Endocrinology and Metabolism (original) (raw)

Original Article

Efficacy and Safety of Stage 5 Connected Insulin Pens in Type 1 or Type 2 Diabetes: Randomized Controlled Trial Protocol

[Ji Yoon Kim](/articles/search%5Fresult.php?term%5Ftype=authors&term=Ji Yoon Kim)1, [Nam Hoon Kim](/articles/search%5Fresult.php?term%5Ftype=authors&term=Nam Hoon Kim)2, [Soo Heon Kwak](/articles/search%5Fresult.php?term%5Ftype=authors&term=Soo Heon Kwak)3, [Chang Hee Jung](/articles/search%5Fresult.php?term%5Ftype=authors&term=Chang Hee Jung)4, [Eun Seok Kang](/articles/search%5Fresult.php?term%5Ftype=authors&term=Eun Seok Kang)5, [Jun Sung Moon](/articles/search%5Fresult.php?term%5Ftype=authors&term=Jun Sung Moon)6, [Sun Joon Moon](/articles/search%5Fresult.php?term%5Ftype=authors&term=Sun Joon Moon)7, [So Yoon Kwon](/articles/search%5Fresult.php?term%5Ftype=authors&term=So Yoon Kwon)8, [Jee Hee Yoo](/articles/search%5Fresult.php?term%5Ftype=authors&term=Jee Hee Yoo)9, [Younghoon Kim](/articles/search%5Fresult.php?term%5Ftype=authors&term=Younghoon Kim)10, [Tae-min Lee](/articles/search%5Fresult.php?term%5Ftype=authors&term=Tae-min Lee)11, [Chung-il Yang](/articles/search%5Fresult.php?term%5Ftype=authors&term=Chung-il Yang)12, [Jae Hyeon Kim](/articles/search%5Fresult.php?term%5Ftype=authors&term=Jae Hyeon Kim)1,10, [Sang-Man Jin](/articles/search%5Fresult.php?term%5Ftype=authors&term=Sang-Man Jin)1

DOI: https://doi.org/10.3803/EnM.2025.2579
Published online: December 12, 2025

1Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

3Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

4Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

5Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea

6Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

7Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

8Division of Endocrinology and Metabolism, Department of Internal Medicine, Daegu Catholic University Medical Center, Daegu, Korea

9Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Korea

10Glucometrics Co., Ltd., Seoul, Korea

11Division of Advanced Technology, G2E Co., Ltd., Seoul, Korea

12Division of Product Development, G2E Co., Ltd., Seoul, Korea

Corresponding authors: Sang-Man Jin. Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-0271, Fax: +82-2-3410-6983, E-mail: sangman.jin@samsung.com

Jae Hyeon Kim. Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-1580, Fax: +82-2-3410-6983, E-mail: jaehyeon@skku.edu

• Received: July 26, 2025 • Revised: September 23, 2025 • Accepted: October 13, 2025

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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ABSTRACT

• Background
  Stage 2 or 3 connected insulin pens (CIPs) refer to tracking insulin pens that are capable of transmitting insulin dose data via cloud connectivity. Stage 4 CIPs feature a bolus calculator that determines appropriate insulin doses based on real-time continuous glucose monitoring (CGM) data, carbohydrate intake, previous dosing history, and preset parameters. Stage 5 CIPs additionally offer advanced decision-support features, such as education modules and coaching. However, the efficacy and safety of Stage 5 CIPs have not yet been established.
• Methods
  In this prospective, open-label, parallel-group, multicenter, randomized controlled trial, we will include adults aged ≥19 and <75 years with type 1 or type 2 diabetes receiving multiple daily insulin injections (MDI) and having glycosylated hemoglobin (HbA1c) levels of 7.5% to 12.0%. In total, 152 participants will be randomized in a 1:1 ratio to receive either Stage 5 CIPs with CGM or tracking insulin pens with CGM. Stage 5 CIPs include a Setup Wizard that recommends individualized initial settings and an algorithm that provides advanced insulin dosing guidance based on analyses of each participant’s CGM and insulin injection data. The primary outcome will be the change in HbA1c levels from baseline to week 12 (ClinicalTrials.gov, NCT07004153).
• Conclusion
  This trial will determine whether Stage 5 CIPs are superior to tracking insulin pens in improving glycemic control among adults with type 1 or type 2 diabetes treated with MDI. Overall, this study may offer a promising strategy for enhancing the management and outcomes of patients with diabetes.
• Keywords: Smart insulin pen; Connected insulin pen; Continuous glucose monitoring; Multiple daily insulin injections; Diabetes mellitus, type 1; Diabetes mellitus, type 2

