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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.
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:
Visit 2 (Baseline:)
Visit 3 (approximately 3 weeks after starting first PN)
Visit 4 (approximately 3 weeks after starting second PN):
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 4 mm / 8 mm PN | Experimental | Subjects randomized to this study arm used either the 4mm PN or the 8mm PN for 3 weeks, then switched to the alternate PN for another 3 weeks. Order of PN use was randomly determined. |
|
| 4 mm / 5 mm PN | Experimental | Subjects randomized to this study arm used either the 4mm PN or the 5mm PN for 3 weeks, then switched to the alternate PN for another 3 weeks. Order of PN use was randomly determined. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 4mm x 32G pen needle | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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)]. | 3 weeks per pen needle, from visit 2-3 and visit 3-4. |
| Measure | Description | Time Frame |
|---|---|---|
| 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)]. | 3 weeks per pen needle, from visit 2-3 and visit 3-4. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | each PN was used for 3 weeks |
| Reported Injection Site Leakage Events, by Pen Needle Type and Droplet Size |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth Kassler-Taub, MD | Becton, Dickinson and Company | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Radiant Research | Birmingham | Alabama | 35209 | United States | ||
| AMCR Institute, Inc. |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20429832 | Result | Hirsch LJ, Gibney MA, Albanese J, Qu S, Kassler-Taub K, Klaff LJ, Bailey TS. Comparative glycemic control, safety and patient ratings for a new 4 mm x 32G insulin pen needle in adults with diabetes. Curr Med Res Opin. 2010 Jun;26(6):1531-41. doi: 10.1185/03007995.2010.482499. | |
| 22762347 | Derived | Hirsch LJ, Gibney MA, Li L, Berube J. Glycemic control, reported pain and leakage with a 4 mm x 32 G pen needle in obese and non-obese adults with diabetes: a post hoc analysis. Curr Med Res Opin. 2012 Aug;28(8):1305-11. doi: 10.1185/03007995.2012.709181. Epub 2012 Jul 18. |
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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.
Subjects were recruited at four independent research centers/diabetes clinics from June 2009 - October 2009
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| ID | Title | Description |
|---|---|---|
| FG000 | 4 mm / 8 mm PN | This group represents all subjects that were randomized to compare the 4mm and 8mm pen needle (PN) during the study. Each PN was used for 3 consecutive weeks; which PN was used first was based on the subject's randomization assignment. |
| FG001 | 4 mm / 5 mm PN | This group represents all subjects that were randomized to compare the 4mm and 5mm pen needle (PN) during the study. Each PN was used for 3 consecutive weeks; which PN was used first was based on the subject's randomization assignment. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 4 mm / 5 mm PN |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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)]. | 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). | Posted | Mean | 95% Confidence Interval | Percent absolute change | 3 weeks per pen needle, from visit 2-3 and visit 3-4. |
|
upon enrollment to study completion
Adverse events collection began once subjects were enrolled and continued throughout the 6 week randomized intervention period.
The Investigator considered all Serious Adverse Events as unlikely to be related to, or not related to, the study devices or procedures.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 8mm PN | All randomized subjects that used the 8 mm pen needle. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspepsia | Gastrointestinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment | all nonserious events including severe unexplained events as defined by the protocol |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kenneth Kassler-Taub, MD | BD Medical, Medical Affairs | 201 847 6729 | kenneth_kassler-taub@bd.com |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003924 | Diabetes Mellitus, Type 2 |
| D003920 | Diabetes Mellitus |
| D007333 | Insulin Resistance |
| D010146 | Pain |
| D007003 | Hypoglycemia |
| D006943 | Hyperglycemia |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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|
|
| 8mm x 31G pen needle | Device | 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. |
|
|
| 5mm x 31G pen needle | Device | 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. |
|
|
| 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. | During 3 weeks using each pen needle |
| 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. | During 3 weeks using each pen needle |
| 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. | Visit 4: 18-24 days after starting 2nd pen needle |
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. |
| each PN was used for 3 weeks |
| Escondido |
| California |
| 92026 |
| United States |
| Atlanta Diabetes Associates | Atlanta | Georgia | 30309 | United States |
| Rainier Clinical Research Center, Inc. | Renton | Washington | 98057 | United States |
| Lost to Follow-up |
|
| Protocol Violation |
|
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.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Diabetes Type | Number | Participants |
|
| Body Mass Index (BMI) | Mean | Full Range | kg/m² |
|
| Hemoglobin A1c (HbA1c) | A blood sample for HbA1c was collected at screening | Mean | Standard Deviation | percent |
|
| Insulin Dose Group | Subjects were assigned to an insulin dosing group (Low or Regular) based on their baseline regimen to help ensure balance among treatment arms. Low Dose: largest single dose of insulin a day, with a pen device, was <=20 units. Regular Dose: largest single dose of insulin a day, with a pen device, 21-40 units. | Number | participants |
|
| Single Largest Daily Insulin Dose | At baseline, subjects described their current insulin regimen, including the largest single daily insulin dose self-administered with a pen needle. | Mean | Full Range | Units |
|
| Serum Fructosamine Concentration | A blood sample was collected at baseline (Visit 2). | Mean | Standard Deviation | umol/L |
|
use of one PN for insulin injections for 3 weeks, followed by 3 weeks with the alternate PN |
| OG001 | 4 mm / 5 mm PN | use of one PN for insulin injections for 3 weeks, followed by 3 weeks with the alternate PN |
|
|
|
| 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)]. | 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. | Posted | Mean | 95% Confidence Interval | Percent absolute change | 3 weeks per pen needle, from visit 2-3 and visit 3-4. |
|
|
|
| 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. | 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. | Posted | Number | participants | During 3 weeks using each pen needle |
|
|
|
| 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. | 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. | Posted | Number | participants | During 3 weeks using each pen needle |
|
|
|
| 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. | Posted | Number | percent of subjects | each PN was used for 3 weeks |
|
|
|
| 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. | 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. | Posted | Mean | Standard Error | mm | Visit 4: 18-24 days after starting 2nd pen needle |
|
|
|
|
| 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. | 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. | Posted | Number | number of events | each PN was used for 3 weeks |
|
|
|
| 2 |
| 84 |
| 24 |
| 84 |
| EG001 | 5mm PN | All randomized subjects that used the 5 mm pen needle. | 0 | 89 | 23 | 89 |
| EG002 | 4mm PN | All randomized subjects that used the 4mm pen needle. | 4 | 173 | 40 | 173 |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypoglycemic seizure | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Myocardial infarction | Cardiac disorders | Non-systematic Assessment |
|
| Non-Hodgkins lymphoma | Blood and lymphatic system disorders | Non-systematic Assessment |
|
|
| hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment | all nonserious events including severe unexplained events as defined by the protocol |
|
| Pain at injection site | Injury, poisoning and procedural complications | Systematic Assessment | The investigator was not required to report mild, self-limited injection site pain as an adverse event |
|
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006946 | Hyperinsulinism |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
As described for the 4 vs. 5mm statistical analysis. |
| t-test, 1 sided |
| <0.001 |
| No |
| Superiority or Other |
| Title | Measurements |
|---|---|
|
| 3+, or 20 ul |
|
| 4+, or 50 ul |
|
| 5+, or > 50 ul |
|