Glucagon Nasal Powder:A Promising Alternativeto Intramuscular Glucagonin Youth With Type 1 DiabetesDiabetes Care 2016;39:555–562 | DOI: 10.2337/dc15-1606

OBJECTIVE

Treatment of severe hypoglycemia outside of the hospital setting is limited tointramuscular glucagon requiring reconstitution prior to injection. The currentstudy examined the safety and dose-response relationships of a needle-free in-tranasal glucagon preparation in youth aged 4 to <17 years.

RESEARCH DESIGN AND METHODS

A total of 48 youthwith type 1 diabetes completed the studyat seven clinical centers.Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) wererandomly assigned to receive either 2 or 3 mg intranasal glucagon in two separatesessions or to receive a single, weight-based dose of intramuscular glucagon. Partic-ipants aged 12 to <17 years received 1mg intramuscular glucagon in one session and3 mg intranasal glucagon in the other session. Glucagon was given after glucose waslowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).

RESULTS

All 24 intramuscular and 58 of the 59 intranasal doses produced a ‡25 mg/dL risein glucose from nadir within 20 min of dosing. Times to peak plasma glucose andglucagon levels were similar under both intramuscular and intranasal conditions.Transient nausea occurred in 67% of intramuscular sessions versus 42% of intra-nasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasaldoses were similar in the youngest cohorts.

CONCLUSIONS

Results of this phase 1, pharmacokinetic, and pharmacodynamic study supportthe potential efficacy of a needle-free glucagon nasal powder delivery system fortreatment of hypoglycemia in youth with type 1 diabetes. Given the similar fre-quency and transient nature of adverse effects of the 2- and 3-mg intranasal dosesin the two youngest cohorts, a single 3-mg intranasal dose appears to be appro-priate for use across the entire 4- to <17-year age range.

The Diabetes Control and Complications Trial conclusively demonstrated that loweringplasma glucose and HbA1c concentrations as close to normal as possible in adolescentsand adults with type 1 diabetes (T1D) could prevent or delay the development of earlymicrovascular complications but at the expense of a marked increase in the risk ofsevere hypoglycemic events causing seizure or loss of consciousness (1,2). Importantly,the T1D Exchange has demonstrated in our youth that although severe hypoglycemia is

1Yale School of Medicine, New Haven, CT2Jaeb Center for Health Research, Tampa, FL3Locemia Solutions ULC, Montreal, Canada4University of Pennsylvania Perelman School ofMedicine, Philadelphia, PA5University at Buffalo School of Medicine andBiomedical Sciences, The State University ofNew York, Buffalo, NY6IndianaUniversity SchoolofMedicine, Indianapolis,IN7Nemours Children’s Specialty Care, Jacksonville,FL8Barbara Davis Center for Childhood Diabetes,Aurora, CO9University of Florida, Gainesville, FL10University of Minnesota, Minneapolis, MN11Northwest Lipid Metabolism and DiabetesResearch Laboratories, Seattle, WA12JSS Medical Research, Saint-Laurent, Canada

Corresponding author: Nicole C. Foster, t1dstats@jaeb.org.

Received 22 July 2015 and accepted 14 January2016.

Clinical trial reg. no. NCT01997411, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-1606/-/DC1.

A slide set summarizing this article is availableonline.

*A complete list of participating investigatorsand coordinators is provided in the Supplemen-tary Data online.

© 2016 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered.

Jennifer L. Sherr,1 Katrina J. Ruedy,2

Nicole C. Foster,2 Claude A. Piche,3

Helene Dulude,3 Michael R. Rickels,4

William V. Tamborlane,1

Kathleen E. Bethin,5 Linda A. DiMeglio,6

Larry A. Fox,7 R. Paul Wadwa,8

Desmond A. Schatz,9

Brandon M. Nathan,10

Santica M. Marcovina,11

Emmanouil Rampakakis,12 LinyanMeng,12

and Roy W. Beck,2 for the T1D Exchange

Intranasal Glucagon Investigators*

Diabetes Care Volume 39, April 2016 555

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not greater with lower HbA1c levels (fre-quency of 4% and 7% in the past year forparticipants with HbA1c,7.0 and.9.0%,respectively), it nevertheless remains aserious threat irrespective of the level ofglycemic control (3).Fear of hypoglycemia can be a deter-

rent for patients and their families tostrive for optimal metabolic control inyouthwith T1D (4,5), especially in parentsof young children with T1D (6,7). Whilesevere hypoglycemic events are alarmingin and of themselves, fear of hypoglyce-mia may be increased by the dauntingtask of treating such eventswith currentlyavailable glucagon emergency kits. Owingto the propensity of glucagon to form fi-brils once in aqueous solution (8), cur-rently available glucagon emergency kitsrequire reconstitution of lyophilized pow-der in a diluent immediately prior to in-tramuscular injection by family membersor others who may not be well trained inor comfortable with giving injections.Investigation of an intranasal route

for administrating glucagon was first re-ported in 1983 (9). While a number ofsmall studies yielded positive results inhealthy volunteers and in adults andchildren with T1D, a product was nevercommercialized (9–15). We recentlycompleted a trial of a novel dry pow-der glucagon formulation, packaged inan easy-to-use intranasal dispenser(Supplementary Fig. 1) in adults withT1D. That study showed that a 3-mgdose of intranasal glucagon was as effec-tive as intramuscular glucagon in revers-ing insulin-induced hypoglycemia (16).Consequently, the current study was un-dertaken to assess the safety and phar-macokinetics and pharmacodynamics ofintranasal glucagon comparedwith com-mercially available intramuscular gluca-gon in children and adolescents withT1D ranging in age from 4 to,17 years.We were particularly interested inwhether adjustment of intranasal gluca-gon dosing would be needed basedon age or weight for younger patients,as weight-based dosing is currentlyrecommended for the intramuscularformulation; therefore, for childrenaged 4 to ,12 years we assessed theexposure-response characteristics ofboth 2- and 3-mg intranasal doses.