GRAPHICAL ABSTRACT

INTRODUCTION

Multiple daily insulin injection (MDI) therapy, which involves the administration of both basal and bolus insulin, is a critical treatment approach for individuals with diabetes who have impaired insulin secretion [1,2]. However, determining the appropriate dosage of bolus insulin can be challenging as it requires the consideration of multiple variables, including carbohydrate intake and blood glucose levels. Further, the complexity of these calculations often leads to inaccurate dosing, resulting in postprandial hyperglycemia or hypoglycemia [3-5].

In contrast to stage 2–3 connected insulin pens (CIPs), which refer to tracking insulin pens capable of transmitting insulin dose data via cloud connectivity, smart insulin pens (SIPs; stage 4–5 CIPs) feature a bolus calculator that automatically calculates the appropriate bolus insulin dose. It utilizes real-time glucose data from a continuous glucose monitoring (CGM) device, the amount of carbohydrates consumed, and preset parameters, such as the insulin-to-carbohydrate ratio (ICR), insulin sensitivity factor (ISF), target glucose levels, and duration of insulin action (DIA) [6-10]. In addition, because SIPs track the insulin dosing history, they automatically subtract the insulin on board (IOB), enabling more accurate dose recommendations. Stage 4 CIPs (with a dose calculator) and stage 5 CIPs are categorized as SIPs; the latter additionally offers advanced decision-support features, such as weight-based setup, basal insulin titration, clinical variable learning, educational modules, and personalized coaching [6-8]. However, the efficacy and safety of stage 5 CIPs have not yet been established.

Thus, through this multicenter trial, we aim to evaluate the efficacy and safety of stage 5 CIPs with advanced decision support in comparison with tracking insulin pens for improving glycemic control in adults with type 1 or type 2 diabetes treated with MDI.

METHODS

Study design

In this prospective, open-label, parallel-group, multicenter, randomized controlled trial (RCT), the efficacy and safety of electric SIPs with advanced decision support (stage 5 CIPs) will be compared with those of tracking insulin pens in adults with type 1 or type 2 diabetes treated with MDI. The overall study design is shown in Fig. 1.

This study was approved by the Institutional Review Boards of all participating centers, including the Samsung Medical Center (IRB number: SMC 2025-02-020). The study protocol complies with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. This trial was registered at ClinicalTrials.gov (registration no. NCT07004153).

Participants

Participants will be recruited from nine medical centers (university hospitals) in South Korea. Adults aged ≥19 and <75 years who have been diagnosed with type 1 or type 2 diabetes at least 1 year prior to screening, have been receiving MDI for at least 3 months, and have glycosylated hemoglobin (HbA1c) levels between 7.5% and 12.0% will be eligible for inclusion in the study. MDI therapy is defined as the daily administration of long-acting or ultra-long-acting insulin in combination with rapid-acting or ultra-rapid-acting insulin injections. The use of a premixed formulation of ultra-long-acting and rapid-acting insulin (e.g., insulin degludec/insulin aspart) along with additional rapid-acting or ultra-rapid-acting insulin, or the use of premixed insulin degludec/insulin aspart ≥3 times per day, also qualifies as MDI therapy. Major exclusion criteria will include patients with an estimated glomerular filtration rate <15 mL/min/1.73 m², current dialysis treatment, or pregnancy. The eligibility criteria are summarized in Table 1. All participants will provide written informed consent prior to enrollment.

