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

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

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.

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.

• Participant Inclusion Criteria:

  1. 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)
  2. At least one positive type 1 diabetes auto-antibody
  3. Age 7 - <18 years at the time of enrollment
  4. Willing to have a parent or legal guardian provide informed consent and child assent
  5. In a female participant with childbearing potential, not currently pregnant and willing to avoid pregnancy and breastfeeding and undergo pregnancy testing throughout the study
  6. English speaking/reading
  7. Able to swallow pills (tested with an inert imitation tablet in clinic prior to randomization)
  8. Willing to not use any non-insulin glucose-lowering agents
  9. Willing to use an insulin approved for the pump (if assigned to HCL)
  10. Willing to avoid medications containing acetaminophen, and no contraindications for ibuprofen use (in case assigned to Medtronic HCL system)

• Participant Exclusion Criteria:

  1. Ongoing use of medications known to influence glucose tolerance such as systemic steroids

  2. Other systemic disease which in the opinion of the investigator precludes participation (including psychiatric illness)

  3. 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

  4. "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

  5. Participation in another research study that involves diabetes care

• Additional exclusion criteria for Cohort A:

  1. Blood pressure (either systolic or diastolic) <5th percentile for age, gender, and height on two out of three measurements
  2. Pulse <2nd percentile for age and gender on two out of three measurements
  3. History of vasovagal syncopal episodes related to hypotension
  4. Abnormal EKG rhythm unless cleared for study participation by a cardiologist
  5. 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
  6. Estimated glomerular filtration rate (eGFR) < 90
  7. AST and/or ALT greater than 1.5 times the upper limit of normal
  8. 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
  9. Any known hypersensitivity reaction to Verapamil