CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`

`

`Summary Basis for Regulatory Action
`
`May 2, 2011
`Curtis J. Rosebraugh, MD, MPH
`Director, Office of Drug Evaluation II
`Summary Review
`NDA 20-280
`
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Tradjenta
`Linagliptin
`
`Tablet
`5 mg
`To improve glycemic control in adults with T2DM as an adjunct to diet
`and exercise
`Approval
`
`Subject
`NDA/BLA #
`Supp #
`Applicant Name
`Proprietary /
`Established
`(USAN) Names
`Dosage Forms /
`Strength
`Proposed
`Indication(s)
`Action:
`
`Introduction
`
`This review will be a brief summary of the basis for the regulatory action regarding linagliptin
`and the reader should refer to the reviews in the action package for a more detailed discussion.
`Linagliptin is an inhibitor of the serine protease enzyme - dipeptidyl peptidase IV (DPP-4)
`which is responsible for the rapid degradation of the incretin hormones, glucagon-like peptide-
`1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are short-
`lived intestinal peptides released in response to food ingestion that have an inhibitory effect on
`glucagon (which would result on inhibiting hepatic glucose synthesis) and an enhancing effect
`on insulin secretion when serum glucose is elevated. DPP-4 inhibitors therefore enhance the
`effect of the incretins by increasing their circulating half-life. While this is a relatively new
`class of anti-diabetic therapy, we have had several applications that have provided us with
`experience regarding this drug category. We also have approved two other DPP-4 inhibitors,
`Januvia (saxagliptin) and Onglyza (sitagliptin) which provides us with marketing safety
`information.
`
`There have been safety concerns with anti-diabetic drugs in general, and some specific issues
`for the DPP-4 drugs, which require attention. From a general safety standpoint common to all
`anti-diabetic drugs, there have been concerns regarding the cardiovascular safety of certain
`diabetic drugs. This has led to requiring evidence that new anti-diabetes drugs are not
`associated with increased cardiovascular risks. Guidance1 has been issued that allows for a
`two-step, ‘step-wise’ assessment of potential cardiovascular risk during drug development.
`The first step, ‘step-one’, is to make a determination that the investigational agent has an upper
`bound of a two-sided 95 percent confidence interval for the estimated risk ratio of less than 1.8
`compared to a control group (with a point estimate near unity). For this first step, we have not
`
`1 Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,
`December 2008, Clinical/Medical.
`
`
`Date
`From
`
`Reference ID: 2940733
`
`

`

`
`
`specified what the control group will be, but we have allowed most of the companies that were
`in late Phase 3 development to use a pooling of comparators. Assuring that there is not an
`eighty percent increase in risk would allow marketing while a longer and larger outcome
`study, which would assure even less risk, is conducted. The boundary of 1.8 was chosen
`because a more conservative ‘goal-post’ to pre-approval testing would be too
`burdensome/prohibitive to drug develop, but this level of assurance (1.8) would be feasible
`and would provide some assurances while further testing was underway. The ‘step-two’
`testing would be accomplished by a larger outcome study that must demonstrate that the
`investigational agent has an upper bound of a two-sided 95 percent confidence interval for the
`estimated risk ratio of less than 1.3 compared to a control group in order for marketing to
`continue and a point estimate near unity. While not explicitly stated in guidance, the control
`group should be chosen such that is known to itself not have a cardiovascular risk (placebo
`comparator add-on to balanced background therapy with rescue as needed). Linagliptin does
`fulfill the criteria that would allow marketing with a post-marketing requirement for a
`definitive trial.
`
`There has been concern with the DPP-4 inhibitors in regard to their potential adverse event
`profile based on whether they have promiscuity toward other DPP enzymes, in particular DPP-
`8/9. During development of a different DPP-4 agent, it was noted that monkeys developed
`dose and duration dependent cutaneous lesions that ranged from some flaking and blistering to
`frank ulceration and necrosis requiring euthanasia of the animals. These findings prevented
`the marketing of this other DPP-4 agent. Both saxagliptin and sitagliptin were very specific
`for DPP-4 (as is linagliptin) and did not have a preclinical signal which allowed for their
`approval for marketing. The nonclinical data for linagliptin also indicates specificity for DPP-
`4 and did not demonstrate a signal of concern.
`
`There have been postmarketing reports of pancreatitis in association with drugs working
`through the incretin system. The nonclinical evaluations of incretin drugs performed by the
`sponsors have been negative for this concern, but there is published literature of animal studies
`that conflicts. Additionally, there have been epidemiologic studies that are also conflicting,
`some showing potential risk while others do not. With that in mind, we look closely for this
`potential with drugs whose mechanism of action is through the incretin system. Linagliptin’s
`package does not contain evidence of this potential that stands out from other DPP-4 agents
`with which we have experience.
`
`The clinical development program for linagliptin is typical of most anti-diabetics and has
`clearly demonstrated efficacy. There has not been any safety signals identified not associated
`with the other marketed DPP-4 drugs. As such, the Division and I agree that linagliptin may
`be approved for marketing as long as appropriate labeling can be agreed upon.
`
`Efficacy
`
`This has been thoroughly discussed in Drs. Parks, Irony, Dunn and Liu reviews and I agree
`with their conclusions. Appropriate dose ranging was performed, and as outlined in the other
`reviews, I agree with the dose selected. Seven Phase 3 trials were performed to demonstrate
`efficacy. The primary efficacy endpoint in all trials was percent change in HbA1c from
`
`
`
`Reference ID: 2940733
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`2
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`