Run-in phase

After providing informed consent and confirming eligibility, the participants will undergo a run-in period lasting a minimum of 7 days and a maximum of 10.5 days, during which they will use a CGM device (Dexcom G7, Dexcom, San Diego, CA, USA) and tracking insulin pens (DIA:CONN P8, G2E, Seoul, Korea). DIA:CONN P8 is a commercially available stage 4 CIP equipped with a bolus calculator; however, during the run-in period, only its tracking and insulin injection functions will be used, and the bolus calculator will be disabled. Participants will be provided with two tracking insulin pens, one for basal insulin and one for bolus insulin, and will receive training on how to use the tracking insulin pens and the CGM device.

Only individuals with a sensor wear time of ≥70% during the run-in period who have injected basal insulin at least four times per week and bolus insulin at least once per day on average using the tracking insulin pen will be eligible for randomization.

Randomization

After completing the run-in phase, eligible participants will be randomized in a 1:1 ratio into either the intervention group (stage 5 CIP; SIP with advanced decision support) or the control group (tracking insulin pen). Stratified block randomization will be performed according to the diabetes type (determined by non-fasting C-peptide levels) using SAS version 9.4 or higher (SAS Institute, Cary, NC, USA) by an independent statistician not involved in this study. Central randomization will be conducted using an interactive web response system. Blinding will not be implemented due to the nature of the interventions.

Study procedure

Following randomization, the participants will use the stage 5 CIPs with CGM (intervention group) or the tracking insulin pens with CGM (control group) for 12 weeks. Study visits will occur at screening (visit 1), week 0 (visit 2; baseline), week 4 (visit 3), week 8 (visit 4), and week 12 (visit 5) (Table 2). Visit 4 will be conducted either in person or via telephone.

At screening, written informed consent will be obtained from the participants, and their age, sex, smoking history, medical and surgical history, and current medication usage will be assessed. Anthropometric measurements (height, weight, and body mass index), vital sign data, physical examination findings, and laboratory test results will be collected. Diabetes type will be classified based on non-fasting (within 5 hours of eating [11]) C-peptide levels, as the coaching algorithm will vary according to the insulin secretory function. Participants with a non-fasting C-peptide level ≥1.8 ng/mL (0.6 nmol/L) will be classified as having diabetes with relatively preserved β-cell function, while those with a level <1.8 ng/mL (0.6 nmol/L) will be classified as having diabetes with β-cell failure [12]. However, if the C-peptide levels are <1.8 ng/mL (0.6 nmol/L) and the concomitant blood glucose level is <70 mg/dL, repeat C-peptide measurements will be performed. Although the stratification factor is based on non-fasting C-peptide levels, diabetes types classified according to the diagnostic criteria of the Korean National Health Insurance Service [13] will also be reported. Eligible participants will then proceed to the run-in period as described above.

At the baseline visit, eligibility will be confirmed, and the eligible participants will be randomized. The intervention group will receive a CGM device (Dexcom G7) and an electric stage 5 CIP (DIA:CONN P8) equipped with a Setup Wizard, CGM-based advanced insulin injection coaching, and a bolus calculator. DIA:CONN P8 used in the intervention group is an enhanced version of the currently commercially available model, incorporating additional decision-support features. Details of stage 5 CIP are provided in the section below. The intervention group will receive education on the following: proper use of the CGM device and SIP, interpretation of coaching messages from the SIP application, interpretation of CGM data, carbohydrate counting, and adjustment of insulin dose and injection timing.

The control group will receive a CGM device (Dexcom G7) and tracking insulin pens, as used during the run-in period. Insulin doses and injection times will be recorded. The control group will receive education on the use of the CGM device and tracking pens, the concepts of meal and correction doses, ICR and ISF, and insulin dosing adjustment based on glucose levels and meal size. Educational sessions for both groups will be delivered at weeks 0, 4, and 8. The duration of each education session will be recorded.

