Download - Functionality and acceptability of a new electronic insulin injection pen with a memory feature*

ORIGINAL ARTICLE

Functionality and acceptability of a new electronic insulin injection pen with a memory feature*Willem J. r. r. Venekamp a, lisa Kerr b, Sherie A. Dowsett b, Patricia A. Johnson b, Deborah Wimberley b, Chris McKenzie b, James Malone b and Zvonko Milicevic b

a Consultant Endocrinologist, Atrium Medical Centre, Brunssum, The Netherlands

b Eli Lilly and Company, Indianapolis, IN, USA

Address for correspondence: Willem J. R. R. Venekamp, Internist Endocrinologist, Atrium Medisch Centrum, locatie Brunssum, Kochstraat 3, 6442 BE Brunssum, The Netherlands. Tel.: +31 45 5279202; Fax: +31 45 5279477; email: [email protected]

Key words: Diabetes – Functionality – Insulin injection delivery device – Patient acceptance – Questionnaire

0300-7995

doi:10.1185/030079906X80477

All rights reserved: reproduction in whole or part not permitted

CurreNT MeDiCAl reSeArCh AND OPiNiON®

Vol. 22, No. 2, 2006, 315–325

© 2006 librAPhArM liMiTeD

Paper 3235 315

Objective: The HumaPen Memoir† (HPM) is a new reusable insulin injection pen. It possesses an electronic component so that 16 insulin doses are stored in the memory. This study’s aim was to evaluate the functionality of the device (i.e., ability to deliver a set dose of insulin), its impact on patient safety, and patient/healthcare professional (HCP) acceptance.Research design and methods: In this 6–10‑week (3 visit) multinational, multi‑centre, open‑label, single‑arm outpatient study, participants with type 1 or type 2 diabetes were assigned to inject either their prandial or basal insulin dose using the HPM and instructed to record all complaints with the study pen or user manual. Investigators submitted a complaint form to the sponsor for each participant complaint, and for adverse events (AEs) potentially related to the study pen. Where a complaint was possibly related to a pen malfunction, the pen was returned to the sponsor for assessment. Participant/HCP acceptance of the HPM was evaluated using questionnaires.Results: Of the 300 participants (mean age 52 [SD 15]

years), 58% were male and 62% had type 2 diabetes. The mean duration of pre‑study pen use was 7 years. The average exposure to the HPM was 8.2 (SD 1.6) weeks. Overall, 314 study pens were used (14 were replacements). Functional complaints were reported for 24 devices (7.6%), of which 8 (2.5%) were permanent electronic failures, and 15 (4.8%) were user‑related (1 pen not returned for assessment). None of these functional issues resulted in a serious AE. Non‑functional complaints were reported for 33 devices (10.5%). There were no pen‑related hypoglycemic episodes and 2 pen‑related hyperglycemic episodes were reported. The majority of participants (81.4%) preferred the HPM over their pre‑study pen. The new insulin pen was generally rated higher than the pre‑study pen for pen features and tasks associated with everyday pen use.Conclusions: No major functional issue of the HPM resulting in a serious AE was reported in this study. Based on the study results this new insulin pen demonstrated a favorable benefit‑risk profile.

A B S T R A C T

Introduction

Improvement in glycemic control can significantly reduce the risk of development and progression of diabetic complications1,2. Insulin pens were developed

with the premise that insulin delivery devices that are more acceptable to the patient could improve patient compliance and make a positive contribution to long‑term diabetes control. Using a mail‑in questionnaire, patient acceptance of insulin injection pens has been reported

* Some of these data have been presented at the Diabetes Technology Annual Meeting, San Francisco, November 10–12, 2005† HumaPen and HumaPen Memoir are trademarks of Eli Lilly and Company, Indianapolis, USA

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316 A new insulin pen: functionality and acceptability © 2006 librAPhArM lTD – Curr Med res Opin 2006; 22(2)

to be more favorable than for conventional syringe and vial in terms of ease of use, activity interference, and social acceptability ( p < 0.05 in all cases, based on scaled responses to a series of questions)3. In a randomized, open‑label, cross‑over study where patient preference for an insulin pen or vial and syringe was assessed using a questionnaire, the study insulin pen scored consistently higher than vial and syringe, for example in terms of ease of use, and confidence in setting and reading the dose4. In a study of 48 children, a pen device was demonstrated to be more accurate in delivering low doses of insulin compared with a syringe and vial5.