`

`163
`8%
`+0.25 (0.07)
`
`
`
`167
`8%
`+0.26 (0.08)
`
`
`
`333
`8%
`-0.44 (0.05)
`
`
`-0.69 (-0.85,-0.53)
`
`336
`8%
`-0.45 (0.05)
`
`
`-0.71 (-0.89,-0.53)
`
`
`
`Placebo
`
`Linagliptin 5 mg
`
`baseline. Trials 1218.16 and 1218.50 were performed to evaluate monotherapy and the results
`are presented below from Dr. Parks’s review (page 12).
`
`Table 5. Study 1218.16 Primary Efficacy Results
`
`Sponsor’s Analysis*
`Number of patients
`Baseline mean HbA1c
`Adjusted mean chg from baseline (SE)
`
`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
`
`FDA’s Analysis**
`Number of patients
`Baseline mean HbA1c
`Adjusted mean chg from baseline (SE)
`
`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
`
`*Analysis of covariance method w/ treatment and prior anti-DM as fixed effects and baseline HbA1c as linear covariate on
`full analysis set
`**mixed model repeated measures method with visit week as an additional fixed effect on the observed completers population
`
`Table 6. Study 1218.50 Primary Efficacy Results (FDA analysis)
`
`Placebo
`Number of patients
`76
`Baseline mean HbA1c
`8.09%
`Adjusted mean chg from baseline (SE)
`+0.25 (0.13)
`
`
`
`Linagliptin 5 mg
`155
`8.12%
`-0.33 (0.09)
`
`
`-0.57 (-0.89,-0.26)
`
`Adjusted mean treatment difference
`(linagliptin-pbo) 95% CI
`
`
`
`Both of these trials confirm the effectiveness of linagliptin 5 mg daily as monotherapy. Dr.
`Parks notes that Phase 2 trials indicate that metformin and glimepiride provide greater
`glycemic control (data not presented here) and that is a fair assessment as well.
`
`Five Phase 3 trials evaluated the addition of linagliptin to other anti-diabetic therapies. Four of
`these trials compared linagliptin add-on to placebo add-on in patients who had not achieved
`adequate glycemic control on other anti-diabetic therapies and are presented in the table below
`from Dr. Parks’s review (page 13-14).
`
`Table 7. Glycemic Control Efficacy Results in Linagliptin Add-on, Placebo-controlled Trials
`Placebo
`Linagliptin
`
`
`
`
`
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`Reference ID: 2940733
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`3
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`