For both groups, the basal insulin will be insulin glargine 100 U/mL (Lantus, Sanofi, Paris, France), while the bolus insulin may include insulin lispro (Humalog, Eli Lilly, Indianapolis, IN, USA), insulin aspart (either rapid-acting [NovoRapid, Novo Nordisk, Bagsværd, Denmark] or ultra-rapid-acting [Fiasp, Novo Nordisk]), and insulin glulisine (Apidra, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany), including during the run-in period. As in the run-in period, participants will use two electric insulin pens: one for basal insulin and one for bolus insulin.

At week 12 (end-of-study visit), laboratory tests, including HbA1c measurement, will be conducted. The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) [14] will be administered at weeks 0 and 12, whereas the Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) [15] will be assessed at week 12. Adverse events and medication usage will be evaluated at each visit. If any unresolved adverse events are observed at week 12, a safety follow-up visit may be conducted for up to 4 weeks after the last use of the investigational medical device.

Description of stage 5 CIP

DIA:CONN P8 is an electric SIP that connects to a smartphone application and provides bolus insulin dose recommendations based on user-defined settings, including target glucose, ICR, ISF, DIA, and peak action time. This application integrates CGM data, allowing real-time glucose levels and trends to be automatically factored into dosing calculations. In this trial, two bolus calculator modes will be available for estimating insulin doses for meals: (1) meal estimation mode, in which the insulin dose is preset for each meal (breakfast, lunch, dinner, and snacks) based on portion sizes (small, regular, and large); and (2) advanced carbohydrate counting mode, in which the insulin dose is calculated based on the user-entered carbohydrate amount, carbohydrate absorption rate, and ICR. In both modes, the correction dose and IOB will be incorporated into the total bolus insulin dose calculation.

Stage 5 CIP includes additional features: (1) a Setup Wizard that recommends initial settings for the bolus calculator based on body weight and total daily insulin dose; (2) daily CGM data analysis with coaching messages sent to users regarding appropriate insulin doses, injection timing, and carbohydrate counting; and (3) real-time guidance on insulin dosing if a missed bolus is suspected. The coaching algorithms were developed by Glucometrics Co. Ltd. (Seoul, Korea).

Specifically, the initial basal and bolus insulin doses will be determined based on the Wizard’s recommendations and confirmed by the study physician. The SIP application will send daily messages recommending the appropriate basal doses, ISF, ICR, and injection timing based on individual CGM data, along with educational materials. Basal insulin dose recommendations are derived from overnight glucose patterns by analyzing the slope of glucose change and applying each individual’s ISF (Fig. 2). Fig. 3 illustrates examples of coaching messages for ICR recommendations. ICR recommendations are generated by considering postprandial glucose levels 4 hours after prandial insulin administration, the target glucose level, ISF, carbohydrate intake, and IOB. If postprandial hyperglycemia or hypoglycemia is detected, the system generates coaching questions to help patients reflect on possible causes. Based on the patient’s responses, the application provides specific guidance, such as revised ICR recommendations. Coaching messages are also delivered for adjustments to both ISF and insulin injection timing, accompanied by related educational materials. If inaccurate carbohydrate counting is suspected, the application will suggest a corrected carbohydrate amount and provide the corresponding guidance. These messages will be sent each morning based on CGM data from the previous day.

Additionally, real-time insulin dose recommendations will be sent if a missed mealtime bolus is suspected. Fig. 4 presents the function of real-time insulin dose recommendations. If patients inject insulin after eating while still entering carbohydrate amounts as if the injection were administered preprandially, the conventional bolus calculator frequently recommends the full pre-meal dose in addition to a correction dose. Consequently, patients often receive an excessive amount of insulin, leading to hypoglycemic episodes. In stage 5 CIP, when preprandial administration of a mealtime insulin dose is suspected to have been missed, the system triggers a real-time insulin recommendation feature, which provides an adjusted insulin dose recommendation and thereby mitigates the risk of post-injection hypoglycemia. Participants can review and modify the suggested dose as necessary.

