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

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ClinicalTrials.gov Identifier: NCT04233034
Recruitment Status : Recruiting
First Posted : January 18, 2020
Last Update Posted : August 19, 2020
Sponsor:
Collaborators:
Juvenile Diabetes Research Foundation
University of Minnesota
DexCom, Inc.
Medtronic
Tandem Diabetes Care, Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Type1 Diabetes Device: HCL Drug: verapamil 120mg tablet Device: non-HCL Drug: placebo Phase 3

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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 131 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New Onset Type 1 Diabetes (CLVer)
Actual Study Start Date : July 9, 2020
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Active Comparator: HCL and 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 the Medtronic 670G 4.0 AHCL. 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
Hybrid Closed Loop therapy

Drug: placebo
placebo pill manufactured to mimic verapamil 120mg tablet

Active Comparator: HCL and verapamil

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 the Medtronic 670G 4.0 AHCL. 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
Hybrid Closed Loop therapy

Drug: verapamil 120mg tablet
verapamil tablet

Active Comparator: non-HCL and verapamil

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
verapamil tablet

Device: non-HCL
Usual diabetes care

Placebo Comparator: non-HCL and 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.]

Device: non-HCL
Usual diabetes care

Drug: placebo
placebo pill manufactured to mimic verapamil 120mg tablet




Primary Outcome Measures :
  1. C-peptide [ Time Frame: 1 year ]
    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.


Secondary Outcome Measures :
  1. CGM Mean Glucose [ Time Frame: 1 year ]
    mean glucose between treatment groups

  2. CGM coefficient of variation [ Time Frame: 1 year ]
    coefficient of variation between treatment groups

  3. CGM time in range [ Time Frame: 1 year ]
    time 70-180 mg/dL between treatment groups

  4. CGM time <70 mg/dL [ Time Frame: 1 year ]
    time <70 mg/dL between treatment groups

  5. CGM time <54 mg/dL [ Time Frame: 1 year ]
    time <54 mg/dL between treatment groups

  6. CGM time >180 mg/dL [ Time Frame: 1 year ]
    time >180 mg/dL between treatment groups

  7. CGM time >250 mg/dL [ Time Frame: 1 year ]
    time >250 mg/dL between treatment groups

  8. HbA1c [ Time Frame: 1 year ]
    HbA1c between treatment groups

  9. Hypoglycemia [ Time Frame: 1 year ]
    Frequency of episodes of severe hypoglycemia between treatment groups

  10. DKA [ Time Frame: 1 year ]
    Frequency of episodes of DKA between treatment groups



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   7 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04233034


Contacts
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Contact: CLVer CC Protocol Monitor, Diana Rojas, CCRP 813-975-8690 drojas@jaeb.org
Contact: CLVer CC Director, Stephanie DuBose, MPH, CCRP 813-975-8690 sdubose@jaeb.org

Locations
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United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94305
Contact: Eliana Frank    650-721-8782    elianaf@stanford.edu   
Principal Investigator: Bruce Buckingham, MD         
United States, Colorado
Barbara Davis Center Recruiting
Boulder, Colorado, United States, 80309
Contact: Lindsey Towers, BA    303-724-8620    Lindsey.towers@cuanschutz.edu   
Principal Investigator: Gregory Forlenza, MD         
United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Amy Steffen    203-737-8852    Amy.steffen@yale.edu   
Principal Investigator: Jennifer Sherr, MD         
United States, Indiana
Indiana University Recruiting
Bloomington, Indiana, United States, 47405
Contact: Jill Kapturowski       jkapturo@iu.edu   
Principal Investigator: Linda DiMeglio, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Jennifer McVean, MD    612-626-3583    mcvea004@umn.edu   
Contact: Shannon Beasley, APRN, CPNP    612-626-5609    beasl103@umn.edu   
Principal Investigator: Antoinette Moran, MD         
United States, Missouri
Children's Mercy Hospital Recruiting
Kansas City, Missouri, United States, 64108
Contact: Erica Livingston    816-960-8941 ext 68941    eelivingston@cmh.edu   
Principal Investigator: Mark Clements, MD         
Sponsors and Collaborators
Jaeb Center for Health Research
Juvenile Diabetes Research Foundation
University of Minnesota
DexCom, Inc.
Medtronic
Tandem Diabetes Care, Inc.
Investigators
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Study Chair: Antoinette Moran, MD University of Minnesota
Study Chair: Jennifer McVean, MD University of Minnesota
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Responsible Party: Jaeb Center for Health Research
ClinicalTrials.gov Identifier: NCT04233034    
Other Study ID Numbers: CLVer
First Posted: January 18, 2020    Key Record Dates
Last Update Posted: August 19, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by Jaeb Center for Health Research:
new onset
verapamil
hybrid closed loop
hcl
beta cell
diabetes
children
T1D
c-peptide
pediatric
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents