Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2
Conditions
Keywords
Pen Needle, Diabetes, Insulin, Glycemic, Pain, Fructosamine, Leakage, Hypoglycemia, Hyperglycemia
Brief summary
Anxiety about needles is a commonly expressed concern by diabetics about beginning insulin therapy. A shorter, thinner pen needle that delivers insulin with the safety and efficacy profile of currently marketed pen needles may appeal to many diabetic patients as the new needle may be perceived as less intimidating and more comfortable. Currently marketed pen needles range in length from 5 to 12.7 millimeters (mm). The primary purpose of this study was to evaluate whether the investigational 4mm x 32 Gauge(G) pen needle manufactured by Becton, Dickinson and Company (BD) provides equivalent glucose control (as measured by fructosamine levels) as the currently marketed BD 5mm x 31 G and BD 8mm x 31 G pen needles (PN)in diabetic subjects with varying insulin dosage regimens.
Detailed description
Within each dose group, subjects were randomly assigned at baseline to one of two study arms. One study arm (4/5 mm PN) compared the BD 4mm PN to the 5mm PN, and the other arm (4/8 mm PN) compared the BD 4mm PN to the 8mm PN, in a crossover fashion. Based on the randomization, subjects used either the 4mm or the other assigned PN (5mm or 8mm) for the first 3 weeks, then switched to the alternate PN for the next 3 weeks. Glycemic control was assessed by serum fructosamine (FRU) levels at the end of each 3 week period. Based on their baseline insulin regimen, subjects were also assigned to an insulin dosing group (Low or Regular) to help ensure balance among treatment arms. Requirements for each group were as follows: Low Dose: largest single dose of insulin each day with a pen device must be less than or equal to 20 units. Regular Dose: largest single dose of insulin each day, with a pen device, must be 21-40 units. Explanation of Visits and Timing of Assessments: Visit 1: * Screening * Informed Consent * Demographics * Inclusion /Exclusion * Hemoglobin A1c measurement (HbA1c) Visit 2 (Baseline:) * Insulin dose group assignment (Low dose or Regular dose) * Randomization * Fructosamine blood sample collected * Dispense pen needle (PN) assigned first Visit 3 (approximately 3 weeks after starting first PN) * Pain rated by subject relative to baseline PN * Review Adverse Events (AEs) and reported events of injection site leakage * Fructosamine blood sample collected * Dispense second assigned PN Visit 4 (approximately 3 weeks after starting second PN): * Review AEs and reported events of injection site leakage * Fructosamine blood sample collected * Pain rated relative to previously used PN * Study Completion
Interventions
DEVICE4mm x 32G pen needle
For 3 weeks, subjects used this pen needle with their own pen device for all daily insulin injections they usually administered themselves with a pen device. Subjects followed their usual insulin regimen and there was no upper limit on total daily insulin dosage or number of injections. Subjects were advised to inject straight in when using the 4mm PN, with no pinch up.
DEVICE8mm x 31G pen needle
For 3 weeks, subjects used this pen needle with their own pen device for all daily insulin injections they usually administered themselves with a pen device. Subjects followed their usual insulin regimen and there was no upper limit on total daily insulin dosage or number of injections. Subjects were directed to use pinch-up when injecting in the abdomen or thigh with the 8mm PN, and no pinch-up at other injection sites.
DEVICE5mm x 31G pen needle
For 3 weeks, subjects used this pen needle with their own pen device for all daily insulin injections they usually administered themselves with a pen device. Subjects followed their usual insulin regimen and there was no upper limit on total daily insulin dosage or number of injections. Subjects were advised to inject straight in when using the 5mm PN, with no pinch up.