Study outcomes

The primary outcome is the change in HbA1c level from baseline to week 12 (Table 3). Secondary outcomes include the percentage of participants with HbA1c <7% at week 12; the percentage of time in range (TIR, 70–180 mg/dL) over the 12-week trial period; the percentage of time in tight range (70–140 mg/dL) over the 12-week trial period; the percentage of time below range (TBR) at <54 mg/dL over the 12-week trial period; the percentage of TBR at <70 mg/dL over the 12-week trial period; the percentage of time above range (TAR) at >180 mg/dL over the 12-week trial period; the percentage of TAR >250 mg/dL over the 12-week trial period; the mean glucose level and glucose management indicator over the 12-week trial period; and the coefficient of variation over the 12-week trial period. CGM metrics will only be reported for participants with a sensor wear time of at least 70%. The exploratory outcomes are summarized in Table 3. Safety outcomes will include adverse events, laboratory test results, vital signs, and physical examination findings.

Sample size calculation

A sample size of 68 participants per group has been calculated to provide at least 80% power to demonstrate the superiority of the stage 5 CIP over the tracking insulin pen, assuming a between-group difference in HbA1c of –0.41%, a standard deviation of 0.85%, and a one-sided significance level of 2.5% based on data from a previous trial [16]. The sample size will be increased to 76 participants per group to account for an anticipated 10% loss to follow-up. Accordingly, we aim to enroll 152 participants in this study.

Statistical analyses

The analyses will follow the intention-to-treat principle and will be conducted using two datasets: the full analysis set (FA set) and the per-protocol set (PP set). Primary efficacy analyses will be performed using the FA set, whereas the PP set will be used for supportive (auxiliary) analyses. The FA set will include participants who undergo randomization, use the investigational medical device and undergo blood glucose measurements, and have at least one subsequent HbA1c measurement. The PP set will include participants who do not violate the study protocol. Safety analyses will be conducted on the safety set, which will include participants who use the investigational medical device and undergo blood glucose measurements at least once. Missing HbA1c values in the FA set will be imputed using the last observation carried-forward method. However, if no post-baseline HbA1c data are available, missing values will not be imputed. All other analyses will be conducted using only the available data.

For the primary outcome, an analysis of covariance (ANCOVA) will be conducted using baseline values, study center, prior CGM use, and type of diabetes (stratification factor) as covariates. The results will be summarized as least squares means (LSMs) and standard errors for each group, LSM difference between groups, corresponding 95% confidence intervals (CI), and two-sided P values. The superiority of the intervention group over the control group will be concluded if the LSM difference in the change in HbA1c (intervention minus control) is less than or equal to the minimum clinically important difference (MCID) of –0.3%, and the upper bound of the 95% CI (i.e., the one-sided 97.5% CI) is below zero. We defined the MCID as –0.3% for the following reasons: (1) a 5% improvement in TIR, which is considered clinically meaningful [17-19], corresponds approximately to a 0.3% change in HbA1c level [20]; and (2) the U.S. Food and Drug Administration and the European Medicines Agency have suggested a non-inferiority margin of 0.3% for HbA1c reduction [21], and it is reasonable to apply this clinically meaningful threshold to CGM-guided interventions.

ANCOVA with baseline values, study center, prior CGM use, and type of diabetes as covariates will be conducted for CGM metrics in the secondary and exploratory analyses. The DTSQ and DTSQc scores will also be assessed using ANCOVA. Subgroup analyses will be conducted for primary efficacy outcomes and CGM endpoints according to bolus calculator mode, age group, type of diabetes, and prior CGM use.

