Human Versus Analogue Insulin for Youth With Type 1 Diabetes in Low-Resource Settings

Study Overview
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Brief Summary
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The primary objective of this trial is to determine whether insulin glargine reduces the risk of serious hypoglycemia or improves Time in Range at 6 months when compared against standard of care human insulin (e.g. NPH or premixed 70/30) among youth living with type 1 diabetes (T1D) in low resource settings.

Detailed Description
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Long-acting insulin analogues have become a de-facto standard of care for patients with T1D living in high-income countries. Unfortunately, insulin analogues remain unavailable or unaffordable for much of the global population. In both 2017 and 2019, applications to add long-acting insulin analogues to the WHO's Model List of Essential Medicines (EML) were rejected due to insufficient evidence of superiority and an unfavorable cost-effectiveness profile when compared against older, less expensive, human insulins (e.g., NPH insulin and premixed 70/30 insulin). In 2021, long-acting insulin analogues were added to the EML but the decision remains controversial since the WHO concluded that magnitude of clinical benefit of long-acting insulin analogues over human insulin for most clinical outcomes was small. Moreover, studies that compare long-acting insulin analogues versus human insulins conducted in high-income settings may not generalize to children and young adults living with T1D in very low-resource settings. To address this unmet need, Pitt has partnered with Brigham and Women's Hospital, The London School of Hygiene and Tropical Medicine, the Clinton Health Access Initiative and Life For a Child to conduct a randomized controlled trial comparing insulin glargine, a long-acting analogue insulin, against intermediate human insulin among 400 children and young adults living with T1D in a lower resource setting.

Official Title
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Human Versus Analogue Insulin for Youth With Type 1 Diabetes in Low-Resource Settings: A Randomized Controlled Trial

Conditions
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Diabetes Mellitus, Type 1, Type 1 Diabetes

Intervention / Treatment
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* Drug: Insulin Glargine
* Drug: NPH or premixed 70/30 (human insulin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children and young adults (age 7-25) Have a clinical diagnosis of type 1 diabetes (T1D) Exclusion Criteria: Prior use of any insulin analogue Patients (or parents for children <18 years old) who refuse to or cannot provide informed consent Who are currently pregnant or plan to become pregnant over the next year Who have previously used a continuous glucose monitor (CGM) for glucose monitoring Who were first diagnosed with T1D less than 12 months ago Who is diagnosed with severe malnutrition

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glargine<br>Insulin glargine (long-acting insulin analogue) | Drug: Insulin Glargine<br>* Formulation: Available as a clear liquid in a glass cartridge (1 cartridge =3ml=300 units). Route: Subcutaneous injection using insulin syringe and needle. At the site in Iraq, glargine will be available only as a prefilled, disposable pen (1 pen = 3ml = 300 units). Amount of each dose: varies depending on baseline basal insulin needs Dose escalation scheme: Participants randomly assigned to glargine will start with a dose that is generally equal to 80% of their total basal human insulin dose prior to the switch (per ISPAD guidelines and the switching guide developed by Life for a Child with the guidance of Dr. Ragnar Hanas and two other ISPAD members familiar with less-resourced settings). Frequency of dose: once per day (usually administered before bedtime)<br>|
| Active Comparator: NPH or premixed 70/30 (human insulin)<br>NPH or premixed 70/30 (human insulin) | Drug: NPH or premixed 70/30 (human insulin)<br>* Drug: NPH or Premixed 70/30 Formulation: Available as a liquid in a glass vial or glass cartridge (10ml=1000IU). At the site in Iraq, NPH will be available only as a prefilled, disposable pen (1 pen = 3ml = 300 units). Route: Subcutaneous injection using insulin syringe and needle Amount of each dose: varies depending on baseline basal insulin needs (per usual care or treating clinician) Frequency of dose: once or twice per day (per usual care or treating clinician) Duration of therapy: 12 months Participants in both groups will receive the same frequency of blood glucose testing and same intensity of education and counseling (e.g. titration advice according to fasting glucose targets and strategies to avoid hypoglycemia). Participants in both groups will have equal access to test strips (sufficient to test up to 5 times per day during the active titration phase and after 3 times/day).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-in-serious hypoglycemia | % spent less than 54mg/dl, averaged across all daily measures averaged across two CGM sensors | 6 months after randomization | 
| Time-in-range (TIR) | % between 70 and 180mg/dl inclusive, averaged across two CGM sensors | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-in-hypoglycemia | % spent less than 70mg/dl | 6 months after randomization | 
| Time-above-range | % spent greater than 180mg/dl | 6 months after randomization | 
| Nocturnal hypoglycemic events | Number of events (defined as >=15mins in duration < 70mg/dl) between 1200 and 0600 | 6 months after randomization | 
| Glycemic control (HbA1c) | Mean HbA1c lab result | baseline, 3, 6, 9 and 12 months after randomization | 
| Rate of severe hypoglycemic events | Events requiring the assistance of an external third party person | 6 months after randomization | 
| Rate of Diabetic Ketoacidosis | Hospitalization or Emergency Room Visit with primary diagnosis of Diabetic Ketoacidosis. This will be measured by self-report and confirmed through review of hospital records | 6 months after randomization | 
| Quality of Life (e.g. PedsQL Pediatric Quality of Life Inventory) | The PedsQLTM 3.2 Diabetes Module is composed of 33 items comprising 5 dimensions for ages 8- 45 years. Items are scaled on a 5-point scale from 0 (never) to 4 (almost always). Scores are transformed on a scale range from 0 to 100. The total score is the sum of all the items over the number of items answered on all scales. | Baseline and at 6 and 12 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 Diabetes, Insulin Glargine, Human Insulin, Insulin Analogue, Bangladesh, Tanzania, Iraq