Sponsors
Becton, Dickinson and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Insulin requiring diabetics (type 1 or type 2) * Using a pen device for injections at least once per day, for at least two months prior to baseline (Study Visit Two). * 18 to 75 years of age, inclusive. * Body Mass Index from 18 to 50 kg/m², inclusive. * Hemoglobin A1c from 5.5 to 9.5 percent (%), inclusive. * Largest single dose of insulin a day less than or equal to 40 units
Exclusion criteria
* Current status or history of a medical condition that would contraindicate treatment with the study product or other conditions which, in the opinion of the Investigator, would place the subject at risk or have the potential to confound interpretation of the study results (i.e. recent history of ketoacidosis, hypoglycemic unawareness, etc.). * Hemophilia or any other disorder which causes excessive bleeding or requires frequent transfusions. * History of intravenous drug abuse (self-reported). * Bleeding disorder, hemophilia or subject is currently taking anti-coagulant medications (e.g., heparin, Coumadin®, warfarin). * Self-reported blood borne infection. * Pregnant (from medical history only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent (%) Absolute Change in Fructosamine | 3 weeks per pen needle, from visit 2-3 and visit 3-4. | Within each study arm (4mm / 5mm PN, or 4mm / 8mm PN) subjects used one pen needle (PN) for 3 weeks then switched to the alternate PN for the next three weeks, for a total of 6 weeks. The principal endpoint measure of glycemic control is the percent absolute change in serum fructosamine concentration, based on the fructosamine (FRU) concentration measured in micromoles per liter (umol/L) at the end of each three week period. The change was calculated according to the following formula: Percent absolute change in FRU, or %\|∆ FRU\|= 100\*\[FRU(4mm)-FRU(5 or 8mm)\]/\[FRU(5 or 8mm)\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Absolute Change in Fructosamine, by Dose Group | 3 weeks per pen needle, from visit 2-3 and visit 3-4. | Glycemic control was determined separately for each insulin dose group in the same manner as described for the primary outcome measure, according to the following formula: %\|∆ FRU\|= 100\*\[FRU(4mm)-FRU(5 or 8mm)\]/\[FRU(5 or 8mm)\]. |
| Number of Subjects With Severe Unexplained Hyperglycemic Events | During 3 weeks using each pen needle | Severe Unexplained Hyperglycemia is defined as requiring a visit to the emergency room or hospitalization and/or having a blood glucose value above 450mg/dL without an identified cause (for example, the subject missed an insulin dose). These events were also reported as Adverse Events. |
| Relative Injection Pain Score Assessed by Subject | Visit 4: 18-24 days after starting 2nd pen needle | After using the second assigned pen needle (PN) for 3 weeks, subjects used a 150mm Visual Analog Scale (VAS) to rate the pain of the second PN relative to the first PN. The VAS was anchored at the center (0mm) with as painful, and at the extreme ends with much less painful (-75mm) and much more painful (+75mm). VAS scores were adjusted for the order of PN use, such that a positive score means that the 4mm PN was scored as more painful than the reference PN (5mm or 8mm), and a negative score indicates that the 4mm PN was less painful than the reference. |
| Number of Subjects With Severe Unexplained Hypoglycemic Events | During 3 weeks using each pen needle | Severe Unexplained Hypoglycemia is defined as an event in which the subject's blood glucose is below 50 milligrams per deciliter (mg/dL) and/or they required assistance from another person for treatment and there is no identified cause (for example, the subject skipped a meal). These events were also reported as Adverse Events. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | each PN was used for 3 weeks | If insulin leakage from the injection site was observed, subjects rated the size of the leakage droplet based on a visual scale provided in their diaries. Scores of 1+, 2+, 3+, and 4+ correspond to droplet sizes of 1, 10, 20 and 50 ul, respectively. Droplets larger than those shown on the scale were scored as 5+. Subjects were not required to make a diary entry if there was no leakage. |
| Percentage of Subjects With at Least One Leakage Event | each PN was used for 3 weeks | After each insulin injection with a study pen needle, subjects recorded in their study diary if they observed insulin leakage from the injection site. Subjects were not required to make a diary entry if there was no leakage. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at four independent research centers/diabetes clinics from June 2009 - October 2009
Pre-assignment details
A total of 205 subjects were screened at four sites. Of those, 32 subjects did not satisfy eligibility criteria or withdrew consent prior to using the test products, and the remaining 173 subjects were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| 4 mm / 8 mm PN This group represents all subjects that were randomized to the study arm comparing the 4 mm and 8 mm pen needles, regardless of whether they completed the study. | 84 |
| 4 mm / 5 mm PN This group represents all subjects that were randomized to the study arm comparing the 4 mm and 5 mm pen needles, regardless of whether they completed the study. | 89 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | 4 mm / 5 mm PN | Total | 4 mm / 8 mm PN |
