Objective
The objective of the CLVerEX extension study is to continue following the participants who completed CLVer for three additional years, to evaluate the longer-term effects of the interventions on preservation of β-cell function as measured by C-peptide levels obtained during a mixed meal tolerance test (MMTT), and to determine if the excellent time-in-range that was achieved during CLVer can be maintained once intensive engagement with the research team is discontinued. At the completion of CLVer, study treatments ended. Thus, during the extension study diabetes management is performed as part of usual care and there is no study-specific treatment.
Background Rationale
This project is highly significant because of the critical need to develop therapies to preserve β-cell function in new onset T1D, especially in the pediatric population where autoimmune cellular destruction is most aggressive. Traditionally, new-onset trials have used immunomodulatory therapies in an attempt to induce immune tolerance. For example, teplizumab has been shown in multiple studies to reduce loss of β-cell function in patients with newly diagnosed T1D. The impact was strongest during the first year after therapy, but significant differences in c-peptide levels persisted between patients who received teplizumab and placebo-treated patients as long as 7 years after treatment. Enthusiasm for teplizumab and other immunomodulatory therapies has been tempered by concerns about immunosuppression of otherwise healthy children. As a potential β-cell preservation strategy, verapamil offers the prospect of an approach that does not expose children to the risk and uncertain long-term effects of immune manipulation, that is inexpensive, and that had an excellent safety profile during CLVer. It is now important to assess whether there is persistence of this beneficial effect over time.
In the case of the younger children in Cohort B, we achieved substantially higher time-in-range over the course of the year than has been previously reported. This may have been due to training these families and setting up expectations early in the course of diabetes, and/or to the intensive involvement of the research team. Following these patients for 3 years after the end of CLVer will demonstrate whether these early gains persist once the research team is no longer intensively involved. Persistence of metabolic control can be expected to result in fewer long term complications.
The CLVer study participants put us in a singular position to evaluate the longer term impact of these two approaches. The study team consists of experienced T1D clinical research centers and investigators who have the knowledge and experience to perform this study, who already have a standing relationship with study participants, and who have the infrastructure in place for seamless transition into the extension study.
Description of Project
CLVer was a randomized clinical trial (RCT) of youth aged 7-<18 years with newly diagnosed stage 3 type 1 diabetes, 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) were 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) were randomly assigned 2:1 in a parallel group design to HCL plus intensive diabetes management or to usual care with no HCL. CLVer randomized 111 subjects, 86 in Cohort A and 25 in Cohort B excluding two Cohort A subjects who dropped post-randomization. The first patient was randomized in July 2020, and the final patient completed the one year intervention in September, 2022.
Anticipated Outcome
We hypothesize that differences in β-cell function and glycemic control observed at the end of the 1 year CLVer study between subjects that received active treatment versus control subjects will be maintained over 3 years of follow-up.
Relevance to T1D
Because children and adolescents have the greatest risk for rapid T1D disease progression as measured by loss of residual C-peptide secretion, it is critical that intervention studies target the pediatric population. While incident T1D can occur at any age, the natural history and burden of disease is different in those diagnosed as children compared to those diagnosed as adults. T1D diagnosed in adulthood is characterized by a longer asymptomatic period before diagnosis and increased likelihood of preservation of residual β-cell function compared to the natural course of youth diagnosed with this chronic condition.