Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New Onset Type 1 Diabetes

Study Overview
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Brief Summary
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Randomized trial of youth aged 7-<18 years with newly diagnosed stage 3 type 1 diabetes (T1D) to assess the effect of both (1) near-normalization of glucose concentrations achieved through use of a hybrid closed loop (HCL) system and (2) verapamil on preservation of β-cell function 12 months after diagnosis. Participants with body weight ≥30 kg (Cohort A) will be randomly assigned in a factorial design to (1) HCL plus intensive diabetes management or usual care with no HCL and (2) verapamil or placebo. Participants with body weight <30 kg (Cohort B) will be randomly assigned 2:1 in a parallel group design to HCL plus intensive diabetes management or to usual care with no HCL.

Detailed Description
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After informed consent is obtained, potential participants will be assessed for eligibility, including eliciting medical history, physical examination, and laboratory testing (including HbA1c, auto-antibody measurement [unless positive auto-antibody results already available], and pregnancy test for females with childbearing potential). Participants who already have positive auto-antibodies can be randomized immediately. All other participants will be scheduled for a randomization visit after the auto-antibody results are available; positive auto-antibodies are required for randomization. Eligible participants with body weight ≥30 kg (Cohort A) will be randomly assigned to one of 4 groups: HCL and placebo, HCL and verapamil, non-HCL and placebo or non-HCL and verapamil. Eligible individuals with body weight <30 kg (Cohort B) will be randomly assigned 2:1 to either HCL or non-HCL. Randomization schedules will be separate for Cohort A and Cohort B and will be stratified by site. Participants assigned to HCL will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations. Participants assigned to non-HCL will receive a Dexcom G6 continuous glucose monitor (CGM) and diabetes management will follow usual care by their personal diabetes health care provider. Participants will be followed for 12 months from diagnosis, completing a 6 week visit timed from randomization and 13, 26, 39, and 52 week visits timed from diagnosis. Participants will have a MMTT performed, HbA1c measured, and blood drawn for mechanistic studies at Randomization, 13, 26, 39 and 52 weeks. At all follow-up visits, a physical exam will be performed, pregnancy testing performed (if indicated), insulin dose (units/kg/day) recorded, and device data downloaded. Safety assessments will be made throughout the study by querying about episodes of severe hypoglycemia and DKA, and overall health. Participants already enrolled in the study and using the Medtronic 670G 4.0 AHCL may transition to the Medtronic 780G if desired. Contacts will be performed to review CareLink data and check for adverse events and device deficiencies on days 1, 3 and 5 after transition from 670G 4.0 AHCL to 780G. Prior to the 780G system becoming commercially available, study participants using the Medtronic system at 52 weeks will have the opportunity to continue using the 780G system at home until the system is commercially available OR until the CLVer trial is complete (last participant's 52-week visit), whichever comes first. Additional Procedures for Cohort A: Drug will be double blinded. Drug dose will be weight-dependent and will be escalated at 2-4 week intervals, up to a weight-dependent maximum if tolerated. Cohort A will have additional safety visits 1 week after initiation of study drug and after each study drug dose increase, to test blood pressure and pulse. Local lab measurement of aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine will occur, and an EKG will be performed at Screening, 6, 26, and 52 weeks. Over the course of the trial, study drug dose may be decreased or discontinued if side effects occur.

Official Title
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Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New Onset Type 1 Diabetes (CLVer)

Conditions
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Type1 Diabetes

Intervention / Treatment
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* Device: HCL
* Drug: verapamil 120mg tablet
* Device: non-HCL
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Participant Inclusion Criteria: New-onset stage 3 T1D within 21 days of diagnosis (timed from start of insulin therapy), with ability to be randomized within 31 days of diagnosis (time from diagnosis to screening can be longer provided all screening testing can be completed within 31 days of diagnosis) At least one positive type 1 diabetes auto-antibody Age 7 - <18 years at the time of enrollment Willing to have a parent or legal guardian provide informed consent and child assent In a female participant with childbearing potential, not currently pregnant and willing to avoid pregnancy and breastfeeding and undergo pregnancy testing throughout the study English speaking/reading Able to swallow pills (tested with an inert imitation tablet in clinic prior to randomization) Willing to not use any non-insulin glucose-lowering agents Willing to use an insulin approved for the pump (if assigned to HCL) Willing to avoid medications containing acetaminophen, and no contraindications for ibuprofen use (in case assigned to Medtronic HCL system) Participant Exclusion Criteria: Ongoing use of medications known to influence glucose tolerance such as systemic steroids Other systemic disease which in the opinion of the investigator precludes participation (including psychiatric illness) Unwilling to abstain from use of HCL therapy for 12 months a. Personal pump and CGM use, including systems with a suspend-before-low function, will be allowed for participants randomized to non-HCL groups Silent diabetes-i.e., Stage 3 diabetes that is identified by routine oral glucose tolerance testing (OGTT) or in the course of surveillance studies but is not accompanied by fasting hyperglycemia or classic symptoms of diabetes Participation in another research study that involves diabetes care Additional exclusion criteria for Cohort A: Blood pressure (either systolic or diastolic) <5th percentile for age, gender, and height on two out of three measurements Pulse <2nd percentile for age and gender on two out of three measurements History of vasovagal syncopal episodes related to hypotension Abnormal EKG rhythm unless cleared for study participation by a cardiologist Underlying cardiac disease (ex. left ventricular dysfunction, hypertrophic cardiomyopathy), certain arrhythmias (ex. Atrioventricular block (AV) block, accessory pathway such as Wolff-Parkinson-White or Lown-Ganong-Levine syndromes), known liver dysfunction, known renal impairment, Duchenne's muscular dystrophy, active Graves disease or hyperthyroidism, and untreated hypothyroidism Estimated glomerular filtration rate (eGFR) < 90 AST and/or ALT greater than 1.5 times the upper limit of normal Need to use of any of the following medications during the study: beta blocker, seizure medication (carbamazepine, phenobarbital, phenytoin), other antihypertensive medications, HMG-CoA reductase inhibitors, lithium, theophylline, clonidine, or aspirin Any known hypersensitivity reaction to Verapamil