|---|---|---|---|
| Age Continuous | 53.8 years | 52.6 years | 51.3 years |
| Body Mass Index (BMI) | 30.9 kg/m² | 30.5 kg/m² | 30.1 kg/m² |
| Diabetes Type Type 1 diabetes | 34 Participants | 64 Participants | 30 Participants |
| Diabetes Type Type 2 diabetes | 55 Participants | 109 Participants | 54 Participants |
| Hemoglobin A1c (HbA1c) | 7.6 percent STANDARD_DEVIATION 1 | 7.5 percent STANDARD_DEVIATION 1 | 7.4 percent STANDARD_DEVIATION 1 |
| Insulin Dose Group Low Dose | 49 participants | 97 participants | 48 participants |
| Insulin Dose Group Regular Dose | 40 participants | 76 participants | 36 participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Black/African American | 16 Participants | 26 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White/Caucasian | 66 Participants | 133 Participants | 67 Participants |
| Serum Fructosamine Concentration | 301.5 umol/L STANDARD_DEVIATION 61 | 299.9 umol/L STANDARD_DEVIATION 55.1 | 298.3 umol/L STANDARD_DEVIATION 48.4 |
| Sex: Female, Male Female | 39 Participants | 75 Participants | 36 Participants |
| Sex: Female, Male Male | 50 Participants | 98 Participants | 48 Participants |
| Single Largest Daily Insulin Dose | 21.3 Units | 20.5 Units | 19.6 Units |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 84 | 23 / 89 | 40 / 173 |
| serious Total, serious adverse events | 2 / 84 | 0 / 89 | 4 / 173 |
Outcome results
Primary
Percent (%) Absolute Change in Fructosamine
Within each study arm (4mm / 5mm PN, or 4mm / 8mm PN) subjects used one pen needle (PN) for 3 weeks then switched to the alternate PN for the next three weeks, for a total of 6 weeks. The principal endpoint measure of glycemic control is the percent absolute change in serum fructosamine concentration, based on the fructosamine (FRU) concentration measured in micromoles per liter (umol/L) at the end of each three week period. The change was calculated according to the following formula: Percent absolute change in FRU, or %\|∆ FRU\|= 100\*\[FRU(4mm)-FRU(5 or 8mm)\]/\[FRU(5 or 8mm)\].
Time frame: 3 weeks per pen needle, from visit 2-3 and visit 3-4.
Population: 167 subjects completed the study. 163 of the 167 completed subjects were included in this analysis. Four (4) of 167 were excluded due to out of window fructosamine samples (3), or laboratory error with fructosamine sample (1).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 4 mm / 8 mm PN | Percent (%) Absolute Change in Fructosamine | 5.5 Percent absolute change |
| 4 mm / 5 mm PN | Percent (%) Absolute Change in Fructosamine | 4.9 Percent absolute change |
Comparison: The effects of pen needle type on glycemic control were tested for statistical significance using analysis of variance (ANOVA). The ANOVA model was used to calculate the absolute percent (%)change in fructosamine (% \|∆ Fru\|), with 95 % confidence intervals.p-value: 0.506ANOVA
Comparison: The effects of pen needle type on glycemic control were tested for statistical significance using ANOVA. The ANOVA model was used to calculate the % \|∆ Fru\|, with 95% confidence intervals.p-value: 0.878ANOVA
Secondary
Number of Subjects With Severe Unexplained Hyperglycemic Events
Severe Unexplained Hyperglycemia is defined as requiring a visit to the emergency room or hospitalization and/or having a blood glucose value above 450mg/dL without an identified cause (for example, the subject missed an insulin dose). These events were also reported as Adverse Events.
Time frame: During 3 weeks using each pen needle
Population: All subjects that were randomized and used at least one of the study pen needles are included. The number of subjects with one or more events while using each PN is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4 mm / 8 mm PN | Number of Subjects With Severe Unexplained Hyperglycemic Events | 0 participants |
| 4 mm / 5 mm PN | Number of Subjects With Severe Unexplained Hyperglycemic Events | 2 participants |
| 8 mm PN | Number of Subjects With Severe Unexplained Hyperglycemic Events | 1 participants |
Secondary
Number of Subjects With Severe Unexplained Hypoglycemic Events
Severe Unexplained Hypoglycemia is defined as an event in which the subject's blood glucose is below 50 milligrams per deciliter (mg/dL) and/or they required assistance from another person for treatment and there is no identified cause (for example, the subject skipped a meal). These events were also reported as Adverse Events.
Time frame: During 3 weeks using each pen needle
Population: All subjects that were randomized and used at least one of the study pen needles are included. The number of subjects with one or more events while using each PN is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4 mm / 8 mm PN | Number of Subjects With Severe Unexplained Hypoglycemic Events | 5 participants |
| 4 mm / 5 mm PN | Number of Subjects With Severe Unexplained Hypoglycemic Events | 5 participants |
| 8 mm PN | Number of Subjects With Severe Unexplained Hypoglycemic Events | 4 participants |
Secondary
Percent Absolute Change in Fructosamine, by Dose Group
Glycemic control was determined separately for each insulin dose group in the same manner as described for the primary outcome measure, according to the following formula: %\|∆ FRU\|= 100\*\[FRU(4mm)-FRU(5 or 8mm)\]/\[FRU(5 or 8mm)\].
Time frame: 3 weeks per pen needle, from visit 2-3 and visit 3-4.
