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

NCT04233034 | Completed Phase 3 Results DMC FDA Drug FDA Device

• 1 other identifier: CLVer
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 6

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.

Conditions

Type1 Diabetes

Keywords

new onset; verapamil; hybrid closed loop; hcl; beta cell; diabetes; children; T1D; c-peptide; pediatric

Outcome Measures

Primary Outcomes (1)

• C-peptide Area Under the Curve (AUC)

  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.

  52 weeks

Secondary Outcomes (20)

• C-peptide AUC

  13, 26 and 39 weeks

• Peak C-peptide

  13, 26, 39 weeks and 52 weeks

• Number of Participants With a Peak C-peptide >= 0.2 Pmol/ml

  13, 26, 39 weeks and 52 weeks

• CGM Mean Glucose

  6, 13, 26, 39 weeks and 52 weeks

• Percentage of CGM Time in Range (70-180 mg/dL)

  6, 13, 26, 39 weeks and 52 weeks

Study Arms (4)

HCL and placebo

ACTIVE COMPARATOR

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; Drug: placebo

HCL and verapamil

ACTIVE COMPARATOR

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; Drug: verapamil 120mg tablet

non-HCL and verapamil

ACTIVE COMPARATOR

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; Device: non-HCL

non-HCL and placebo

PLACEBO COMPARATOR

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; Drug: placebo

Interventions

HCL DEVICE

Hybrid Closed Loop therapy

HCL and placebo; HCL and verapamil

verapamil 120mg tablet DRUG

verapamil tablet

HCL and verapamil; non-HCL and verapamil

non-HCL DEVICE

Usual diabetes care

non-HCL and placebo; non-HCL and verapamil

placebo DRUG

placebo pill manufactured to mimic verapamil 120mg tablet

HCL and placebo; non-HCL and placebo

Eligibility Criteria

• Age: 7 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Jaeb Center for Health Research: lead
• Juvenile Diabetes Research Foundation: collaborator
• University of Minnesota: collaborator
• DexCom, Inc.: collaborator
• Medtronic: collaborator
• Tandem Diabetes Care, Inc.: collaborator

Study Sites (6)

Stanford University

Palo Alto, California, 94304, United States

Location

Barbara Davis Center

Aurora, Colorado, 80045, United States

Location

Yale University

New Haven, Connecticut, 06511, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64111, United States

Location

Related Publications (3)

• Ekhlaspour L, Buckingham B, Bauza C, Clements M, Forlenza GP, Neyman A, Norlander L, Schamberger M, Sherr JL, Bailey R, Beck RW, Kollman C, Beasley S, Cobry E, DiMeglio LA, Paprocki E, Van Name M, Moran A; CLVer Study Group. Safety and prescribing recommendations for verapamil in newly diagnosed pediatric type 1 diabetes (T1D): The CLVer experience. J Clin Transl Endocrinol. 2024 May 18;36:100352. doi: 10.1016/j.jcte.2024.100352. eCollection 2024 Jun.

  PMID: 38860154 DERIVED

• Forlenza GP, McVean J, Beck RW, Bauza C, Bailey R, Buckingham B, DiMeglio LA, Sherr JL, Clements M, Neyman A, Evans-Molina C, Sims EK, Messer LH, Ekhlaspour L, McDonough R, Van Name M, Rojas D, Beasley S, DuBose S, Kollman C, Moran A; CLVer Study Group. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2023 Mar 28;329(12):990-999. doi: 10.1001/jama.2023.2064.

  PMID: 36826844 DERIVED

• McVean J, Forlenza GP, Beck RW, Bauza C, Bailey R, Buckingham B, DiMeglio LA, Sherr JL, Clements M, Neyman A, Evans-Molina C, Sims EK, Messer LH, Ekhlaspour L, McDonough R, Van Name M, Rojas D, Beasley S, DuBose S, Kollman C, Moran A; CLVer Study Group. Effect of Tight Glycemic Control on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2023 Mar 28;329(12):980-989. doi: 10.1001/jama.2023.2063.

  PMID: 36826834 DERIVED

MeSH Terms

Conditions

Leukemia, Hairy Cell; Diabetes Mellitus

Interventions

Verapamil; Tablets

Condition Hierarchy (Ancestors)

Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Colleen Bauza
• Organization: Jaeb Center for Health Research

cbauza@jaeb.org

813-975-8690

Study Officials

• Antoinette Moran, MD

  University of Minnesota

  STUDY CHAIR

• Gregory Forlenza, MD

  Barbara Davis Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2020
• First Posted: January 18, 2020
• Study Start: July 9, 2020
• Primary Completion: September 15, 2022
• Study Completion: September 30, 2022
• Last Updated: November 27, 2024
• Results First Posted: November 27, 2024

Record last verified: 2024-11

Locations

US (6)