding of NMD epidemiology in Canada
  • To understand variations in disease management in Canada
  • Foster collaborative research initiatives amongst Canadian investigators
  • Identify important research questions
  • Create a tool for clinical knowledge translation allowing more uniform standards of care in Canada
  • Attract international trial opportunities by making Canada more congruent with the international neuromuscular (NM) community

PESQOL: Impact Pediatric Epilepsy Surgery on Health Related QOL.

Principal Investigator: Dr. Ed Leung

Epilepsy in children often has catastrophic consequences on multiple domains of health-related quality of life (HRQL). These effects include poorer physical and social functioning, diminished emotional well-being, and impaired cognition and behavior. The detrimental effects of poor HRQL that occurs with childhood epilepsy continues well into adult life, with more than 50% of patients having psychiatric or social problems, failing to achieve college or higher education, unemployed, and unable to engage in stable relationships.

Medically refractory epilepsy refers to poorly controlled epilepsy in spite of treatment with two or more antiepileptic drugs. The two main treatments for medically refractory epilepsy are medical treatment with antiepileptic drugs or surgery. Surgery is considered to be the best option for seizure cure and improved HRQL, but this assumption has not yet been tested in a rigorous and comprehensive way. The traditional method of evaluating the success of epilepsy surgery using a single clinical measure of seizure control is grossly inadequate, since epilepsy affects many facets of the patients’ lives as delineated above. The relation between seizure control and HRQL is not at all clear, since some domains of HRQL improve while others do not change with improvement in seizure control

The objective of this study is to evaluate the effectiveness of two treatments, epilepsy surgery relative to medical therapy, on improving HRQL longitudinally. The surgical group will be compared to a medical treatment group which has undergone work-up for surgery but deemed unsuitable for surgery. These two groups have been shown to have similar baseline characteristics. Outcome will be addressed using a novel comprehensive model that acknowledges a number of variables such as clinical status (seizure control), patient factors (mood and self-concept) and family factors (caregivers’ mood, family adaptation, resources and demands) can affect changes in HRQL. 

This is the first multi-site Canadian study on HRQL outcome of pediatric epilepsy surgery. This study has been endorsed by the Canadian Pediatric Epilepsy Network as one of its research priorities to better understand the multi-dimensional outcome of pediatric epilepsy surgery. The proposed study will bridge knowledge gaps so that we understand who will improve, to what extent they will improve and what factors may influence the changes in HRQL following treatment. This in turn will impact on our decision-making process regarding treatment options. The results of this study will also tell us which aspects of HRQL will improve and which ones do not, so that we can implement early psychosocial interventions targeted to those attributes that do not improve with treatment. This study will provide the evidence on the effectiveness of epilepsy surgery for the stakeholders to justify the cost of surgery and increase access to surgery.

JIA Trial: Identifying Trajectories of Disease Activity States in Juvenile Idiopathic Arthritis (JIA) Early After Treatment: Shortening Time to Decision to Change Treatment

Principal Investigator: Dr. Lily Lim

LIFT: Lactoferrin Infant Feeding Trial

Principal Investigator: Dr. Deepak Louis

Almost 3,000 very low birth weight(VLBW <1500g) preterm infants are born and treated in Canada annually. About 1,200 either die or survive with severe brain or lung injury, retinopathy of prematurity (ROP), late-onset sepsis or necrotizing enterocolitis (NEC),each of which is associated with substantial risk of childhood disability. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions.5, 6Lactoferrin has been shown to be effective against infection when tested in animals and in the laboratory. The systemic effects of oral lactoferrin are generally thought to be indirect and probably are initiated by contact with intestinal epithelial cells and gut-associated lymphoid tissue (GALT).10, 11Lactoferrin and other similar products in human milk create an environment for growth of beneficial bacteria in the gut, reducing colonization with pathogenic bacteria. However, most VLBW infants receive insufficient human lactoferrin (hLF) from human breast milk in the first months of life, resulting in suboptimal protection. Because human lactoferrin is expensive, bovine lactoferrin has been considered as an alternate supplement to improve this suboptimal protection as it has 77% amino acid homology with human lactoferrin with the same N-terminal peptide. Thus, lactoferrin has emerged as a new tool for the prevention of serious neonatal morbidities..

PD-CIS: Pediatric MS – QOL

Principal Investigator: Dr. Ruth Ann Marrie

Edmonton Newborn Cardiac Follow-Up Program

Principal Investigator: Dr. Diane Moddemann

Extubation Study: Early Versus Delayed Extubation In Extremely Preterm Neonates: A Retrospective Multicenter Cohort Study

Principal Investigator: Dr. Michael Narvey 

The objective of this study is to comparatively evaluate clinical outcomes associated with early extubation (within 24 hours of meeting extubation criteria) compared to later extubation (>24 hours after meeting extubation criteria) among preterm infants <26 weeks’ GA in the first week of postnatal life. 