The HumaPen Memoir (HPM) is a reusable pen for use with Eli Lilly 3.0‑mL (300‑U) pre‑filled insulin cartridges. It is the first pen that possesses a memory feature permitting the previous 16 doses (including priming dose) to be stored with the date and time of dosing. Other features include a digital display and a two‑way dial to minimize insulin wastage.

The primary objective of the present study was to determine whether the HPM demonstrated acceptable functionality in a take‑home setting, as assessed primarily through patient complaints recorded in a diary. Functionality was defined as the ability of the device to deliver the set dose of insulin. Other aspects related to pen use were also assessed, including safety associated with use of this new insulin pen, and its acceptance by patients and healthcare professionals (HCPs).

Participants and methodsStudy design and population

This was a multinational, multi‑centre, open‑label, single‑arm study of patients with type 1 or type 2 diabetes, recruited at 21 sites in four countries (India, South Africa, Germany, and The Netherlands). The study protocol was approved by the ethical review boards at all participating institutions, and all participants gave written informed consent for participation in this study.

Inclusion criteria were as follows: type 1 or type 2 diabetes, age 18–75 years, and using an insulin injection device to inject at least two insulin doses per day for at least 2 months immediately prior to the study. Participants were also required to be using an Eli Lilly insulin as their prandial dose (insulin lispro [Humalog‡], insulin lispro low mixture 25/75 [Humalog Mix25‡] and/or insulin lispro mid‑mixture 50/50 [Humalog Mix50‡]), and using NPH insulin (neutral‑protamine human insulin, Humulin‡ N) or insulin glargine (Lantus§) as their basal insulin if using insulin lispro for the majority of their prandial injections.

The study involved three office visits over a period of 6–10 weeks. Study participants used the HPM to inject their basal or prandial insulin dose(s) and pen functionality, safety, and acceptability were assessed.

At Visit 1, participants were assigned to inject either their prandial or basal insulin using the HPM, as outlined in Table 1. Those using NPH insulin prior to the study were stratified to the prandial and basal insulin groups in a 3 to 2 ratio in an attempt to ensure that sufficient participants (20%) used the study pen to inject basal insulin. Those participants using insulin glargine prior to the study continued to use this insulin during the study with their pre‑study insulin delivery device, and used the HPM for their prandial dose. This ensured that there was minimal impact on the pre‑study insulin formulations and doses. While participants continued using their usual insulin formulations, following the same dosage schedule that they used prior to the study, insulin doses could be adjusted as needed. Those on oral antihyperglycemic agents prior to the study continued to use them during the study.

Assessment of complaints

At Visit 1, study participants were instructed to record in a diary any complaints that they had with the study pen or the accompanying User Manual over the course of the study. Investigators reviewed the diary entries with the participant at Visits 2 and 3. Participants could also report complaints to the investigative site by telephone if they were not able to use the pen without further instruction.

For each complaint, whether by telephone or written in a diary, an electronic complaint form was completed by the investigator and submitted to the sponsor. Complaint forms were also submitted if the investigator believed that an adverse event (AE) was related to the study pen, even if a complaint was not reported by the participant. Those study pens which elicited a

‡ Humalog, Humalog Mix25, Humalog Mix50, and Humulin are trademarks of Eli Lilly and Company, Indianapolis, USA§ Lantus is a registered trademark of Aventis Pharmaceuticals, Paris, France

Pre‑study regimen includes: Group assignment

Insulin glargine (Lantus) and insulin lispro

Prandial*

Human NPH (Humulin N) and insulin lispro

Prandial* or basal† (assigned by stratification)

Insulin lispro or insulin lispro mixture (Humalog)

Prandial

* Participants assigned to inject their prandial dose (i.e. insulin lispro) using the HPM

†Participants assigned to inject their basal dose (i.e. Human NPH) using the HPM

Table 1. Assignment of participants to inject either their prandial or basal insulin dose(s) using the HPM

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© 2006 librAPhArM lTD – Curr Med res Opin 2006; 22(2) A new insulin pen: functionality and acceptability Venekamp et al. 317

complaint from a participant that was considered to be potentially related to a pen malfunction were returned to the sponsor for assessment.