`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline
`(SE)
`Adjusted mean treatment diff (95%
`CI)
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline
`(SE)
`Adjusted mean treatment diff (95%
`CI)
`
`
`
`
`Study 1218.15 (24 wks)
`Compared lina+pio to
`pbo+pio in drug-naïve or
`patients wash-out of current
`anti-DM therapies
`24-wk trial
`
`Study 1218.17 (24 wks)
`Compared lina+metformin
`to pbo+metformin in patient
`inadequately controlled on
`metformin
`
`
`Study 1218.18 (24 wks)
`Compared lina + met/su to
`pbo + met/su in patients
`inadequately controlled on
`met/su
`
`
`Study 1218.35 (18 wks)
`Compared lina+SU to
`pbo+SU in patients
`inadequately controlled on
`SU
`
`
`130
`8.6 (0.08)
`-0.85 (0.09)
`
`
`
`177
`8.0 (0.07)
`0.08 (0.07)
`
`
`
`263
`8.1 (0.05)
`-0.11 (0.05)
`
`
`
`84
`8.6 (0.08)
`-0.13 (0.10)
`
`
`259
`8.6 (0.05)
`-1.30 (0.06)
`-0.46 (-0.67, -0.24)
`
`
`523
`8.1 (0.04)
`-0.58 (0.04)
`-0.66 (-0.82,-0.50)
`
`
`792
`8.2 (0.03)
`-0.72 (0.03)
`-0.61 (-0.73, -0.49)
`
`
`161
`8.6 (0.07)
`-0.60 (0.07)
`-0.47 (-0.71,-0.22)
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline
`(SE)
`Adjusted mean treatment diff (95%
`CI)
`
` N
`
`
`Mean baseline HbA1c (SE)
`Adjusted mean chg from baseline
`(SE)
`Adjusted mean treatment diff (95%
`CI)
`
` N
`
`
`These trials confirm the effectiveness of linagliptin 5 mg daily as add-on therapy.
`
`The final Phase 3 trial (Study 1218.20) was an active-control trial comparing linagliptin 5 mg
`daily to glimepiride. This trial was designed to be a 104-wk (2-yr) trial with only the interim
`results presented (52 wk data). The primary hypothesis is that linagliptin is non-inferior to
`glimepiride. It is important to note that this trial was the longest in duration, and provides the
`bulk of the CV safety data used in the meta-analysis. The results from Dr. Parks review (page
`14) are below.
`
`
`After 52 weeks of treatment, the mean treatment difference in HbA1c from
`baseline of linagliptin compared to glimepiride was 0.20% (97.5% CI: 0.11,
`0.30) based on the FDA analysis (note that Table 3.1.10 in Dr. Liu’s review
`has the treatment difference reversed wherein negative values should be
`positive and the 97.5% boundaries are presented in reverse order – upper to
`lower bound).
`
`Linaglipin 5 mg daily dosing yielded lower glycemic control than glimepiride
`1 to 4 mg with the loss in efficacy potentially being as higher as 0.30%.
`Although the upper bound of the 97.5% CI is still below the pre-specified NI
`margin of 0.35%, it should also be noted that the lower bound excludes zero,
`
`
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`Reference ID: 2940733
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`4
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`indicating that linagliptin is both statistically non-inferior and inferior to
`glimepiride.
`
`
`
` I
`
` agree that the non-inferiority confidence interval does not cross zero, and for all intents and
`purposes linagliptin is less effective than glimepiride. I also note that the glimepiride dose was
`limited to 4 mg per day, while the label indicates the highest dose is 8 mg per day. This
`indicates that the differences of effect may have been even larger if the maximal dose of
`glimepiride had been used. It is not surprising, based upon the results of the Phase 2 trials, that
`linagliptin yielded lower glycemic control than glimepiride.
`
` I
`
` believe the totality of the data indicate that linagliptin is an effective anti-diabetic agent, but
`may not be as effective as other anti-diabetic agents of different classes.
`
`
`Safety
`
`As noted above, we now require assessment of potential cardiovascular risk of anti-diabetic
`medications during development. This clinical development program was in Phase 3
`development at the time of our Guidance issuance. As with previous anti-diabetic drug
`applications that were in late phase development during our policy change regarding
`cardiovascular assessment, a meta-analysis of Phase 2 and 3 trials was conducted. It should be
`noted that the analysis in this application was not prospectively designed as future programs
`are required to do because of the late stage of development. Below are summary tables from
`Dr. Parks’ review (page 16-19) of the trials included, number of events per trial and results.
`
`Table 8. Trials Included in CV Meta-analysis
`
`Description of
`Linagliptin
`trials/design
`considered in
`MA
`24-wks, placebo-
`controlled
`
`Placebo
`
`Active
`Comparators
`
`259
`336
`524
`793
`
`130
`167
`177
`265
`
`-
`-
`-
`-
`
`52-wks, active-
`control
`(glimepiride)
`
`12-wk, placebo-
`controlled
`26-wk, active-
`controlled
`(voglibose)
`
`18-wks, placebo-
`
`779
`
`319
`
`161
`
`5
`
`-
`
`80
`
`84
`
`781
`
`162
`
`-
`
`Study 1218.15
`Study 1218.16
`Study 1218.17
`Study 1218.18
`
`Study 1218.20*
`
`
`Study 1218.23**
`
`
`Study 1218.35
`
`
`
`Reference ID: 2940733
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`

