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

Phase 3

Completed

• Conditions: Type1 Diabetes
• Interventions: Drug: verapamil 120mg tablet; Device: HCL; Drug: placebo; Device: non-HCL

• Registration Number: NCT04233034
• Lead Sponsor: Jaeb Center for Health Research

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-01-14
• Study First Submitted QC: 2020-01-15
• Study First Posted: 2020-01-18
• Study Start: 2020-07-09
• Primary Completion: 2022-09-15
• Study Completion: 2022-09-30
• Results First Submitted: 2024-03-15
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-20
• Last Update Submitted: 2024-11-20
• Results First Posted: 2024-11-27
• Last Update Posted: 2024-11-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 113

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
non-HCL and verapamil	verapamil 120mg tablet	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
HCL and placebo	placebo	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
HCL and verapamil	HCL	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
HCL and placebo	HCL	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
HCL and verapamil	verapamil 120mg tablet	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
non-HCL and verapamil	non-HCL	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
non-HCL and placebo	non-HCL	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
non-HCL and placebo	placebo	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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]

Primary Outcome Measures

Name	Time	Method
C-peptide Area Under the Curve (AUC)	52 weeks	The primary outcome is the C-peptide in response to a 2-hour MMTT at 52 weeks. C-peptide was measured at 0, 15, 30, 45, 60, 90, and 120 minutes following the start of the mixed meal tolerance test (MMTT). This is summarized 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.

Secondary Outcome Measures

Name	Time	Method
Percentage of CGM Time >140 mg/dL	6, 13, 26, 39 weeks and 52 weeks	CGM sensor glucose values \>140 mg/dL between treatment groups
Percentage of CGM Time >180 mg/dL	6, 13, 26, 39 weeks and 52 weeks	CGM sensor glucose values \>180 mg/dL between treatment groups
C-peptide AUC	13, 26 and 39 weeks	C-peptide AUC between treatment groups. C-peptide was measured at 0, 15, 30, 45, 60, 90, and 120 minutes following the start of the mixed meal tolerance test (MMTT). This is summarized 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.
Peak C-peptide	13, 26, 39 weeks and 52 weeks	Maximum of all C-peptide values during the MMTT
Number of Participants With a Peak C-peptide >= 0.2 Pmol/ml	13, 26, 39 weeks and 52 weeks	Percentage where maximum of all C-peptide values during the MMTT \>= 0.2 pmol/ml
CGM Mean Glucose	6, 13, 26, 39 weeks and 52 weeks	Mean glucose between treatment groups
Percentage of CGM Time in Range (70-180 mg/dL)	6, 13, 26, 39 weeks and 52 weeks	CGM sensor glucose values from 70 to 180 mg/dL between treatment groups
Percentage of CGM Time in Range 70-140 mg/dL	6, 13, 26, 39 weeks and 52 weeks	Percentage of CGM sensor glucose values from 70 to 140 mg/dL between treatment groups
Number of Participants With CGM Time in Range 70-180 mg/dL >=70% at 52 Weeks	52 Weeks	Percentage of patients with \>=70% sensor glucose values from 70 to 180 mg/dL between treatment groups
Percentage of CGM Time >250 mg/dL	6, 13, 26, 39 weeks and 52 weeks	Percentage of CGM sensor glucose values \>250 mg/dL between treatment groups
Percentage of CGM Time <54 mg/dL	6, 13, 26, 39 weeks and 52 weeks	Percentage of CGM sensor glucose values \<54 mg/dL between treatment groups
Percentage of CGM Time <70 mg/dL	6, 13, 26, 39 weeks and 52 weeks	Percentage of CGM sensor glucose values \<70 mg/dL between treatment groups
CGM Coefficient of Variation	6, 13, 26, 39 weeks and 52 weeks	Coefficient of variation between treatment groups. Calculated as the standard deviation of CGM glucose values divided by the mean of CGM glucose values.
HbA1c	13, 26, 39 weeks and 52 weeks	HbA1c between treatment groups
Number of Participants With HbA1c <7.0%	13, 26, 39 weeks and 52 weeks	Percentage of participants with HbA1c \< 7.0% between treatment groups
Number of Participants With HbA1c <6.5%	13, 26, 39 weeks and 52 weeks	Percentage of participants with HbA1c \< 6.5% between treatment groups
Total Daily Insulin Per kg	6, 13, 26, 39 weeks and 52 weeks	Total daily insulin per kg between treatment groups
Basal:Bolus Ratio	6, 13, 26, 39 weeks and 52 weeks	Ratio of basal:bolus insulin between treatment groups
Severe Hypoglycemia	52 weeks	Frequency of episodes of severe hypoglycemia between treatment groups
DKA	52 weeks	Frequency of episodes of DKA between treatment groups

Trial Locations

Locations (6)

Indiana University; 🇺🇸 Indianapolis, Indiana, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Barbara Davis Center; 🇺🇸 Aurora, Colorado, United States

Yale University; 🇺🇸 New Haven, Connecticut, United States

Children's Mercy Hospital; 🇺🇸 Kansas City, Missouri, United States