Complaints were assigned to complaint and analysis categories by the study sponsor (quality control, and a design or quality engineer). Complaint categories were assigned based on the information provided by the investigator in the complaint form, which included answers to specific questions about each complaint as well as a free‑form description of the actual complaint. Analysis categories were assigned based on the information provided in the complaint form and, where applicable, the findings of an assessment of the device by the sponsor. All complaints were also categorized as functional, non‑functional, or related to the User Manual, based on the complaint and analysis categories assigned. Functional complaints were those interfering with the ability of the study pen to deliver a set dose of insulin, and included those complaints related to pen malfunction and those arising due to the participant failing to operate the device correctly (user related). Non‑functional complaints were defined as those not relating to the functionality of the device, for example concerns over device esthetics.

Safety assessment

Participants were instructed to record all hypoglycemic episodes (defined as when the participant felt or another person observed that the participant experienced a symptom/sign associated with hypoglycemia or a blood glucose < 3.5 mmol/L), any hyperglycemic episode (defined as blood glucose > 18 mmol/L) that they believed was related to the study pen, and any other AEs in their diary. They were also asked to document whether they considered the AE to be related to the use of the study pen and, if so, why.

laboratory procedures

To evaluate glycemic control, HbA1c

and fasting plasma glucose were measured at Visit 1 and the final visit. Laboratory procedures were performed at Covance Central Laboratories (Geneva, Switzerland; Cape Town, South Africa; and Singapore). HbA

1c was

assayed using ion‑exchange high performance liquid chromatography (VARIANT I, Bio‑Rad Laboratories, Hercules, CA). Glucose testing was performed using the Modular Analytics (Roche Diagnostics, Indianapolis, USA).

Participant questionnaires

The Insulin Delivery System Evaluation (IDSE) questionnaire was developed to measure satisfaction

with, preference for, and confidence in an insulin delivery system. The IDSE was adapted from the Insulin Injection Preference questionnaire (IIP‑q)6, a previously validated questionnaire designed to assess patient views of a pen’s attributes that would relate to preference.

Participants completed the IDSE at Visit 1 and their final visit. IDSE questions related to the pre‑study insulin injection pen at Visit 1, and to the HPM and its features at the final visit. The final visit questionnaire also included questions relating to the participant’s preference (pre‑study device [replaced by HPM] versus HPM).

healthcare professional questionnaires

To evaluate HCP acceptance of the HPM as a method of delivering insulin in comparison to other insulin injection devices, a Health Care Professional Evaluation (HCPE), adapted from the IDSE, was completed by an HCP at each study site, in consultation with other individuals at that site who conducted training and/or were involved in follow‑up of study participants. An initial HCPE was completed before training participants to use the study pen at their site, with questions relating to the insulin pen their patients most often used. A second HCPE was completed after all participants had completed their final visit, with questions pertaining to the study pen and its features. Where possible, the same HCP completed both HCPEs. The HCPE questionnaire included questions relating to the pen features and time needed to train a patient to use the pen.

Statistical analysis

Since this was a single‑arm study with no direct device comparisons, a formal power calculation was not performed. However, if no serious functionality complaints were reported in this study, with a sample size of 300 participants there would be a 95% confidence level that a serious functionality complaint would not occur in more than 1% of the HPM‑user population. A serious functionality complaint was defined as the inability of the device to deliver a set dose of insulin that resulted in a serious AE.

Analyses were conducted using data from all enrolled participants injecting at least one dose of insulin with the HPM. In accordance with the stratification, subgroup analyses were performed on the basal versus prandial insulin groups. Subgroup analyses were also performed for simple (administering the same insulin lispro formulation for all prandial injections) versus complex (administering different insulin lispro formulations for their prandial injections) insulin regimens and by country. All tests of subgroup effects were conducted at a two‑sided alpha level of 0.05 unless otherwise stated, using a Fisher’s exact test or a

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Pearson’s chi‑square test. No adjustments for multiple comparisons were performed.

Study pen complaints were summarized using descriptive statistics for the frequency (number of complaints) and incidence (number of pens with at least one complaint). Additional summarizations were reported by complaint category and complaint‑by‑analysis category.

Item responses in the IDSE and HCPE were summarized using descriptive statistics. Comparisons between Visit 1 (pre‑study insulin delivery device replaced with HPM) and endpoint (HPM) responses on the IDSE and HCPE were performed using an ordered logistic regression analysis that utilized the proportional odds model7. This technique modeled the cumulative logits for the response scales.

Results

Of the 304 participants who received a HPM, 300 reported using the pen device at least once. Of those four participants who did not report using the study pen, three discontinued because of a personal conflict and one was lost to follow‑up. Overall, 287 completed all three visits of the study (Figure 1). The baseline characteristics of the 300 study participants are shown in Table 2. The majority of pre‑study insulin delivery devices were the HumaPen Ergo¶ (63.1%) and pens of the OptiPen** Pro series (Aventis, France) (19.2%).