`

`*Trial is 104-wk long but only 52-wk interim data reviewed
`**Trial has 4 treatment arms with different objectives: 12-wk comparison to pbo and 26-wk comparison to voglibose
`***Trial has 2nd phase, double-blind, active control using glimepiride. Only 18wk data reviewed
`
`
`-
`
`943
`-781 glimepiride
`-162 voglibose
`
`
`
`Study 1218.50***
`
`Number of patients
`
`controlled
`
`151
`
`3322
`
`76
`
`979
`
`
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`Reference ID: 2940733
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`
`
`Table 10. Summary of Events of Primary Composite Endpoint by Study and Treatment Group
`(Safety Population) – Table obtained from FDA statistical review
`
`
`
`Comparator
`
`23/1920 (1.2%)
`11/3319 (0.33%)
`-0.69% (-1.17, -0.21%)
`0.34 (0.15, 0.74)
`0.36 (0.16, 0.78)
`
`3/1139 (0.26%)
`8/2541 (0.31%)
`0.06% (-0.34, 0.46%)
`1.21 (0.35, 4.26)
`1.23 (0.29, 7.27)
`
`3/977 (0.31%)
`6/2541 (0.24%)
`-0.04% (-0.45, 0.37%)
`0.86 (0.23, 3.26)
`0.85 (0.18, 5.32)
`
`
`Table 11. Analyses of Incidence of Primary CV Composite Endpoint in Meta-Analysis
`(adapted from review by Drs. Ding and Soukup)
`
`
`Linagliptin
`Overall Results
`Incidence of Events
`MH Risk Difference (95% CI)
`MH Relative Risk Ratio (95% CI)
`Exact Stratified OR (95% CI)
`
`Excluding Study 1218.20
`Incidence of Events
`MH Risk Difference (95% CI)
`MH Relative Risk Ratio (95% CI)
`Exact Stratified OR (95% CI)
`
`Linagliptin vs Placebo Controls Only
`Incidence of Events
`MH Risk Difference (95% CI)
`MH Relative Risk Ratio (95% CI)
`Exact Stratified OR (95% CI)
`
`
`
`
`
`
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`Reference ID: 2940733
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`

