DIABETES TECHNOLOGY & THERAPEUTICS
`Volume 10, Number 4, 2008
`© Mary Ann Liebert, Inc.
`DOI: 10.1089/dia.2008.0035
`
`Dosing Accuracy with a Novel Pen Device (SoloST AR®)
`as Performed by Patients with Diabetes in a Clinical Setting
`
`Norbert Hermanns, Ph.D., Bernhard Kulzer, Ph.D., and Thomas Haak, M.D.
`
`Abstract
`
`Background: Pen devices can help to overcome some of the barriers associated with insulin therapy. The pres(cid:173)
`ent study evaluated the accuracy of dose delivery by people with diabetes using the novel prefilled, dispos(cid:173)
`able SoloSTAR® device with insulin glargine (Lantus®) and insulin glulisine (Apidra®) (all from sanofi-aven(cid:173)
`tis, Paris, France).
`Methods: People with type 1 or type 2 diabetes (insulin users or insulin naive) were eligible to participate in
`this randomized, single-center, open-label study. Each participant delivered six separate insulin doses into a
`sponge using SoloSTAR (three with glargine [10, 40, and 80 units] and three with glulisine [5, 15, and 30 units]).
`Pens were weighed before and after each test dose to determine the dose delivered. Thresholds for dosing ac(cid:173)
`curacy were calculated according to the 2000 International Organization for Standardization (ISO) recommen(cid:173)
`dations (Guideline 11608-1).
`Results: All doses of glargine and glulisine delivered (60 participants; 360 individual doses) were within the
`ISO limits. Mean (standard deviation) glargine doses delivered were 9.87 (0.24), 39.63 (0.36), and 79.02 (0.62)
`units for 10, 40, and 80 units, respectively. Insulin glulisine doses delivered were 4.98 (0.20), 14.87 (0.29), and
`29.67 (0.34) units for 5, 15, and 30 units, respectively.
`Conclusions: The SoloST AR pen allows people with diabetes to achieve a dosing accuracy with glargine and
`glulisine similar to that achieved in laboratory conditions. The dosing accuracy and ease of use of SoloST AR
`may provide greater confidence in the precision and accuracy of the device while titrating glargine and/ or
`glulisine to goal.
`
`Introduction
`
`A LTHOUGH THE EFFICACY of insulin therapy is well estab(cid:173)
`
`lished in terms of reducing the risk of diabetes-related
`complications, 1,2 many barriers to its successful use by pa(cid:173)
`tients with diabetes exist, including hypoglycemia, social ac(cid:173)
`ceptability, and the individual's perceived ability to self(cid:173)
`manage his or her treatment with injections that may be
`difficult and painful to administer. 3
`The introduction of pen devices has increased patients' ac(cid:173)
`ceptance of insulin therapy, by helping to overcome the fear
`of injections associated with using a standard syringe.4,5 Pens
`can also increase accuracy of dosing (and, therefore, glyce(cid:173)
`mic control) in people with diabetes. 6- 8 However, the abil(cid:173)
`ity of patients to accurately administer the correct insulin
`dose can vary between pen devices. 6
`Accurate dosing with an easy-to-use device can increase
`a patient's confidence in his or her ability to self-manage di-
`
`abetes,6,9 leading to improved treatment adherence. 10,11
`SoloSTAR® (sanofi-aventis, Paris, France) is a disposable,
`prefilled insulin pen device for administration of insulin
`glargine (Lantus®; sanofi-aventis) or
`insulin glulisine
`(Apidra®; sanofi-aventis). Unlike other disposable insulin
`pens, the body of the SoloST AR pen is color coded to aid
`with the correct identification of basal and bolus insulins,
`even in patients with impaired vision. 12 In addition, the
`SoloST AR pen requires a lower injection force and can de(cid:173)
`liver a higher maximum dose than some other disposable
`pens. 13
`Laboratory studies have shown that using the SoloSTAR
`pen to deliver insulin glargine is highly accurate for three
`different doses, 13 according to procedures and standards de(cid:173)
`fined by the International Organization for Standardization
`(ISO) (Guideline 11608-1).14 However, accuracy in the lab
`does not necessarily reflect the real-life setting in which pa(cid:173)
`tients administer their own injections. Therefore, the present
`
`FIDAM GmbH, Forschungsinstitut Diabetes-Akademie, Bad-Mergentheim, Germany.
