Improving Renal Complications in Adolescents With Type 2 Diabetes Through REsearch Cohort Study (National iCARE Study) (iCARE)

The overall aim of the project is to elucidate the primary bio-psycho-social (BPS) risk factors for albuminuria in youth with type 2 diabetes (T2D) and the mechanisms by which they cause renal injury. The Study Aims include:

1. Characterize the primary BPS risk factors associated with prevalent and progressive albuminuria in youth with T2D.
2. Determine individual, family and community level factors that influence biological and psychological risk factors and behaviors (adherence) that could be modified to protect against prevalent and progressive albuminuria.
3. Determine if systemic and renal inflammation is the common pathway through which BPS risk factors lead to albuminuria in youth with T2D.

Study Hypotheses include:

1. Biological factors (poor glycemic control and systolic ambulatory hypertension), and psychological and social adversity (stress, mental distress and poverty) are significant predictors of prevalent and progressive albuminuria in youth with T2D.
2. Community and family support will be negatively associated with stress, and a lower risk of both prevalent and progressive albuminuria.
3. Systemic and renal inflammation is the common pathway through which BPS risk factors lead to albuminuria in youth with T2D.

Study Overview

• Status: Recruiting
• Conditions: Stress; Proteinuria; Type 2 Diabetes; Nephropathy

Detailed Description

The investigators will conduct a case-control study within a two-year, prospective observational cohort study of 400 prevalent cases of T2D diagnosed <18 years of age. The investigators will evaluate the primary BPS risk factors associated with prevalent albuminuria using a principal component analysis (PCA) of associations between primary exposure variables at enrollment. After confirming the relevant BPS factors in the PCA analysis, the investigators will utilize a structural equation modeling approach to confirm the developed model.

• Study Type: Observational
• Enrollment (Anticipated): 400

Contacts and Locations

• Study Contact: Name: Brandy A Wicklow, MD, MSc; Phone Number: 2047871222; Email: bwicklow@hsc.mb.ca
• Study Contact Backup: Name: Melissa Del Vecchio, MSc; Phone Number: 2047893827; Email: mdelvecchio@chrim.ca

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Recruiting
      • Children's Hospital Research Institute of Manitoba/University of Manitoba
      • Contact: Brandy A Wicklow, MD, MSc; Phone Number: 2047871222; Email: bwicklow@hsc.mb.ca
      • Principal Investigator: Brandy A Wicklow, MD, MSc
      • Principal Investigator: Allison Dart, MD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Prevalent youth 10-18 years of age being treated for T2D at 8 pediatric endocrinology clinics across Canada (Stollery Hospital in Edmonton, Alberta Children's Hospital in Calgary, Children's Hospital of Saskatoon, Children's Hospital of Winnipeg, McMaster Children's Hospital in Hamilton, Children's Hospital of Eastern Ontario in Ottawa, SickKids Hospital in Toronto, and the IWK Health Centre in Halifax)

Description

Inclusion Criteria:

• All youth with T2D that do not meet exclusion criteria are eligible for the study.

Criteria for Diagnosis of T2D:

1. Diagnosis of diabetes will be made according to the Canadian Diabetes Association criteria. There must be 2 abnormal blood glucose tests on different days OR 1 abnormal blood glucose test + symptoms of diabetes:

   • Fasting plasma glucose of > 7.0 mmol/L or
   • Random glucose > 11.1mmol/L or
   • 2 hour glucose > 11.1 mmol/L after a standard oral glucose tolerance test (75g).

2. Distinguishing T2D from type 1 diabetes (T1D) will be based on clinical risk factors including:

   • Presence of overweight/obesity,
   • Other evidence of insulin resistance (acanthosis nigricans)
   • Family history of type 2 diabetes (1st degree relative)
   • Intrauterine exposure to hyperglycemia,
   • Family heritage from a high-risk ethnic group (Indigenous, Hispanic, South Asian, Asian or African descent)
   • Absence of diabetes associated auto-antibodies
   • HNF-1 alpha heterozygote or homozygote

Exclusion Criteria:

1. Diabetes secondary to medication use or surgery
2. Antibodies suggestive of type 1 diabetes
3. Current treatment with oral steroids or immunosuppressive agents as they may interfere with cortisol assessment and inflammatory markers
4. Ever cancer
5. Other chronic illness associated with systemic inflammation (ex. Juvenile rheumatoid arthritis, Crohns disease)
6. Patient and or caregiver unable or unwilling to provide voluntary informed assent/consent

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent Albuminuria	Persistent albuminuria Definition: Albumin:creatine (ACR) > 2.0mg/mmol in at least two urine samples within 6 months at least 1 month apart.; ACR > 2.0mg/mmol with a timed overnight urine or first am urine collection.	2 years
Change in albumin excretion over time.	Change in albumin excretion over 2 years. The change in albumin:creatinine ratio, treated as a continuous outcome measure was selected as a valid evaluation of progression of renal injury over time.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in estimated glomerular filtration rate (eGFR) over time.	This outcome will be exploratory as significant changes are not expected during a 2-year follow-up period. However, as GFR reflects actual kidney function, this outcome will become increasingly important as chronic kidney disease (CKD) progresses in the cohort over time. GFR will be determined with serum creatinine measurements, utilizing a new eGFR formula for overweight youth, which have been validated utilizing iohexol GFR data from the initial cohort. eGFR will be calculated with the pediatric Schwartz formula and iCARE equation. This equation was previously validated for use in the iCARE cohort.	2 years

Collaborators and Investigators

• Sponsor: University of Manitoba
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Brandy A Wicklow, MD, MSc, University of Manitoba, Children's Hospital Research Institute of Manitoba

Publications and helpful links

General Publications

• Dart AB, Wicklow BA, Sellers EA, Dean HJ, Malik S, Walker J, Chateau D, Blydt-Hansen TD, McGavock JM; iCARE investigators. The Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch (iCARE) Cohort Study: rationale and Protocol. Can J Diabetes. 2014 Oct;38(5):349-55. doi: 10.1016/j.jcjd.2014.07.224.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 27, 2016
• First Submitted That Met QC Criteria: June 28, 2016
• First Posted (Estimate): June 29, 2016

Study Record Updates

• Last Update Posted (Actual): April 19, 2022
• Last Update Submitted That Met QC Criteria: April 18, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Urination Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 2; Proteinuria
• Other Study ID Numbers: B2011:024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This is a multi-site trial where the use and compilation of individual level data is being discussed amongst the various ethics boards across Canada.