Other secondary and exploratory outcomes assessing the proportion of participants meeting specific criteria, such as the proportion of participants with HbA1c <7% at week 12, will be presented with the exact 95% CIs for each group. To compare the intervention and control groups, logistic regression analysis will be performed, adjusting for the study center, prior CGM use, and type of diabetes. The results will be summarized as odds ratios with corresponding 95% CIs and two-sided P values.

Insulin dosage and dosing behavior will be compared between the groups using a two-sample _t_-test, Wilcoxon rank-sum test, Pearson’s chi-square test, or Fisher’s exact test, as appropriate. For safety analyses, adverse events will be reported and compared using the Pearson’s chi-square test or Fisher’s exact test. Within-group and between-group comparisons of laboratory test results, vital signs, and physical examinations will be performed.

All statistical analyses will be performed using SAS version 9.4 or higher, and two-sided tests will be conducted at a significance level of 5%, unless otherwise specified. A detailed statistical analysis plan will be finalized before the database lock, and any deviations from the originally planned methods will be documented and justified in future publications reporting the study results.

DISCUSSION

To the best of our knowledge, this is the first RCT to investigate the efficacy and safety of stage 5 CIPs. Moreover, as there are no stage 5 CIPs currently available in the market, our study provides invaluable and novel evidence. The SIP used in this trial, DIA:CONN P8, fulfills all the proposed criteria for a stage 5 CIP [6-8]. It features a Setup Wizard that recommends individualized initial settings and an algorithm that provides advanced insulin injection coaching based on CGM and insulin injection data. The coaching messages include recommendations for basal insulin dose titration, ICR and ISF adjustments, and guidance on carbohydrate counting and injection timing, accompanied by educational materials. In addition, when a missed bolus is suspected, the SIP recommends an appropriate insulin dose.

In a previous RCT that evaluated the efficacy of a CGM device combined with structured education, participants receiving both CGM and structured education achieved better glycemic control than those receiving CGM alone [16,22,23]. Specifically, in an RCT comparing CGM with structured education (intervention) versus CGM alone (control) in adults with type 1 diabetes [22], the between-group difference in TIR after 12 weeks was 15.3% (63.4% in the intervention group vs. 44.5% in the control group). The HbA1c levels also decreased more substantially in the intervention group, with an additional reduction of 0.5%. Similarly, in a multicenter RCT involving adults with type 2 diabetes receiving MDI [16], patients who received CGM with structured education (−1.00%±0.12%; intervention group) demonstrated superior HbA1c reduction compared to those who received self-monitoring of blood glucose with conventional education (−0.58%±0.13%; _P_=0.0193 vs. intervention group) as well as those who received CGM with conventional education (−0.63%±0.13%; _P_=0.0367 vs. intervention group). These findings highlight the critical role of structured education in improving glycemic outcomes. Stage 5 CIPs provide individualized education and coaching based on daily analyses of CGM and insulin dosing data. Therefore, we anticipate that stage 5 CIPs will lead to improved glycemic control compared to tracking insulin pens in patients with diabetes. In a previous trial [16], the average duration of education provided to patients in the intervention group was 3.1 hours per participant—an amount of time that is often difficult to achieve in routine clinical practice. Automated coaching messages delivered by stage 5 CIP may help address this challenge by providing continuous, personalized education without requiring substantial clinician time.

Although insulin pumps such as automated insulin delivery (AID) systems are beneficial for glycemic control [24-28], several patients are reluctant to use them because of the discomfort associated with wearing the device continuously [29-31]. The high cost of insulin pumps and their limited insurance coverage also pose barriers to their adoption. In South Korea, only 0.4% of the population with type 1 diabetes uses sensor-augmented pumps or AID systems [32]. SIPs offer a practical alternative, particularly for patients hesitant to adopt insulin pump therapy. Given that individuals receiving insulin therapy often exhibit suboptimal glycemic control and face a high risk of diabetes-related complications [33-36], we anticipate that this RCT will help establish an effective strategy for improving glycemic outcomes in individuals with type 1 or type 2 diabetes.