`
`322
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`SOLOSTAR DOSE ACCURACY BY PATIENTS
`
`323
`
`TABLE 1. PATIENT CHARACTERISTICS
`
`Characteristic
`
`Total number of patients
`Mean ± SD age (years)
`Female (n [%])
`Type of diabetes (n [%])
`Type 1
`Type 2
`Mean ± SD duration of diabetes (years)
`Diabetes therapy (n [%])
`Oral antidiabetic drugs
`Oral antidiabetic drugs + insulin
`Insulin
`Previous insulin pen experience (n [%])
`Mean ± SD duration of insulin therapy
`(years)
`Moderate motor impairment (n [%])
`Moderate visual impairment (n [%])
`
`study was designed to determine the dosing accuracy of
`SoloSTAR, when used by patients with diabetes to deliver
`clinically relevant doses of insulin glargine (10, 40, and 80
`units) and insulin gluisine (5, 15, and 30 units).
`
`Research Design and Methods
`
`Study design
`
`This was a prospective, open-label, single-center study,
`which was conducted over a period of 1 week at our dia(cid:173)
`betes research clinic (Forschungsintitut Diabetes GmbH,
`Bad-Mergentheim, Germany).
`
`Patients
`
`A minimum of 54 patients was considered sufficient to
`demonstrate validity of the study; considering that 10% of
`dose deliveries could be non-evaluable, the target sample
`size was 60 patients. Men and women 18-79 years old with
`
`60
`55.9 ± 13.0
`24 (40)
`
`11 (18)
`49 (82)
`14.0 ± 9.5
`
`6 (10)
`22 (37)
`32 (53)
`53 (88)
`8.1 ± 6.4
`
`7 (12)
`9 (15)
`
`• • •• • •• • . .........
`• • ... •
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`•
`
`♦
`
`...
`
`•
`...
`
`~
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`T
`
`A
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`e Q)
`"C
`. 2:
`Q)
`"C
`Q)
`VI
`0
`C
`
`11 .5
`
`11 .0
`
`10.5
`
`10.0
`
`9.5
`
`9.0
`
`8.5
`0
`
`B
`
`... T.
`
`I
`
`. ..........
`
`•
`
`•
`•
`•
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`•
`•
`•
`
`50
`
`60
`
`I
`
`I
`
`• •• •
`
`Upper limit (11.0 units) according to ISO 11608-1
`...
`•• •
`•
`••
`• •
`•
`
`...
`Lower limit (9 .0 units) according to ISO 11608-1
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`Upper limit (42 .0 units) according to ISO 11608-1
`
`. ..
`
`...
`
`♦ ♦
`
`...
`
`♦
`♦
`
`j
`43.0
`C:
`2. 42.0
`'g 41.0
`... Q)
`40.0
`.2:
`Q)
`"C
`~ 38.0
`0
`C
`
`37.0
`
`39.0
`
`'ii, 86.0
`~
`C:
`2.
`e Q)
`"C
`~
`Q)
`"C
`Q)
`VI
`0
`C
`
`84.0
`
`82.0
`
`80.0
`
`78.0
`
`76.0
`
`74.0
`
`... •
`•
`•••• ••
`... ••
`...
`T
`
`♦
`
`•
`...
`...
`....
`♦ • ••••
`• • ♦ • • • ••
`
`...
`:
`•• •••
`
`♦
`♦
`
`♦
`♦ :
`
`Lower limit (38.0 units) according to ISO 11608-1
`
`0
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`Upper limit (84.0 units) according to ISO 11608-1
`
`•
`
`60
`
`50
`
`I
`
`I
`
`C
`
`......
`
`T
`
`.. ••• ♦
`
`•
`♦ . . . . . • • • • • • ♦
`
`♦ •
`
`♦
`
`♦ ...
`
`•
`
`♦
`
`♦ ♦
`
`•
`
`•
`
`• T···· • • ♦ • • • T • • • ♦ T .
`........
`I
`
`Lower limit (76 .0 units) according to ISO 11608-1
`
`0
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`50
`
`60
`
`FIG. 1. Accuracy of the SoloSTAR pen when delivering (A) 10-, (B) 40-, and (C) 80-unit doses of insulin glargine. The up(cid:173)
`per and lower limits, as defined by the ISO standard, 11608-1, are indicated for each dose. Each data point represents the
`dose delivered by an individual person.
`
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`324
`
`HERMANNS ET AL.
`
`a confirmed diagnosis of type 1 or type 2 diabetes were eli(cid:173)
`gible to participate in the study. Patients were required to
`be current or past users of injectable insulin or to be insulin
`naive and considered to be candidates for initiation of in(cid:173)
`sulin therapy. Current insulin users with experience of dis(cid:173)
`posable pens (including SoloSTAR) and/or reusable pens
`were eligible to participate in the study. Patients were re(cid:173)
`quired to speak and read German.