During the study, the study pen was used for the basal dose in 34 participants (11.3%), and the prandial dose in 266 participants (88.7%). These 266 participants comprised 76.0% injecting insulin lispro,

¶ HumaPen Ergo is a registered trademark of Eli Lilly and Company, Indianapolis, USA** OptiPen is a registered trademark of Aventis Pharmaceuticals, Paris, France

313 participants enrolled

Completed all three visits (N = 287)

Did not receive a HumaPen Memoir (N = 9):Personal conflict (n = 6)Entry criteria not met (n = 3)

Discontinued (N = 17):Personal conflict/patient decision (n = 7)Physician decision (n = 2)Protocol violation (n = 5)Sponsor's decision (n = 2)Loss to follow up (n = 1)

304 entered the study*

313 participants enrolled

304 entered the study*

Memoir, 300 used it at least once*Of the 304 participants who received a HumaPen

Demographic Total (N = 300)

Mean age ± SD (range), years 51.7 ± 14.6 (18.0–75.5) % male 58 Weight ± SD (range), kg 86.3 ± 19.3 (41.0–151.0) BMI group (%)

≤ 30 kg/m2 58.5 > 30 kg/m2 41.5

Ethnic origin (%) Caucasian 84.7 Western Asian 15.0 African 0.3

Type of diabetes (%) Type 1 38.0 Type 2 62.0

Concomitant oral antihyperglycemic medication (%) 22.7 Mean duration of diabetes ± SD (range), years 13.7 ± 9.0 (0.4–55.0) Mean duration of use of pre‑study insulin delivery device ± SD (range), years

7.1 ± 5.9 (0.25–40.0)

SD = standard deviation

Figure 1. Flow of study participants

Table 2. Baseline characteristics of the 300 study participants who received an HPM

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10.7% injecting insulin lispro low mixture 25/75, and 2.0% injecting insulin lispro mid‑mixture 50/50.

In 89% of cases, participants continued to use a pre‑study device during the study to inject a different insulin formulation(s). In 39% of cases, this was the same type of device that was replaced with the HPM.

The total exposure to the HPM was 2446 person‑weeks, and the mean exposure was 8.2 (standard deviation [SD] 1.6) weeks. The mean daily dose of insulin injected with the study pen device during the study was 24.6 (SD 12.3) units for the basal dose, and 28.5 (SD 20.2) units for the prandial dose.

Seven participants (2.3%) used a backup device (i.e., used another device in their possession in place of the study pen, due to difficulties using the study pen) for seven or more consecutive days during the study. The HPM was replaced with another HPM for 14 participants (4.7%).

Assessment of complaints

Complaints were reported for 56 (17.8%) of the 314 study pens; twenty‑four complaints (7.6%) were considered functional, and 33 (10.5%) non‑functional (one pen elicited both a functional and non‑functional complaint). There were no complaints considered to be related to the User Manual. There was no difference in the number of functional or non‑functional complaints in the basal versus prandial insulin groups and the simple versus complex insulin regimen groups for all comparisons ( p > 0.14). Both the number of functional and non‑functional complaints was different among the countries

( p = 0.006 and p = 0.009, respectively). The percentage of participants from each country reporting a functional complaint was 13.3% for The Netherlands, 11.5% for S. Africa, 10.7% for India, and 2.7% for Germany. The percentage of participants from each country reporting a non‑functional complaint was 23.1% for S. Africa, 10.8% for The Netherlands, 10.7% for India, and 6% for Germany.

Complaint and analysis categories for those complaints that were considered functional are listed in Table 3. Of those pens eliciting complaints from participants that were considered functional, technical assessment revealed that eight (2.5%) were considered device failures (i.e., premature battery expiration, permanent error), and 15 (4.8%) were considered user‑related (i.e., recoverable errors) (Table 3). None of the functional complaints were considered serious (i.e., resulted in a serious AE). Complaint and analysis categories for complaints that were considered non‑functional are listed in Table 4.

Glycemic control and safety assessment

Glycemic control was maintained during the study; at Visit 1 and endpoint, mean HbA

1c levels were 7.56%

(SD 1.41) and 7.52% (SD 1.29), respectively, and mean fasting plasma glucose levels were 9.5 (SD 3.8) and 9.7 (SD 3.6) mmol/L, respectively.