`
`
`
`These results demonstrate that overall, linagliptin had a point estimate less than 1 and an upper
`confidence interval less than 1.8. This fulfills criteria for marketing approval, but must be
`viewed with great caution because this was an unplanned analysis, evaluated low risk subjects,
`there were imbalances in Framingham risk score in groups with higher risk in the groups
`compared to linagliptin, there were few events, and one trial (1218.20) drove the analysis.
`Trial 1218.20 compared linagliptin to an active comparator (glimepiride) and not against
`placebo. While the results compared to glimepiride may seem to indicate that linagliptin does
`not have a cardiovascular risk or may even look favorable, this interpretation is not
`supportable at this time. We do not know whether linagliptin has an intrinsic risk or not,
`because we do not know the cardiovascular risk status of glimepiride (in addition to the issues
`I mention above). The most that can be said is that there does not seem to be any greater risk
`than with an already marketed drug, recognizing that we do not know what the risk associated
`with glimepiride may be. A definitive cardiovascular safety trial comparing linagliptin to a
`comparator that is known to not have a cardiovascular risk (likely placebo on balanced
`background therapy as all the others have done) will be necessary for accurate assessment.
`
`Hypoglycemia, as noted for all the DPP-4 inhibitor drugs when co-administered with other
`anti-diabetic drugs (insulin secretagogues), was noted. The rate seems comparable to other
`agents in this class.
`
`Hypersensitivity and exfoliative reactions have been noted with other DPP-4 agents. There
`was a slight imbalance not favoring linagliptin, but this is based on a limited number of events,
`so is fragile at best. However, as this does seem to be a class effect, we should expect that
`there will be events with marketing approval, and labeling should reflect the potential of this
`type of reaction.
`
`Pancreatitis has been reported in spontaneous postmarketing reports for exenatide and
`sitagliptin. It is unknown what role incretin agents may have in pancreatitis. Patients with
`diabetes may have up to a 3-fold2 increased rate compared to matched controls making this a
`common event which makes post-marketing reporting even more difficult to interpret
`(compared to assessment of rare events). Also confusing the safety issue is that healthclaims
`databases and animal studies have conflicting results regarding incretins possible association
`with pancreatitis. There were numerical imbalances of pancreatitis in this database (which
`may not be exist when time-exposure is considered) not favoring linagliptin, but there was a
`small number of events making the data too fragile upon which to draw conclusions. As with
`the other agents in this class, labeling should reflect this concern and the sponsor will be
`conducting required post-marketing evaluation.
`
`Advisory Committee
`
`This application was not discussed before a public advisory committee for the following
`reasons:
`•
`it is not a first-in-class anti-diabetic therapy
`
`2 Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease
`observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009 May; 32(5):834-8
`
`
`
`Reference ID: 2940733
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`8
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`
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`•
`
`the indication sought is based on a well-established efficacy endpoint used in the
`approval of 11 different classes of anti-diabetic therapies
`• clinical trials assessing efficacy and safety are typical of diabetes programs for
`approval of anti-diabetic therapies
`• no unexpected nonclinical or clinical safety concerns were identified
`
`
`Conclusions and Recommendations
`
`
`The data submitted support that there is an appropriate risk-benefit to allow marketing of
`linagliptin. Thus, I recommend approval with appropriate labeling and PMR commitments as
`outlined in Dr. Parks’ review. The sponsor must conduct a Post Marketing Requirement
`(PMR) to further evaluate any potential cardiovascular effects, and as part of that trial obtain
`further data regarding potential pancreatitis.
`
`Regarding the cardiovascular safety PMR, the sponsor has already begun an active-control
`trial comparing linagliptin to glimepiride in the Cardiovascular Safety of Linagliptin vs
`Glimepiride in Patients with T2DM at High CV Risk (CAROLINA). This proposal is unique
`compared to the other outcome trials we have required as it would compare linagliptin to an
`active control (upon balanced baseline therapy) instead of placebo. It is important to recognize
`that many currently market drugs do not have assessment of their cardiovascular risk, and any
`information on their risk would be valuable. The proposed trial design could give us a relative
`comparison of two drugs. However, this trial design does not answer whether there is any
`cardiovascular risk that is intrinsic to linagliptin itself as we do not know if glimepiride has a
`risk and there is not a control arm (placebo) upon which to make comparisons. Therefore, the
`cardiovascular risk of linagliptin can only be answered in a placebo control trial. Trying to
`draw conclusions based on CAROLINA could lead us to make erroneous assumptions. As an
`example, suppose, as an academic exercise, that glimepiride has a 2.5-fold increase in
`cardiovascular events compared to placebo. With the current trial design, linagliptin could
`have a 2-fold increase in cardiovascular events, be determined to be ‘superior’ regarding
`cardiovascular risk to glimepiride, but still carry an excess risk that we would not know about
`because of the lack of a placebo control. This may draw clinicians to the false assumption that
`linagliptin was free of cardiovascular events (although in this premise it would have less
`toxicity than glimepiride), when in fact it is not. Carrying this exercise even further, if those
`drugs that are comparing themselves to placebo are found not to have a risk, they may still be
`considered less desirable than linagliptin in our above example because linagliptin would have
`demonstrated an advantage to glimepiride, while in fact it may still have a risk greater than
`placebo and the drugs demonstrating non-inferiority or superiority to placebo (on background
`therapy). Even worse, carrying our hypothetical example above further, consider if linagliptin
`was considered non-inferior to glimepiride. Then both marketed drugs would have a 2.5-fold
`increase, and we would not know it. Therefore, while it may tempt some to consider that a
`risk similar to a marketed drug is appropriate (or this comparison tempting as it may define the
`risk of marketed drugs), lack of knowledge regarding marketed drugs should not influence us
`to allow approval and marketing of new anti-diabetic drugs with potentially equally adverse
`cardiovascular effects. This would defeat the purpose of our initiative to not allow marketing
`of anti-diabetic drugs with cardiovascular risk.
`
`
`
`Reference ID: 2940733
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`9
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`

`
`
`
`What would be the most useful is to add a placebo arm to CAROLINA. Although I don’t
`think we could require the sponsor to include an active control (glimepiride) in a
`cardiovascular safety trial, the information would be very valuable to the medical profession.
`As stated though, I do not think, under our current regulatory authority, that we can require
`more than a placebo trial, and CAROLINA will have to be altered to have a placebo control
`for the primary analysis or the sponsor will have to conduct an independent placebo control
`cardiovascular safety trial. However, if the sponsor would care to go to the added expense of
`having an active control, it would be an important question to answer (cardiovascular risks
`associated with a drug in the sulfonylurea class), and something the medical community would
`greatly appreciate. From the sponsor’s standpoint, should they demonstrate convincing
`evidence of greater cardiovascular safety compared to glimepiride, this could potentially lead
`to labeling (depending on the comparison to placebo).
`
`
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`Reference ID: 2940733
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`10
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CURTIS J ROSEBRAUGH
`05/02/2011
`
`Reference ID: 2940733
`
`