`Exclusion criteria included the presence of a substance use
`disorder, severe visual or motor impairment, or a diagnosis
`of dementia, as recorded in the patient's medical files, which
`were reviewed after an initial screening visit. Patients with
`mental illnesses rendering them unable to understand the re(cid:173)
`quirements and implications of the study and those consid(cid:173)
`ered unlikely to adhere to the study protocol were also ex(cid:173)
`cluded. All patients provided written informed consent prior
`to study entry.
`A total of 63 patients participated in the study (Table 1).
`The majority of patients had type 2 diabetes (82%), the mean
`disease duration was 14 years, and 88% had previous expe(cid:173)
`rience with insulin pens. Seven participants had moderate
`motor impairment, and nine had moderate visual impair(cid:173)
`ment. All participants were instructed in the use of the
`SoloSTAR pens prior to the study. Results from three par(cid:173)
`ticipants were excluded. In one case, 15 units of insulin gluli(cid:173)
`sine was injected twice instead of one 5-unit and one 15-unit
`injection, in another case, a single patient was excluded for
`providing a second set of measurements, and in the third
`case, a patient with severe motor impairment was incorrectly
`included.
`
`Study design
`
`Patients were required to deliver six separate insulin in(cid:173)
`jections into a sponge. Study nurses demonstrated the use of
`SoloSTAR pen. Patients were asked if they had any ques(cid:173)
`tions regarding the use of the SoloSTAR pen. After that pa(cid:173)
`tients were requested to give a test injection of 10 units into
`a sponge.
`Each participant dialed and delivered three doses with the
`insulin glargine SoloSTAR pen (10, 40, and 80 units) and
`three doses with the insulin glulisine SoloSTAR pen (5, 15,
`and 30 units); the order of pen usage and dose delivery was
`randomized. Between the study doses, the pens were primed
`with an insulin dose of 2 units. The randomization list was
`generated by the lead investigator using SYSTAT (Systat
`Software, Inc., Chicago, IL) before the start of the study with
`allocations sealed in envelopes, which were opened by the
`nurse during the participant's visit.
`The SoloSTAR pens were weighed by the investigators fol(cid:173)
`lowing the priming doses and again following the test in(cid:173)
`jections delivered by the patients, using a precision balance
`(P 205 DR/M, Mettler Toledo GmbH, Giessen, Germany).
`Pens were fitted with 0.25-mm (31-gauge) X 8-mm needles
`(Becton Dickinson GmbH, Heidelberg, Germany) for all
`tests.
`
`Statistical analysis
`
`Dosing accuracy was assessed by comparing pre- and
`post-injection weights of the SoloSTAR pens. Mean± stan(cid:173)
`dard deviation (SD) of the delivered doses were calculated
`for each test dose for both insulins. The level of dosing ac-
`
`curacy was assessed by applying ISO analyses. 14 In brief, ISO
`11608-1, which is applicable for insulin pen devices, provides
`a set of criteria against which the dosing accuracy of an in(cid:173)
`sulin pen is assessed. Results are normally presented as mil(cid:173)
`liliters; for insulin formulations of 100 units/mL, results can
`be presented in units for easier interpretation (as has been
`done here).
`The ISO limits are as follows:
`
`• For doses of 2-20 units, the tolerance is ±5% (e.g., 38-42
`units for the 40-unit dose; Eq. 1)
`• For doses <20 units, the tolerance is ±0.01 mL (e.g., 4-6
`units for the 5-unit dose), as defined in the ISO recom(cid:173)
`mendations (ISO 11608-1)
`
`Further calculations were performed according to ISO
`11608-1, as shown in Eq. 2, to confirm whether the data sets
`were within the threshold limits. This calculation is valid for
`k values of 2.667, for a P value of 0.975, and with a 95% con(cid:173)
`fidence interval (CI).
`Upper threshold value = Vset + Vset · 5%
`
`Lower threshold value = Vset - Vset · 5%
`
`(1)
`
`where Vset = volume set (i.e., 40 units [0.4 mL]).
`x + (k · s) -,c:: upper threshold value
`
`x -
`
`(k · s) 2- lower threshold value
`
`(2)
`
`where s = standard deviation and x = mean dose delivered.
`The k value was derived from a lookup table, which was
`based on the number of samples and a P value of 0.975 with
`a 95% CI (using the Clopper-Pearson method). 14 The k value
`used was 2.667.
`A third evaluation was the proportion of doses delivered
`by the patients that were within the ISO ranges, with a suc(cid:173)
`cess criterion of 2-90%.