Ebola PREP: Vaccine for Ebola-Zaire

Principal Investigator: Dr. Guillaume Poliquin

Objectives Primary: To compare the immune response 3 years following primary vaccination with VSVΔG-ZEBOV-GP vaccine (V920) and a homologous booster immunization at 18 months versus primary  vaccination with rVSVΔG-ZEBOV-GP vaccine (V920) without a booster at month 18. 

At month 18 following primary vaccination, eligible and consenting participants will be randomized to a single booster immunization with the same dose of study vaccine as the primary dose (2 x 107 pfu/mL) or to no boost. The inclusion and exclusion criteria below will be assessed both at the beginning of the study and prior to randomization at month 18. 

If at any time during the observation period antibody levels fall below a pre-defined seroprotective threshold (yet to be defined in parallel or newly planned studies) a booster may be offered to study participants with antibody levels below that protective threshold. If this occurs before month 18, there will be no randomization. Participants will continue to be followed through 36 months and descriptive analyses will be performed.

IPSS: International Paediatric Stroke Study : Towards the Establishment of Standards of Practice and the Initiation of Multi-Center, Multi-National Clinical Trials for Neonates and Children with Stroke

Principal Investigator: Dr. Mubeen Rafay

People do not usually know that children and young adults can have a stroke. We want to find as many children as we can in Canada and around the world who had a stroke. If we find and study lots of children, we can understand the causes of stroke, and also find out what medicines work best to make you better. 

Brain Canada: IPSS Sub-study: Advanced neuroimaging in Pediatric Stroke: Pathophysiology of injury and repair in children with focal brain ischemia 

Principal Investigator: Dr. Mubeen Rafay

BIPED: (Bronchiolitis)

Principal Investigator: Dr. Scott Sawyer               

Primary Objective: To determine if treatment of infants presenting with bronchiolitis to the emergency department (ED) with nebulized epinephrine and a 2-day course of oral dexamethasone is effective in reducing the need for admission to hospital (due to bronchiolitis) by day 7 post enrolment compared to placebo.

Secondary Objectives:

  1. To determine if treatment of infants presenting with bronchiolitis to the ED with nebulized epinephrine and a 2-day course of oral dexamethasone is effective in reducing admissions to hospital (for bronchiolitis) at enrolment ED visit compared to placebo.
  2. To determine if there is a difference between groups in all cause admission within 21 days post enrolment, all cause health care provider visits over 21 days post enrolment, and health care-related costs.

MiTy Kids: Metformin in Women with Type 2 Diabetes in Pregnancy Kids Trial

Principal Investigator: Dr. Elizabeth Sellers

Primary: To determine whether treatment with metformin during pregnancy, in women with type 2 Diabetes, leads to a reduction in adiposity as measured by anthropometric measurements in the offspring at 2 years of age.

Secondary:

  1. To determine whether treatment with metformin during pregnancy, in women with type 2 Diabetes, leads to a decrease in weight gain over time during critical early periods and overall, in the offspring.
  2. To determine whether treatment with metformin during pregnancy, in women with type 2 Diabetes, leads to a reduction in insulin resistance, and metabolic parameters that are associated with insulin resistance, in the offspring.
  3. To determine predictors of insulin resistance and childhood adiposity in offspring of women with type 2 diabetes in pregnancy.

GUM: The Impact of Chewing Gum on Post-operative Ileus

Principal Investigator: Dr. Anna Shawyer

Given that chewing gum is thought to act as a “pro-kinetic agent” [25], and that patients with a POI have increased morbidity – the belief is that chewing gum will stimulate the bowel to hasten the return of bowel function. This in turn will decrease the length of time with the ileus (which is related to LOS and other morbidities associated with a prolonged stay) [7-11].    

This study is a prospective randomized, controlled trial. Patients will be eligible if they are more than or equal to 5 years of age and less than 18 years old  (i.e. 5 – 17 years) who undergo abdominal surgery with an expected LOS longer than 24 hours after surgery at Winnipeg Children’s Hospital from March 2018 – March 2020 (approximately based on final sample size). (A change in LOS within less than 24 hours after surgery was not deemed clinically significant based on a poll of local pediatric surgeons). The effect of chewing 1 piece of sugarless gum 3 times a day on return of intestinal function will be assessed.

The prospective nature permits meaningful and complete data gathering through the prospective implementation of the CRF. Randomization will balance confounding factors between groups. The clinicians looking after the patients will not be blinded to gum chewing (as it may be obvious when assessing the patient), but attempts at blinded data collection will be made, and data analysis will be done in a blinded fashion.

