Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New Onset Type 1 Diabetes (CLVer)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 113
- 试验地点
- 6
- 主要终点
- C-peptide Area Under the Curve (AUC)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 7 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
- •Participant
排除标准
- •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
- •Additional exclusion criteria for Cohort A:
- •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
研究组 & 干预措施
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 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.]
干预措施: HCL (Device)
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 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.]
干预措施: placebo (Drug)
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 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.]
干预措施: HCL (Device)
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 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.]
干预措施: verapamil 120mg tablet (Drug)
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.]
干预措施: verapamil 120mg tablet (Drug)
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.]
干预措施: non-HCL (Device)
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.]
干预措施: non-HCL (Device)
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.]
干预措施: placebo (Drug)
结局指标
主要结局
C-peptide Area Under the Curve (AUC)
时间窗: 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.
次要结局
- 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)
- HbA1c(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)
- Percentage of CGM Time in Range 70-140 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- Number of Participants With CGM Time in Range 70-180 mg/dL >=70% at 52 Weeks(52 Weeks)
- Percentage of CGM Time >140 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- Percentage of CGM Time >180 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- Percentage of CGM Time >250 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- Percentage of CGM Time <54 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- Percentage of CGM Time <70 mg/dL(6, 13, 26, 39 weeks and 52 weeks)
- CGM Coefficient of Variation(6, 13, 26, 39 weeks and 52 weeks)
- Number of Participants With HbA1c <7.0%(13, 26, 39 weeks and 52 weeks)
- Number of Participants With HbA1c <6.5%(13, 26, 39 weeks and 52 weeks)
- Total Daily Insulin Per kg(6, 13, 26, 39 weeks and 52 weeks)
- Basal:Bolus Ratio(6, 13, 26, 39 weeks and 52 weeks)
- Severe Hypoglycemia(52 weeks)
- DKA(52 weeks)