`
`TABLE 2. DOSE ACCURACY FOR INSULIN GLARGINE
`DELIVERED USING SowSTAR
`
`Target dose
`
`10 units (ISO limit, ±1 unit: 9, 11 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`40 units (ISO limit, ±5%: 38, 42 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`80 units (ISO limit, ±5%: 76, 84 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`
`Values for observed dose are mean:+: SD.
`"Calculated using Eq. 2.
`
`Dose (units)
`
`9.87 ± 0.24
`9.15
`10.54
`9.23
`10.50
`
`39.54 ± 0.36
`38.50
`40.33
`38.58
`40.49
`
`79.02 ± 0.62
`76.83
`80.31
`77.35
`80.69
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`SOLOSTAR DOSE ACCURACY BY PATIENTS
`
`325
`
`For statistical analysis the SYSTAT version 10.2 software
`(Systat Software, Inc.) was used.
`
`Results
`
`Accuracy of doses delivered
`
`For insulin glargine, the mean delivered dose in each test
`was marginally below the target dose (between -0.9 and
`-1.3%). For all three doses (10, 40, and 80 units), 100% of in(cid:173)
`dividual deliveries were within the established tolerance lim(cid:173)
`its according to the ISO standard (Fig. 1 and Table 2). When
`the data sets were analyzed, the 95% CI (Eq. 2) for each dose
`was within the tolerance limits, thus passing the ISO stan(cid:173)
`dards.
`The mean delivered dose in each test for insulin glulisine
`was marginally below the target dose (between -0.4 and
`-1.1 %). For all three doses (5, 15, and 30 units), 100% of in-
`
`dividual deliveries were within the established tolerance lim(cid:173)
`its according to the ISO standard (Fig. 2 and Table 3). When
`the data sets were analyzed, the 95% CI (Eq. 2) for each dose
`was within the tolerance limits, thus passing the ISO stan(cid:173)
`dards.
`The predefined success rate of ::>:90% of delivered doses
`within the ISO ranges was also achieved for both insulin
`glargine and insulin glulisine.
`
`Discussion
`
`The results of this study are consistent with those reported
`previously in a clinical setting, when used by patients with
`diabetes, and also in a laboratory setting, when delivered by
`trained technicians. As required for regulatory approval,
`and as previously demonstrated, 13 in a laboratory setting
`with doses delivered by technicians, the SoloSTAR device
`
`A
`
`I
`
`Upper limit (6 .0 units) according to ISO 11608-1
`
`I
`
`...
`~•·
`••••
`•• &
`.
`• •
`•
`•
`
`•
`
`•
`
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`•
`....
`y • • • •• •••
`•
`
`~
`
`~
`
`•
`•
`.... • •••••• y
`
`&
`
`•
`
`y
`
`"ii,
`
`-'i::
`
`2.
`'O
`e!
`Cl)
`. :?
`Cl)
`'O
`Cl)
`Ill
`0
`C
`
`6.5
`
`6.0
`
`5. 5
`
`5.0
`
`4.5
`
`4.0
`
`3.5
`
`•• • •
`•
`• •• . y • •
`
`50
`
`60
`
`I
`
`I
`
`Lower limit (4 .0 units) according to ISO 11608-1
`
`20
`
`30
`Dose number
`
`40
`
`Upper limit (16.0 units) according to ISO 11608-1
`
`I
`
`I
`
`0
`
`10
`
`B
`
`16.5
`
`16.0
`
`15.5
`
`15.0
`
`~
`
`y
`
`•
`
`.... y
`
`y
`
`"ii,
`:!::
`C:
`2.
`'O
`Cl) ... Cl)
`.:?
`ai
`'O
`Cl)
`Ill
`0
`C
`
`13.5
`0
`
`C
`
`• .
`•
`
`TY
`
`• •
`
`y
`
`14.5
`
`14.0
`
`. .. •
`•
`.
`.
`•
`•
`
`...
`
`....
`•
`
`•
`
`•
`• ....... •
`•
`•
`• ~•
`• •
`•••• • •
`••
`....
`....
`•
`
`•
`
`...
`
`...
`•
`•
`
`I
`
`Lower limit (14.0 units) according to ISO 11608-1
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`50
`
`60
`
`I
`
`u, 32 .5
`:!::
`32.0
`C:
`2. 31 .5
`31 .0
`'O
`e!
`30.5
`Cl)
`30.0
`.:?
`29 .5
`ai
`29 .0
`'O
`28.5
`Cl)
`Ill
`28 .0
`0
`C
`27 .5
`0
`
`• ·~
`
`.
`• ....
`•
`• •
`
`I
`
`~
`
`Upper limit (31 .5 units) according to ISO 11608-1
`
`I
`
`-
`
`•
`.... ... ....