Treatment‑emergent AEs were reported in 72 participants (24%). Common (> 2% incidence) treatment‑emergent AEs were influenza (4.7%), nasopharyngitis (4.3%), and headache (2.3%).

Complaint category Analysis category* N

Permanent error Permanent error 5 Device defective Premature expiration 1 Device expired Premature expiration 1 Other Premature expiration 1

Recoverable error Recoverable error 6 Does not understand how to use device Recoverable error 5 Device not working Recoverable error 2 Electronic display Recoverable error 1 Improper storage temperature Recoverable error 1 Device delivered less than expected NA† 1

Total number of study pens 24

*Analysis categories defined as follows. Permanent error – the HPM software detects a problem and causes the display to show a permanent error code (F0–F8). The problem cannot be cleared and the display is inoperable. Premature expiration – a non‑flashing battery icon appears in the device display before the end of the expected device operating life. The condition cannot be cleared and the display is inoperable. Recoverable error – the HPM software detects a problem and causes the display to show all dashes. The error may be cleared by the user resetting the pen manually

†Pen not returned to sponsor and analysis category thus not assigned

Table 3. Number of study pens with functional complaints by complaint category and analysis category. Complaints and analysis categories were assigned by the sponsor, based on complaint reports from investigators and further assessment by

the sponsor. Device failures (N = 8) fell under the analysis categories ‘Permanent error’ and ‘Premature expiration’. Other functional complaints (analysis category ‘Recoverable error’) were considered user‑related (N = 15)

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Serious AEs (defined as those resulting in death, hospitalization, disability/incapacity, or necessitating medical or surgical intervention to prevent permanent damage, or that were life‑threatening) were reported for 3 participants (hypertensive crisis; asthma and hypoglycemia; and vomiting), and none were reported to be related to the use of an insulin delivery device. There were no discontinuations due to AEs.

Overall, a hypoglycemic event (either reported by the study participant or detected by measurement of fasting blood glucose at Visit 1 or the final visit) was recorded for 106 participants (34.9%), with a rate of 0.94 (SD 2.5) events per participant per 30 days. No HPM‑related hypoglycemic events were reported during the study. Hyperglycemic events (defined as blood glucose level ≥ 18 mmol/L) were only collected when they were considered potentially related to the study pen. Two hyperglycemic events were reported for one study participant.

Participant questionnaires

Of the 290 study participants who completed a questionnaire at Visit 1 and at the final visit, 54.2% of participants were satisfied with their pre‑study device and 77.9% with the HPM. When asked at the final visit if they preferred either the pre‑study device or the study pen, 81.4% of participants preferred the HPM, and 18.6% preferred their pre‑study device. The HPM was considered easier and more convenient to use than the pre‑study pen and rated higher than the pre‑study pen for controlling blood sugar, attaching/removing the cartridge holder, and most tasks related to insulin dosing, including the ability to read the dose used/selected and injecting the dose (Figure 2A and B) (p‑values were calculated from the proportional odds model (cumulative logits) using the ordinal response scales for the respective parts of the questionnaire). The most important aspects of the memory feature to the participants and their top reasons for recom‑mending the HPM are shown in Figures 3 and 4.

Complaint category Analysis category(s) N

Does not understand how to use device 9† Date/time setting (n = 1) Dose memory (n = 1) Drooling (n = 2) Recoverable error (n = 3) Other (n = 1) NA* (n = 1) Recoverable error 5‡ Dial sensor (n = 1) Invalid dose (n = 1) Recoverable error (n = 4) Unspecified 3§ Drooling (n = 1) Recoverable error (n = 3) Device not working 2** Dose memory (n = 1) Recoverable error (n = 1) Dose knob Normal 2 Priming difficulty Needle clogged 2 Priming drop versus stream Esthetic defect 2 Device weight Esthetic defect 2 Cartridge insertion Other 1 Device time not accurate Date/time setting 1 Device size Esthetic defect 1** Electronic display Esthetic defect 1 Ergonomic Esthetic defect 1 Leaking after injection from device NA* 1† Needle attachment Normal 1 Pen jam Normal 1

Total number of study pens 33

* Pen not returned to sponsor and analysis category thus not assigned †One pen had two complaints, captured under two complaint categories (‘Does not understand how to use device’ and ‘Leaking after injection from device’)

‡One pen had two complaints under the complaint category ‘Recoverable error’, captured under two analysis categories (‘Invalid dose’ and ‘Recoverable error’)