Article information

CONFLICTS OF INTEREST

Younghoon Kim and Jae Hyeon Kim are Chief Executive Officers of Glucometrics Co., Ltd. Tae-min Lee and Chung-il Yang are Chief Technology Officer and Chief Product Officer of G2E Co., Ltd, respectively.

ACKNOWLEDGMENTS

This work was supported by the Korea Medical Device Development Fund grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: RS-2023-00250888). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

AUTHOR CONTRIBUTIONS

Conception or design: J.H.K., S.M.J. Acquisition, analysis, or interpretation of data: J.Y.K., N.H.K., S.H.K., C.H.J., E.S.K., J.S.M., S.J.M., S.Y.K., J.H.Y., Y.K., T.L., C.Y., J.H.K., S.M.J. Drafting the work or revising: J.Y.K., S.M.J. Final approval of the manuscript: J.Y.K., J.H.K., S.M.J.

Fig. 1.

Overall study design. CIP, connected insulin pen; SIP, smart insulin pen; CGM, continuous glucose monitoring.

Fig. 2.

Principles for assessing basal insulin dose. Basal insulin dose recommendations are derived from overnight glucose patterns by analyzing the slope of glucose change (Δy/Δx).

Fig. 3.

Examples of coaching messages for insulin-to-carbohydrate ratio (ICR) recommendations. When postprandial hyperglycemia is detected (A), the application provides specific guidance, including revised ICR recommendations (B).

Fig. 4.

Real-time insulin dose recommendation function. When preprandial administration of a mealtime insulin dose is suspected to have been missed, the system triggers a real-time insulin recommendation feature, which provides an adjusted insulin dose recommendation and thereby mitigates the risk of post-injection hypoglycemia.

Table 1.

Inclusion and Exclusion Criteria

Table 2.

Study Schedule

| | Screening & Run-in perioda | Trial period | | | | | | ------------------------------------------------------------------- | ------------------ | ---------------------- | ------------------------------- | ---------------------- | -------- | | Visit 1 (screening) | Visit 2 (baseline) | Visit 3 | Visit 4b | Visit 5 (end-of-study) | | | Week ~ –4 | Week 0 | Week 4 | Week 8 | Week 12 | | | Visit window | - | - | ±10 days | ±10 days | ±10 days | | Informed consent | √ | | | | | | Demographics | √ | | | | | | Diabetes-related information | √ | | | | | | Medications | √ | √ | √ | √ | √ | | Medical and surgical history | √ | | | | | | Anthropometric measurements and vital signsc | √ | √ | √ | (√) | √ | | Physical examination | √ | √ | √ | (√) | √ | | Laboratory testsd | √ | √ | | | √ | | Pregnancy test | √ | | | | √ | | Eligibility assessment | √ | √ | | | | | Randomization | | √ | | | | | Continuous glucose monitoring | ←―――――→ | ←――――――――――――――――――――→ | | | | | (7–10.5 days) | | | | | | | Smart insulin pen/Tracking insulin pen | ←―――――→ | ←――――――――――――――――――――→ | | | | | (7–10.5 days) | | | | | | | DTSQs and DTSQce | | √ | | | √ | | Adverse event assessment | | √ | √ | √ | √ |

Table 3.

Efficacy Outcomes

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Efficacy and Safety of Stage 5 Connected Insulin Pens in Type 1 or Type 2 Diabetes: Randomized Controlled Trial Protocol

Fig. 1. Overall study design. CIP, connected insulin pen; SIP, smart insulin pen; CGM, continuous glucose monitoring.

Fig. 2. Principles for assessing basal insulin dose. Basal insulin dose recommendations are derived from overnight glucose patterns by analyzing the slope of glucose change (Δy/Δx).