`
`• •
`.... •• & . . . . . . .
`··••~
`••
`• •
`....
`
`y
`
`• • • • . . . . . . . . &
`
`....
`
`•
`•
`•. • ....
`•
`
`•
`
`.....
`
`....
`
`....
`
`....
`
`•
`I
`
`Lower limit (28.5 units) according to ISO 11608-1
`
`•
`I
`
`10
`
`20
`
`30
`Dose number
`
`40
`
`50
`
`60
`
`FIG. 2. Accuracy of the SoloSTAR pen when delivering (A) 5-, (B) 15-, and (C) 30-unit doses of insulin glulisine. The up(cid:173)
`per and lower limits, as defined by the ISO standard, 11608-1, are indicated for each dose. Each data point represents the
`dose delivered by an individual person.
`
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`

`

`326
`
`HERMANNS ET AL.
`
`TABLE 3. DOSE ACCURACY FOR INSULIN GLULISINE
`DELIVERED UsrNG SowSTAR
`
`Target dose
`
`5 units (ISO limit, ±1 unit: 4, 6 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`15 units (ISO limit, ±1 unit: 14, 16 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`30 units (ISO limit, ±5%: 28.5, 31.5 units)
`Observed dose
`Lowest dose delivered
`Highest dose delivered
`ISO calculated minimuma
`ISO calculated maximuma
`
`Values for observed dose are mean± SD.
`"Calculated using Eq. 2.
`
`Dose (units)
`
`4.98 ± 0.20
`4.50
`5.55
`4.44
`5.52
`
`14.87 ± 0.29
`14.07
`15.48
`14.09
`15.65
`
`29.67 ± 0.34
`28.93
`30.69
`28.76
`30.57
`
`achieved repeated doses and accuracy well within the ISO
`standards. In the clinical setting, people who had not previ(cid:173)
`ously used an insulin pen device were able to accurately de(cid:173)
`liver repeated doses of insulin glargine with the SoloSTAR
`pen. 15 The majority of participants in the present study were
`experienced in the use of insulin pens; therefore, this may
`be considered a true test of dosing accuracy rather than us(cid:173)
`ability of the SoloSTAR device.
`In the present study, we evaluated the inter-subject vari(cid:173)
`ability in dose accuracy. For future studies, it would also be
`of interest to evaluate the intra-subject variability to confirm
`whether people with diabetes can consistently deliver the re(cid:173)
`quired dose. In addition, future studies could also evaluate
`the dose accuracy of SoloSTAR compared with alternative
`pen devices or the vial and syringe, to investigate if other
`devices achieve the same standards when used by patients
`as shown here for SoloST AR.
`This study confirms that people with diabetes can achieve
`a level of accuracy with the SoloSTAR device similar to that
`of technicians in a controlled lab environment that is con(cid:173)
`sistently within ISO standards across the dosing range of the
`pen.
`
`Conclusions
`
`When considered together, the dosing accuracy and ease
`of use associated with the SoloSTAR device16,17 may en(cid:173)
`courage patients and healthcare professionals alike to strive
`for optimal glycemic control with greater confidence in the
`precision and accuracy of the device while titrating insulin
`glargine and/ or insulin glulisine to treatment goals.
`
`Acknowledgments
`
`This study was supported by sanofi-aventis. Editorial sup(cid:173)
`port was provided by the Global Publications Group of
`sanofi-aventis.
`
`Author Disclosure Statement
`
`N.H. is a member of the Global Diabetes educator advi(cid:173)
`sory board for Eli Lilly. B.K. is a member of an advisory
`board for Roche Diagnostics. T.H. is a member of the Global
`Advisory Board for sanofi-aventis.
`
`References
`
`1. Diabetes Control and Complications Trial Research Group:
`The effect of intensive treatment of diabetes on the devel(cid:173)
`opment and progression of long-term complications in in(cid:173)
`sulin-dependent diabetes mellitus. The Diabetes Control and
`Complications Trial Research Group. N Engl J Med 1993;
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`Sanofi Exhibit 2130.005
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`SOLOSTAR DOSE ACCURACY BY PATIENTS
`
`327
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`
`Address reprint requests to:
`Professor Norbert Hermanns, Ph.D.
`FIDAM GmbH
`Forschungsinstitut Diabetes-Akademie
`Theodor-Klotzbiicher-Strafle 12
`97980 Bad-Mergentheim, Germany
`
`E-mail: hermanns@diabetes-zentrum.de
`
`Sanofi Exhibit 2130.006
`Mylan v. Sanofi
`IPR2018-01676
`
`