Population: 4 of the 167 completed subjects were excluded for out of window fructosamine samples (3), or lab error with a sample (1).~For 4 mm/8 mm: this includes 45 subjects in the Low Dose insulin group and 35 in the Regular Dose group. For 4 mm/5 mm: this includes 47 subjects in the Low Dose insulin group and 36 in the Regular Dose group.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| 4 mm / 8 mm PN | Percent Absolute Change in Fructosamine, by Dose Group | Low Insulin Dose Group | 5.5 Percent absolute change |
| 4 mm / 8 mm PN | Percent Absolute Change in Fructosamine, by Dose Group | Regular Insulin Dose Group | 5.3 Percent absolute change |
| 4 mm / 5 mm PN | Percent Absolute Change in Fructosamine, by Dose Group | Low Insulin Dose Group | 5.5 Percent absolute change |
| 4 mm / 5 mm PN | Percent Absolute Change in Fructosamine, by Dose Group | Regular Insulin Dose Group | 4.2 Percent absolute change |
Secondary
Relative Injection Pain Score Assessed by Subject
After using the second assigned pen needle (PN) for 3 weeks, subjects used a 150mm Visual Analog Scale (VAS) to rate the pain of the second PN relative to the first PN. The VAS was anchored at the center (0mm) with as painful, and at the extreme ends with much less painful (-75mm) and much more painful (+75mm). VAS scores were adjusted for the order of PN use, such that a positive score means that the 4mm PN was scored as more painful than the reference PN (5mm or 8mm), and a negative score indicates that the 4mm PN was less painful than the reference.
Time frame: Visit 4: 18-24 days after starting 2nd pen needle
Population: Of the 167 subjects that completed the study, 137 subjects had within-window VAS pain scores for Visit 4 and were included in this analysis. Per the protocol, the allowable visit window was 18-24 days from Visit 3, when the subject switched from the 1st to 2nd assigned pen needle.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 4 mm / 8 mm PN | Relative Injection Pain Score Assessed by Subject | -23.26 mm | Standard Error 4.24 |
| 4 mm / 5 mm PN | Relative Injection Pain Score Assessed by Subject | -11.91 mm | Standard Error 5.61 |
Comparison: The null hypothesis is that the pain from the 4mm is the same or greater than the pain for the reference. The alternative hypothesis is that the pain from the 4mm is less than the pain for the reference.p-value: 0.019t-test, 1 sided
Comparison: As described for the 4 vs. 5mm statistical analysis.p-value: <0.001t-test, 1 sided
Other Pre-specified
Percentage of Subjects With at Least One Leakage Event
After each insulin injection with a study pen needle, subjects recorded in their study diary if they observed insulin leakage from the injection site. Subjects were not required to make a diary entry if there was no leakage.
Time frame: each PN was used for 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 4 mm / 8 mm PN | Percentage of Subjects With at Least One Leakage Event | 44 percent of subjects |
| 4 mm / 5 mm PN | Percentage of Subjects With at Least One Leakage Event | 47 percent of subjects |
| 8 mm PN | Percentage of Subjects With at Least One Leakage Event | 56 percent of subjects |
Other Pre-specified
Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size
If insulin leakage from the injection site was observed, subjects rated the size of the leakage droplet based on a visual scale provided in their diaries. Scores of 1+, 2+, 3+, and 4+ correspond to droplet sizes of 1, 10, 20 and 50 ul, respectively. Droplets larger than those shown on the scale were scored as 5+. Subjects were not required to make a diary entry if there was no leakage.
Time frame: each PN was used for 3 weeks
Population: The number of participants shown is the number of subjects that reported at least one event of leakage (see previous data table). The number of reported leakage events is presented for each droplet size category. No data were collected if there was no leakage.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 4 mm / 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 4+, or 50 ul | 12 number of events |
| 4 mm / 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 3+, or 20 ul | 44 number of events |
| 4 mm / 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 1+, or 1 ul | 372 number of events |
| 4 mm / 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 2+, or 10 ul | 221 number of events |
| 4 mm / 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 5+, or > 50 ul | 1 number of events |
| 4 mm / 5 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 3+, or 20 ul | 50 number of events |
| 4 mm / 5 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 1+, or 1 ul | 289 number of events |
| 4 mm / 5 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 2+, or 10 ul | 120 number of events |
| 4 mm / 5 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 4+, or 50 ul | 20 number of events |
| 4 mm / 5 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 5+, or > 50 ul | 2 number of events |
| 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 5+, or > 50 ul | 1 number of events |
| 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 4+, or 50 ul | 5 number of events |
| 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 1+, or 1 ul | 200 number of events |
| 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 3+, or 20 ul | 25 number of events |
| 8 mm PN | Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size | 2+, or 10 ul | 126 number of events |