An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic Adult Survivors of Childhood Cancer

Study Overview
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Brief Summary
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This is a first-in survivor, single-arm pilot study with the goal of establishing evidence of feasibility and safety of a combined pharmacologic (metformin) and lifestyle intervention (using an existing digital platform) to prevent diabetes in prediabetic adult survivors of childhood cancer. Primary Objective The primary aim of this proposal is to establish the feasibility and safety of a 24-week combined metformin + intensive lifestyle intervention among adult survivors with prediabetes (including a 12-week lifestyle alone run-in followed by 12-week combined intervention among survivors remaining prediabetic). Primary endpoints of this trial will be adherence to 1) daily metformin administration and 2) completion of required core-curriculum of the lifestyle change intervention. Safety will be assessed using the Global Rating of Side Effects Burden Secondary Objectives The secondary aim is to assess preliminary evidence for efficacy of the combined metformin + intensive lifestyle intervention on glycemic control and insulin resistance. Glycemic control will be measured by fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) and insulin resistance measured by the homeostatic model assessment (HOMA-IR) and IGF- binding protein 1 (IGF-BP1; a measure of insulin sensitivity strongly correlated with euglycemic insulin clamp testing). Exploratory Objectives To assess preliminary evidence for efficacy of the combined metformin + intensive lifestyle intervention on weight, other anthropometric measures, blood pressure and lipid profile, physical activity (self-reported and as measured by accelerometer), frailty measures, and health-related quality of life (HRQOL). We will also assess diabetes development at future SJLIFE visits. To assess measures of participation in the lifestyle change program as well as barriers to participation and medication adherence.

Detailed Description
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Eligible subjects who meet inclusion criteria will be enrolled in a 12 week run-in period of the digital lifestyle intervention program. At the 12 week study visit, those who remain prediabetic will received metformin extended release daily, first at lower dose (500 mg/day) to minimize gastrointestinal side effects (diarrhea, nausea, flatulence, bloating), then escalated to a maximum dose of 1000 mg/day at week 14. The digitally delivered lifestyle change program will include a core curriculum focused on diet quality, food types, exercise and behavioral strategies for goal setting, and self- monitoring.

Official Title
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An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic Adult Survivors of Childhood Cancer

Conditions
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PreDiabetes, Adult Children

Intervention / Treatment
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* Drug: Metformin
* Behavioral: Digital Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Investigators will recruit to enroll 55 survivors who are at least 18 but <45 years of age who participate in the St. Jude Lifetime Cohort Study (SJLIFE) and have been identified to have prediabetes defined as hemoglobin A1c (HbA1c) Participant in SJLIFE ≥18 and <45 years of age Prediabetic: fasting plasma glucose 105-125 mg/dL, hemoglobin A1c 5.7- 6.4% (either or both criteria may be present) According to institutional and NIH policy, the study will accession research participants regardless of sex and ethnic background. Institutional experience confirms broad representation in this regard. Exclusion Criteria: Absence of treatment related diabetes risk. Survivors will be excluded if their cancer treatment required observation only, surgery alone not involving the abdomen or brain, radiation alone not involving the chest (pancreatic risk), abdomen or brain (e.g. retinoblastoma treated with enucleation alone, melanoma of an extremity treated with excision alone, neuroblastoma in an infant requiring observation only) Diabetes at baseline assessment: FPG ≥126 mg/dL, HbA1c ≥6.5% or previous diagnosis by a physician (except gestational diabetes that resolved post-partum) BMI <19 kg/m2 Current metformin use (including for any period ≥30 days in the past 1yr) Known allergy to metformin Current use of other oral glucose lowering medications, non-insulin injectable diabetes medications or insulin (Appendix) Current participation in a lifestyle change program Chronic kidney disease ≥ stage IIIb (eGFR < 45 mL/min) Severe cardiovascular disease or recent intervention (NYHA class ≥2 or heart failure hospitalization in the past 6mo, Aortic stenosis, Heart block including LBBB or 3rd degree AV block, SBP >180 or DBP >105 mmHg, myocardial infarction or coronary revascularization in the past 1 month) Severe hepatic dysfunction: cirrhosis or AST/ALT >3 times upper limit of normal Pulmonary disease with dependence on oxygen or daily use of bronchodilators Weight loss >10% in the past 6 months Bariatric surgery in the past 2 years Pregnant, within 3 months post-partum, nursing, or planning to become pregnant Anemia: hematocrit <36% in males or <33% in females Ongoing alcohol or substance abuse using criteria from the AUDIT and DAST questionnaires (Appendix) Diagnosis of schizophrenia or other psychotic disorder Vision impairment limiting ability to interface with the digital program Unable to swallow medication Non-English speaking Cognitive impairment defined by IQ <80 Current active cancer or undergoing treatment for active cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 44 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. | Drug: Metformin<br>* To begin week 12 for participants who remain prediabetic after 12 week lifestyle run-in. Dosage and Route of Administration: 500 mg dose/ day to be taken orally, increased to 1000 mg dose/ day at week 14 through week 24. The dose should be taken immediately following the evening meal and at approximately the same time daily<br>* Other names: Metformin ER;Behavioral: Digital Intervention<br>* Lifestyle Change Digital Intervention - This is a digital platform that will include a core curriculum focused on diet, exercise, and behavioral strategies for goal setting and self-monitoring to improve diet including a weight loss On Day 1, participants will begin their digital lifestyle intervention using their smart-phone application with their lifestyle coach and peer group. On day 14, participants will be contacted by phone (+/- 4 days, day 10 to 18) and adherence assessed using virtual pill counts via phone calls. At weeks 4, 8, 16 and 20 a phone-based pill count for adherence and adverse event symptom log will be completed and study medication dispensed. At week 12 (interim assessment) and 24 (study-end), the participant will return to St. Jude Children's Research Hospital (SJCRH) for an in-person assessment. The digital lifestyle change program will complete at week 24.<br>* Other names: Lifestyle Change Digital Intervention;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence for feasibility | Adherence to the intervention with 80% adherence to prescribed metformin and completion of 60% of the digitally-delivered core education curriculum through the lifestyle change platform. | 2 years | 
| Digitally-delivered core education curriculum through the lifestyle change platform | Adherence will be monitored by completion logs of lessons | At end of Week 24 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 4 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 8 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 12 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 14 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 16 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 20 | 
| Safety and Adverse Events (Symptom Log including monitoring for AEs) | An Adverse Event Monitoring Log with Global Rating of Side Effects Burden | Week 24 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 2 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 4 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 8 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 12 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 16 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 20 | 
| Drug adherence/Pill Counts | Adherence will be monitored by pill counts showing participant taking study drug, metformin ER, 80% of the time. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic Control | Glycemic Control will be measured by Change in Hemoglobin A1c | Baseline to Week 24 (on campus labs at Baseline, Week 12 and 24) | 
| Glycemic Control | Glycemic Control will be measure by Change in Fasting Plasma Glucose | Baseline to Week 24 (on campus labs at Baseline, Week 12 and 24 |