§One pen had two complaints under the complaint category ‘Unspecified’, captured under two analysis categories (‘Drooling’ and ‘Recoverable error’)

**One pen had two complaints, captured under two complaint categories (‘Device not working’ and ‘Device size’)

Table 4. Number of study pens with non‑functional complaint and analysis category. Complaints and analysis categories were assigned by the sponsor, based on complaints reports from investigators

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79

84

51

67

83

72

41

54

70

55

80

75

92

96

65

60

83

80

43

48

80

54

79

74

0 10 20 30 40 50 60 70 80 90 100

Easy to see dose of insulin used

Easy to select dose

Easy to control blood sugar

Easy to carry for use away from home

Does not interfere with short trip plans

Easy to fit into daily life

Not noticeable to others when used

Reduces embarrassment when used away from home

Convenient to use

Reduces my reluctance to take injections

Helps me manage my diabetes at home

Helps me manage my diabetes away from home

% Agree or Strongly Agree

Pre-study pen (Visit 1) HPM (final visit)

*

p < 0.001

*

*

*

93

81

76

91

92

71

91

97

98

91

98

78

97

89

97

97

91

91

94

96

0 10 20 30 40 50 60 70 80 90 100

Learning to use the pen

Using power button to turn pen on

Ability to read time and date

Ability to read dose

Setting time and date

Attaching/removing cartridge holder

Holding pen while injecting

Injecting dose

Viewing doses in memory

Understanding display message

Using the User Manual

Using the Quick Guide

Overall ease of use

% Rating Easy or Very Easy

Pre-study pen (Visit 1) HPM (final visit)

*

*

*

*

*

*

(A)

(B)

*

Figure 2. Rating of the pre‑study pen device and the HPM by study participants (N = 290).

(A) For each question, participants were asked to respond on a scale of 1 (strongly disagree) to 7 (strongly agree). The percentages of participants responding with a 6 or 7 are shown.

(B) For each question, participants were asked to respond on a scale of 1 (very difficult) to 5 (very easy) or “not applicable”. The percentages of participants rating the task a 4 or 5 are shown.

*p < 0.05, In [A], p‑values were calculated from the proportional odds model (cumulative logits) using the ordinal response scale (1‑7). P‑values are thus based on comparisons of actual scores (1‑7) and not percentage of participants who agreed with the statement (6 or 7 response). Significant p‑values indicate differences in the resulting scales between the pre‑study pen device (Visit 1) responses and HPM (final visit) responses. In [B], p‑values were calculated from the proportional odds model (cumulative logits) using the ordinal response scale (1‑5) and did not include “not applicable” responses. P‑values are thus based on comparisons of actual scores (1‑5), and not percentage of participants rating the task easy (4 or 5 response). Significant p‑values indicate differences in the resulting scales between the pre‑study pen device (Visit 1) responses and HPM (final visit) responses

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38

25

5

23

16

55

14

15

2

44

44

0

19

25

63

6

0

0

0 10 20 30 40 50 60 70 80 90 100

Ability to view the number ofunits of previous insulin dose

Ability to view the time ofprevious insulin dose

Ability to view the date ofprevious insulin dose

Ability to view the previous16 doses

Ability to view previous doseinfo to make current dose

decision

Ability to confirm injectiontaken

Ability to use info to fill outblood glucose logbook

Memory feature not important

Other

Percentage

Study participant HCP

87

2

1

12

69

39

26

43

22

8

8

54

9

6

100

0

6

6

50

31

31

38

56

0

6

75

0

0

0 10 20 30 40 50 60 70 80 90 100

Would use/recommend

Size

Weight

Appearance

Easy to use

Easy to read numbers

Digital display

Easy to push the dose knob/inject

Can dial back easily without wasting insulin

Easy to carry

Easy to teach

Memory feature

Easy to hold

Other

Percentage

Study participant HCP

Figure 3. The most important aspects of the memory feature of the HPM according to study participants (N = 290) and healthcare professionals (HCPs) (N = 16). In the final visit IDSE and HCPE questionnaires, study participant and HCPs, respectively, were

asked to check the two most important aspects of the memory feature from a list of eight possible aspects of importance

Figure 4. The top reasons for using/recommending the HPM according to study participants (N = 290) and healthcare professionals (HCPs) (N = 16). In the final visit IDSE and HCPE questionnaires, study participant and HCPs, respectively, were asked if they would use/recommend the HPM and to check the three reasons for using/recommending the HPM from a

list of 14 possible recommendation reasons

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healthcare professional questionnaires