PTN-POPS: Pediatric Trials Network PK of Understudied Drugs 

Principle Investigator: Dr. Geert ‘t Jong

The majority of drugs administered to children are used off label and PK studies to define appropriate dosing are lacking across pediatric age groups. Challenges associated with clinical trials in children limit the ability to conduct PK and dosing trials in this population. Studies capitalizing on standard of care procedures have proven successful in characterizing the PK of drugs used in children. The purpose of this study is to characterize the PK of understudied drugs administered to children per standard of care as prescribed by their treating caregiver. This study will serve as a tool to better understand drug exposure in children receiving drugs per standard of care. The data collected through this initiative will provide valuable PK and dosing information drugs in different pediatric age groups as well as special pediatric populations (i.e., obese).In addition, the data collected in this study will serve as preliminary data to design and plan the best and most efficacious BPCA trials; proof of concept studies associated with biomarkers; as well as data to support applications for extramural funding. This project will involve biological sample collection (non-scavenged (fresh) and scavenged (leftover)) from children receiving drugs per standard of care as prescribed by the treating caregiver. The prescribing of drugs to children will not be part of this protocol. This principle will allow for a minimal risk study, an expanded enrollment net, evaluation of off-patent drugs, and capitalization on procedures performed per standard of care to maximize study efficiency and data collection. One of the limitations of this approach is compromised data quality. However, the careful consideration and planning of the data collection for this study by experienced pediatric clinical pharmacology experts and strong data management team will minimize this potential limitation of the study. Other limitations include challenges associated with PK modeling of limited samples; participant selection bias; and other unknown biases.

Allergan LIN-MD-63 (IBD): RDBPC-RCT – Linaclotide – IBS -C

Principal Investigators: Dr. Geert ‘t Jong, and Quais Mujaar

To evaluate the dose response, safety, and efficacy of 4 weeks of treatment with 1 of 3 linaclotide doses (A, B, or C) or 290 ug (as an exploratory objective in the adolescent patients 12 – 17 years of age using the approved adult dose) compared with placebo in pediatric patients 7 to 17 years of age who fulfill the  come III criteria for child/adolescent irritable bowel syndrome (IBS) and modified Rome III criteria for child/adolescent functional constipation (FC).

Allergan 3030-202-002: RDBPC-RCT – Dose-Ranging Study Eluxadoline IBS-D

Principal Investigators: Dr. Geert ‘t Jong, and Dr. Quais Mujaar

The primary objectives of this study are:

  • To explore the therapeutic effect of eluxadoline in treating IBS-D in pediatric patients 12-17 years of age.
  • To evaluate the pharmacokinetics (PK) of eluxadoline in pediatric patients with IBS-D.
  • To evaluate the safety and tolerability of eluxadoline in pediatric patients with IBS-D.

The results of this dose-ranging study will allow the selection of an optimal dose(s) of eluxadoline to evaluate in the subsequent confirmatory efficacy study.

FACT-4: Folic Acid Clinical Trial – 4

Principal Investigator: Dr. Shayne Taback

Primary Objective: FACT 4 Child is a follow up study of mothers who participated in FACT and their children when the children are between 4-6 years of age. The objective is to determine the effect of high dose folic acid supplementation on social impairments associated with Autism Spectrum Disorders (ASDs), and deficiencies in a range of executive function and emotional and behavioural problems in young children, and the risk of death.

Secondary Objectives: To evaluate the effect of high dose folic acid supplementation during pregnancy on the incidence of severe morbidity in offspring aged 4-6 years.

MIREC-ENDO: Maternal- Infant Research on Environment Chemicals: Pubertal Timing, Endocrine & Metabolic Function

Principal Investigator:  Dr. Shayne Taback

Primary objective: The main objective is to determine whether prenatal exposure to elevated levels of various environmental chemicals, as well as other in utero factors are related to the onset and progression of puberty, child metabolic function and growth. The in utero factors will focus on maternal health status during pregnancy (i.e. obesity, gestational diabetes, and hypertension).

Secondary objectives: The secondary objectives are:  1) to explore the effect of maternal health status and exposure to environmental chemicals during the MIREC index pregnancy on long-term maternal metabolic function, 2) to measure exposure to various emerging environmental chemicals (not previously measured in MIREC) in stored maternal biospecimens; and 3) to measure current exposure to more persistent environmental chemicals in MIREC children.

DINAMO: DIabetes study of liNAgliptin and eMpagliflozin in children and adOlescents

Principal Investigator: Dr. Brandy Wicklow

The objective of this study is to assess the efficacy and safety of an empagliflozin dosing regimen and one dose of linagliptin versus placebo after 26 weeks of treatment in children and adolescents with type 2 diabetes mellitus. In addition, this study will assess long-term safety of empagliflozin and linagliptin after 52 weeks of treatment.

Ellipse (site 432, study 3659)

Principal Investigator: Wicklow, Brandy