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 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: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: HCL and placebo<br>Participants assigned to HCL group will initially be randomly assigned 1:1 to use either the Tandem t:slim X2 with Control-IQ technology or a Medtronic HCL system (Medtronic 670G 4.0 AHCL (prior to protocol version 5.0) or Medtronic 780G (starting with protocol version 5.0)). This group will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations. Placebo will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets. Whether drug is active or placebo is blinded to both participant and site. [Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.] | Device: HCL<br>* Hybrid Closed Loop therapy<br>Drug: placebo<br>* placebo pill manufactured to mimic verapamil 120mg tablet<br>|
| Active Comparator: HCL and verapamil<br>Participants assigned to HCL group will initially be randomly assigned 1:1 to use either the Tandem t:slim X2 with Control-IQ technology or a Medtronic HCL system (Medtronic 670G 4.0 AHCL (prior to protocol version 5.0) or Medtronic 780G (starting with protocol version 5.0)). This group will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations. Verapamil will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets. Whether drug is active or placebo is blinded to both participant and site. [Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.] | Device: HCL<br>* Hybrid Closed Loop therapy<br>Drug: verapamil 120mg tablet<br>* verapamil tablet<br>|
| Active Comparator: non-HCL and verapamil<br>Participants assigned to non-HCL will receive a Dexcom G6 CGM and diabetes management will follow usual care by their personal diabetes health care provider. Verapamil will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets. Whether drug is active or placebo is blinded to both participant and site. [Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.] | Drug: verapamil 120mg tablet<br>* verapamil tablet<br>Device: non-HCL<br>* Usual diabetes care<br>|
| Placebo Comparator: non-HCL and placebo<br>Participants assigned to non-HCL will receive a Dexcom G6 CGM and diabetes management will follow usual care by their personal diabetes health care provider. Placebo will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets. Whether drug is active or placebo is blinded to both participant and site. [Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.] | Device: non-HCL<br>* Usual diabetes care<br>Drug: placebo<br>* placebo pill manufactured to mimic verapamil 120mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide | The primary outcome is the C-peptide in response to a 2-hour MMTT at 52 weeks. This is measured as the area under the stimulated C-peptide curve (AUC). AUC is computed using a trapezoidal rule, which is a weighted sum of the C-peptide values over the 120 min. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide AUC | C-peptide AUC between treatment groups | 13, 26 and 39 weeks | 
| Peak C-peptide | Maximum of all C-peptide values during the MMTT | 13, 26, 39 weeks and 1 year | 
| Peak C-peptide >= 0.2 pmol/ml | Percentage where maximum of all C-peptide values during the MMTT >= 0.2 pmol/ml | 13, 26, 39 weeks and 1 year | 
| CGM Mean Glucose | Mean glucose between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time in range (70-180 mg/dL) | CGM sensor glucose values from 70 to 180 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time 70-140 mg/dL | CGM sensor glucose values from 70 to 140 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| >=70% CGM time in range | Percentage of patients with >=70% sensor glucose values from 70 to 180 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time >140 mg/dL | CGM sensor glucose values >140 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time >180 mg/dL | CGM sensor glucose values >180 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time >250 mg/dL | CGM sensor glucose values >250 mg/dL between treatment groups | 1 year | 
| CGM time <54 mg/dL | CGM sensor glucose values <54 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM time <70 mg/dL | CGM sensor glucose values <70 mg/dL between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| CGM coefficient of variation | Coefficient of variation between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| HbA1c | HbA1c between treatment groups | 13, 26, 39 weeks and 1 year | 
| HbA1c <7.0% | Percentage of patients with HbA1c < 7.0% between treatment groups | 13, 26, 39 weeks and 1 year | 
| HbA1c <6.5% | Percentage of patients with HbA1c < 6.5% between treatment groups | 13, 26, 39 weeks and 1 year | 
| Total daily insulin per kg | Total daily insulin per kg between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| Basal:Bolus ratio | Ratio of basal:bolus insulin between treatment groups | 6, 13, 26, 39 weeks and 1 year | 
| Severe Hypoglycemia | Frequency of episodes of severe hypoglycemia between treatment groups | 1 year | 
| DKA | Frequency of episodes of DKA between treatment groups | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hybrid closed loop, hcl, new onset, verapamil, beta cell, diabetes, children, T1D, c-peptide, pediatric