NCT04233034 · REGISTRY CONDITION SEARCH

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

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2024-11-27

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

C-peptide Area Under the Curve (AUC)

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outcome · POSTED

C-peptide AUC

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outcome · POSTED

Peak C-peptide

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outcome · POSTED

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

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outcome · POSTED

CGM Mean Glucose

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outcome · POSTED

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

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outcome · POSTED

Percentage of CGM Time in Range 70-140 mg/dL

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outcome · POSTED

Number of Participants With CGM Time in Range 70-180 mg/dL >=70% at 52 Weeks

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outcome · POSTED

Percentage of CGM Time >140 mg/dL

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outcome · POSTED

Percentage of CGM Time >180 mg/dL

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outcome · POSTED

Percentage of CGM Time >250 mg/dL

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outcome · POSTED

Percentage of CGM Time <54 mg/dL

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outcome · POSTED

Percentage of CGM Time <70 mg/dL

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outcome · POSTED

CGM Coefficient of Variation

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outcome · POSTED

HbA1c

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outcome · POSTED

Number of Participants With HbA1c <7.0%

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outcome · POSTED

Number of Participants With HbA1c <6.5%

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outcome · POSTED

Total Daily Insulin Per kg

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outcome · POSTED

Basal:Bolus Ratio

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outcome · POSTED

Severe Hypoglycemia

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outcome · POSTED

DKA

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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
healthy Volunteers: false
maximum Age: 17 Years
minimum Age: 7 Years
sex: ALL
std Ages: CHILD

Treatment arms and interventions

arm Groups

description
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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
intervention Names
Device: HCL
Drug: placebo
label
HCL and placebo
type
ACTIVE_COMPARATOR
description
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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
intervention Names
Device: HCL
Drug: verapamil 120mg tablet
label
HCL and verapamil
type
ACTIVE_COMPARATOR
description
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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
intervention Names
Drug: verapamil 120mg tablet
Device: non-HCL
label
non-HCL and verapamil
type
ACTIVE_COMPARATOR
description
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. \[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]
intervention Names
Device: non-HCL
Drug: placebo
label
non-HCL and placebo
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
HCL and placebo
HCL and verapamil
description
Hybrid Closed Loop therapy
name
HCL
type
DEVICE
arm Group Labels
HCL and verapamil
non-HCL and verapamil
description
verapamil tablet
name
verapamil 120mg tablet
type
DRUG
arm Group Labels
non-HCL and placebo
non-HCL and verapamil
description
Usual diabetes care
name
non-HCL
type
DEVICE
arm Group Labels
HCL and placebo
non-HCL and placebo
description
placebo pill manufactured to mimic verapamil 120mg tablet
name
placebo
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

FACTORIAL

masking Info

masking: TRIPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR

primary Purpose

TREATMENT

Enrollment

count: 113
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
C-peptide Area Under the Curve (AUC)
time Frame
52 weeks

secondary Outcomes

description
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.
measure
C-peptide AUC
time Frame
13, 26 and 39 weeks
description
Maximum of all C-peptide values during the MMTT
measure
Peak C-peptide
time Frame
13, 26, 39 weeks and 52 weeks
description
Percentage where maximum of all C-peptide values during the MMTT \>= 0.2 pmol/ml
measure
Number of Participants With a Peak C-peptide >= 0.2 Pmol/ml
time Frame
13, 26, 39 weeks and 52 weeks
description
Mean glucose between treatment groups
measure
CGM Mean Glucose
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
CGM sensor glucose values from 70 to 180 mg/dL between treatment groups
measure
Percentage of CGM Time in Range (70-180 mg/dL)
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
Percentage of CGM sensor glucose values from 70 to 140 mg/dL between treatment groups
measure
Percentage of CGM Time in Range 70-140 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
Percentage of patients with \>=70% sensor glucose values from 70 to 180 mg/dL between treatment groups
measure
Number of Participants With CGM Time in Range 70-180 mg/dL >=70% at 52 Weeks
time Frame
52 Weeks
description
CGM sensor glucose values \>140 mg/dL between treatment groups
measure
Percentage of CGM Time >140 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
CGM sensor glucose values \>180 mg/dL between treatment groups
measure
Percentage of CGM Time >180 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
Percentage of CGM sensor glucose values \>250 mg/dL between treatment groups
measure
Percentage of CGM Time >250 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
Percentage of CGM sensor glucose values \<54 mg/dL between treatment groups
measure
Percentage of CGM Time <54 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks
description
Percentage of CGM sensor glucose values \<70 mg/dL between treatment groups
measure
Percentage of CGM Time <70 mg/dL
time Frame
6, 13, 26, 39 weeks and 52 weeks

Full study description

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.

Source references

references

citation
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
type
DERIVED
citation
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
type
DERIVED
citation
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
type
DERIVED

Source notices and limitations

Discovery and provenance

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Preserved source evidence · Not medical advice