Nineteen HCPs completed the HCPE at Visit 1, and 16 completed it at the final visit. Of these 16 HCPs, 15 were the same HCPs as completing the Visit 1 HCPE. HCP ratings of the most commonly used insulin delivery pen and the HPM are shown in Figure 5. The study pen was rated higher than the most commonly used insulin delivery pen with regard to ability to read the dose and injecting the dose (p‑values were calculated from the proportional odds model (cumulative logits) using the ordinal response scales for the respective parts of the questionnaire). The most important aspects of the memory feature to the HCPs and their top reasons for recommending the HPM are shown in Figures 3 and 4. The average times that HCPs estimated it would take to train a person with diabetes to use the most commonly used insulin delivery pen at the site and the HPM are shown in Figure 6. The majority (88%) of HCPs reported that it took less than 30 min to train study participants to use the HPM, and 50% reported that it took less than 15 min.

Discussion

This was a 6–10‑week study designed to determine whether the HPM, a new insulin delivery pen, demon‑strated acceptable functionality in a take‑home setting in patients with type 1 or type 2 diabetes. During the study, 8 electronic failures occurred but there were no serious functionality concerns with any HPM. Metabolic control during the study was maintained, with no association between use of this new pen and any reported hypoglycemic event. Two hyperglycemic events potentially related to the study device were reported. Study participants and HCPs rated the features of the new insulin pen highly. Based on the results of this study, the HPM appears to exhibit an acceptable safety profile for use in the clinical setting.

Insulin pens can make a positive contribution to self care in patients with type 1 or type 2 diabetes3–5. The HPM is an electronic pen with a memory feature, and offers potential advantages over some currently available pens, including the ability to check the

Figure 5. Rating of the pre‑study pen device and the HPM by healthcare professionals (HCPs) (N = 16). For each question, HCPs were asked to respond on a scale of 1 (very difficult) to 5 (very easy) or ‘not applicable’. The percentages of HCPs

rating the task a 4 or 5 are shown.

*p < 0.05. P‑values were calculated from the proportional odds model (cumulative logits) using the ordinal response scale (1–5) and did not include ‘not applicable’ responses. p‑values are thus based on comparisons of actual scores (1–5), and not percentage of HCPs rating the task easy (4 or 5 response). Significant p‑values indicate differences in the resulting scales between the most commonly used device (Visit 1) responses and HPM (final visit) responses

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Training patient to use

Using power button to turn pen on

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Attaching/removing cartridge holder

Holding pen while injecting

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Using the User Manual

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% Rating Easy or Very Easy

Most commonly-used pen (Visit 1) HPM (final visit)

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previous insulin dose, as well as the time of the dose, and the ability to record the previous 16 doses (including priming dose). The electronic display may also assist with more accurately selecting the appro‑priate insulin dose. Although electronic insulin delivery pens are still in their early stage of development, their potential for assisting with improved glycemic control is recognized.

In the present study, the population comprised patients with type 1 or 2 diabetes, with some experi‑ence in using insulin pens (mean 7.1 [SD 5.9] years). Overall, 18% of study pens elicited complaints from study participants. This incidence of reported complaints was not unexpected, and is most probably related to the study design (complaint information was solicited), as well as the complexity of the electronic display. However, it is important to note that only 8 out of 56 complaints (2.5% overall) were related to an electronic malfunction of the device (i.e., device failure). Other concerns related to the HPM were either non‑functional, or were functional but temporary in nature, and related to inappropriate use of the pen. The absence of any apparent safety concern associated with its use is a further indicator of the clinical acceptability of this pen. The 2 cases of hyperglycemia that were reported to be possibly related to use of the HPM were, on further investigation, shown to be related to

incorrect needle insertion, and to inappropriate use of the pen resulting in a temporary error (data not shown).

In this study, questionnaires were used to obtain both the study participants and HCP perspective of the new pen. Features of the HPM were generally rated highly by both patients and HCPs, and both groups considered this new insulin pen easy to use. In support of these findings, training study participants to use the pen did not appear to be time consuming, with 50% of HCPs reporting training to take less than 15 min. Study participants and HCPs had similar views on the advantages of this electronic pen. The memory feature and its ease of use were two of the most frequently chosen reasons by both groups for recommending the HPM.