Fig. 3. Examples of coaching messages for insulin-to-carbohydrate ratio (ICR) recommendations. When postprandial hyperglycemia is detected (A), the application provides specific guidance, including revised ICR recommendations (B).

Fig. 4. Real-time insulin dose recommendation function. When preprandial administration of a mealtime insulin dose is suspected to have been missed, the system triggers a real-time insulin recommendation feature, which provides an adjusted insulin dose recommendation and thereby mitigates the risk of post-injection hypoglycemia.

Graphical abstract

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Graphical abstract

Efficacy and Safety of Stage 5 Connected Insulin Pens in Type 1 or Type 2 Diabetes: Randomized Controlled Trial Protocol

| | Screening & Run-in perioda | Trial period | | | | | | -------------------------------------------- | ------------------ | ---------------------- | -------- | ---------------------- | -------- | | Visit 1 (screening) | Visit 2 (baseline) | Visit 3 | Visit 4b | Visit 5 (end-of-study) | | | Week ~ –4 | Week 0 | Week 4 | Week 8 | Week 12 | | | Visit window | - | - | ±10 days | ±10 days | ±10 days | | Informed consent | √ | | | | | | Demographics | √ | | | | | | Diabetes-related information | √ | | | | | | Medications | √ | √ | √ | √ | √ | | Medical and surgical history | √ | | | | | | Anthropometric measurements and vital signsc | √ | √ | √ | (√) | √ | | Physical examination | √ | √ | √ | (√) | √ | | Laboratory testsd | √ | √ | | | √ | | Pregnancy test | √ | | | | √ | | Eligibility assessment | √ | √ | | | | | Randomization | | √ | | | | | Continuous glucose monitoring | ←―――――→ | ←――――――――――――――――――――→ | | | | | (7–10.5 days) | | | | | | | Smart insulin pen/Tracking insulin pen | ←―――――→ | ←――――――――――――――――――――→ | | | | | (7–10.5 days) | | | | | | | DTSQs and DTSQce | | √ | | | √ | | Adverse event assessment | | √ | √ | √ | √ |

Table 1. Inclusion and Exclusion Criteria

HbA1c, glycosylated hemoglobin.

Table 2. Study Schedule

DTSQs, Diabetes Treatment Satisfaction Questionnaire Status Version; DTSQc, Diabetes Treatment Satisfaction Questionnaire Change Version.

a

The run-in period will be conducted for 7–10.5 days within the maximum 4-week window between the screening and baseline visits. It is recommended to initiate the run-in period in a way that allows it to be concluded by the time of the baseline visit; for example, starting 7–10.5 days before the scheduled baseline visit;

b

Visit 4 may be conducted either in person or via telephone. If conducted via telephone, concomitant medication use, blood glucose measurements, and occurrence of adverse events will be assessed through structured phone interviews with the participants. Education for this visit will be delivered remotely. Vital signs and physical examinations will be performed only during in-person visits and omitted during telephone visits;

c

Anthropometric measurements will be obtained only at the screening visit (visit 1), whereas vital signs will be assessed at all visits, except when visit 4 is conducted via telephone;

d

Laboratory tests will be performed as follows: at visit 1, non-fasting (within 5 hours of eating) C-peptide, non-fasting glucose, glycosylated hemoglobin (HbA1c), and creatinine will be measured; at visits 2 and 5, complete blood count, HbA1c, fasting glucose, blood urea nitrogen, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, creatinine, routine urine analysis, urine albumin, and urine creatinine will be assessed after at least 8 hours of fasting;

e

The DTSQs will be administered at visits 2 and 5, while the DTSQc will be administered only at visit 5.

Table 3. Efficacy Outcomes

HbA1c, glycosylated hemoglobin; DTSQs, Diabetes Treatment Satisfaction Questionnaire Status Version; DTSQc, Diabetes Treatment Satisfaction Questionnaire Change Version.

a

CGM metrics will be reported only for participants with a sensor wear time of at least 70%.

Table 1.

Table 2.

Table 3.