There are several limitations to the design of this study. It was a single‑arm study, so that direct compar‑ison with other devices was not feasible. However, use of questionnaires did permit comparison with other pre‑study pen devices to some extent through the eyes of both the patient and HCP. A number of study participants continued to use their pre‑study pen during the study (39%), and in these cases, a more direct comparison of the pre‑study pen and the HPM was possible. The HCP questionnaire was completed by 19 (Visit 1) or 16 (final visit)

Figure 6. The average times that healthcare professionals (HCPs) (N = 16) estimated it would take to train a person with diabetes to use the most commonly used insulin pen and HPM, based on each HCP checking one of the four time‑range

categories in the final visit HCPE questionnaire

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HCPs, limiting our ability to draw conclusions from these data. While the participant and HCP questionnaires used in this study were adapted from validated questionnaires, neither questionnaire used in the present study was validated. The study duration was short (mean, 8 weeks) and a longer period of observation would be necessary to assess device durability in the clinical setting. Post‑marketing surveillance will provide further valuable insight to functionality and patient acceptance of this new insulin pen. Finally, it should be noted that participants in this study (clinical trial setting) may have received more rigorous device training than might occur for some patients in clinical practice.

Conclusion

No major functional issue of the HPM resulting in a serious AE was reported in this study. Based on assessment of safety, complaints and patient/HCP acceptance, this new insulin pen demonstrated a favorable benefit–risk profile, and appears to be a valuable and innovative addition to the insulin delivery pens currently available.

Acknowledgments

We are grateful to Jinghui Hu (Eli Lilly and Company) for computational support, Yelena Rice (Eli Lilly and Company) for assessment of complaints and methodological input into the manuscript, Risa Hayes (Eli Lilly and Company) for scientific input, and investigators for their involvement in this study: In Germany, Dr. Petra Algenstaedt, Hamburg; Dr. Gerhard Klausmann, Aschaffenburg; Dr. Stephan Maxeiner, Bosenheim; Dr. Ludger Rose, Münster, Dr. Jörg Steindorf, Schkeuditz; Dr. Hans‑Christoph Treichel, Genthin; Dr. Hermann Josef Strotmann,

Rotenburg. In India, Dr. Anil Bhansali, Chandigarh; Dr. Vijay Vishwanathan, Chennai; Dr. Chittaranjan S Yajnik, Pune; Dr. Vairamuthu Sekar, Coimbatore. In The Netherlands, Dr. Klaas Hoogenberg, Groningen; Dr. Thiemen Veneman, Almelo; Dr. Rene Wouters, Emmen; Dr. Roel P Hoogma, Gouda; Dr. Max Jebbink, Delft. In South Africa, Dr. Mary E Seeber, Pretoria; Dr. Aslam Amod, Durban; Dr. Puvanesveri Naiker, Durban; Dr. R Moore, Umhlanga.

This study was sponsored by Eli Lilly and Company. Willem Venekamp was an investigator in this study and is a member of a European Advisory Board for Eli Lilly and Company. Lisa Kerr, Sherie Dowsett, Patricia Johnson, Deborah Wimberley, Chris McKenzie, James Malone, and Zvonko Milicevic are full‑time employees and stockholders at Eli Lilly and Company.

References 1. The Diabetes Control and Complications Trial Research Group.

The effect of intensive treatment of diabetes on the development and progression of long‑term complications in insulin‑dependent diabetes mellitus. New Engl J Med 1993;329:977‑86

2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood‑glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352: 837‑53

3. Summers KH, Szeinbach SL, Lenox SM. Preference for insulin delivery systems among current insulin users and nonusers. Clin Ther 2004;26:1498‑505

4. Korytkowski M, Bell D, Jacobsen C, Suwannasari R, FlexPen Study Team. A multicenter, randomized, open‑label, compar‑ative, two‑period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003;25:2836‑48

5. Lteif AN, Schwenk WF. Accuracy of pen injectors versus insulin syringes in children with type 1 diabetes. Diabetes Care 1999;22:137‑40

6. Szeinbach SL, Barnes JH, Summers KH, Lenox SM. Develop‑ment of an instrument to assess expectations of and preference for an insulin injection pen compared with the vial and syringe. Clin Ther 2004;26:590‑7

7. Stokes M, Davis C, Koch G. Categorical data analysis using the SAS® system. Cary (NC): SAS Institute Inc.; 1995

CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO‑3235_5, Accepted for publication: 22 November 2005Published Online: 05 January 2006doi:10.1185/030079906X80477

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