RESEARCH DESIGN AND METHODS

The study was conducted in the ClinicalResearch Center or outpatient infusion

center affiliated with seven diabetesclinics within the T1D Exchange ClinicNetwork (17). The institutional reviewboard of each participating institutionapproved the study protocol. Parents/guardians provided written informedconsent, and assent from minors was ob-tained as required. Full protocol detailsare available on clinicaltrials.gov (clinicaltrial reg. no. NCT01997411).

Study DesignThe study included three cohorts of chil-dren 4 to ,8, 8 to ,12, and 12 to ,17years of age. A sample size of 48 partic-ipants (12 in the older cohort and 18 ineach of the two younger cohorts) wasselected based on the U.S. Food andDrug Administration (FDA) guidancefor pediatric pharmacokinetic studies,which indicates a standard approach isto administer either single or multipledoses of a drug to a relatively small (6–12)group of participants.

Participants 12 to ,17 years of agewere randomly assigned in a 1:1 ratioto receive either 3 mg intranasal gluca-gon or 1 mg intramuscular glucagon(GlucaGen HypoKit, Novo Nordisk) (18)for the first dosing visit, with the otherglucagon preparation administered dur-ing the second dosing visit in a crossoverfashion.

Studies in the 4- to ,8- and 8- to,12-year age-groups were designedto compare the efficacy, safety, andpharmacokinetics of the 2-mg and3-mg intranasal doses of glucagonwith one another, as well as withweight-based dosing of intramuscularglucagon. For minimization of thenumber of dosing visits/proceduresto a maximum of two, participants inthe youngest cohort were randomly as-signed to one of two groups in a 2:1 ratio.One group of 12 was studied twice, re-ceiving 2 mg intranasal glucagon in onevisit and 3mg intranasal glucagon in theother visit in a double-blind, randomorder. The dosing visits were carriedout within 7–28 days of each other, un-less the second visit needed to occurlater in order to accommodate the vol-ume of blood required for some of thesmaller participants. The other group(N = 6) was studied once, receiving asingle weight-based dose of intramuscu-lar glucagon. Intramuscular glucagonwas administered per labeling guidelineswith participants weighing ,25 kg

receiving a 0.5-mg dose and those$25 kg receiving a 1-mg dose (18).

During each visit, glucagon was given5 min after the plasma blood glucosewas ,80 mg/dL, and successful treat-ment (the primary efficacy outcome)was defined as a $25 mg/dL rise inplasma glucose from nadir within20 min of receiving glucagon without re-ceipt of additional actions to increasethe blood glucose level.

Eligibility CriteriaParticipants included children meetingthe following eligibility criteria: aged 4to ,17 years with T1D duration of atleast 1 year and in good general health.Exclusion criteria included history of asevere hypoglycemic episode in themonth prior to enrollment; pheochro-mocytoma or insulinoma; history of epi-lepsy or seizure disorder; cardiovascular,gastrointestinal, liver, or kidney disease;or use of medications such as b-blockers.

Study MedicationThe intranasal AMG504-1 product(Locemia Solutions) contains 2 mg glu-cagon in 20 mg dry powder or 3 mg glu-cagon in 30mg dry powder, depending onthe dose. The nasal powder is adminis-tered with a single-use one-step dis-pensing device. The tip of the devicewas inserted in one nostril, and thedose was delivered by simply depress-ing a plunger connected to a piston thatgently discharges the powder into thenostril (Supplementary Fig. 1). No inha-lation or other cooperative measure isrequired from the patient, as absorptiontakes place through the nasal mucosa.An earlier phase 1 study showed that na-sal congestion, with or without concom-itant use of a decongestant, did notadversely affect glucagon pharmacoki-netics or the glycemic response in other-wise healthy subjects given the 3-mgdose during and after recovery from acommoncold (C.A. Piche,written commu-nication). A phase 2 study established adose response for intranasal glucagonthat attained a maximal increase in bloodglucose with the 3-mg dose, presumablydue to saturable absorption across thenasal mucosa (19).

Intramuscular glucagon adminis-tered for study visits was the GlucaGenHypoKit (Novo Nordisk), which when re-constitutedwith the sterilewaterprovidedin the kit contains 1 mg/mL glucagon

556 Intranasal Glucagon in Pediatric T1D Diabetes Care Volume 39, April 2016

(18). Preparation and administration ofthe intramuscular glucagon was com-pleted by a trained health care profes-sional per the package guidelines, withweight-based dosing used when appropri-ate (18).

Study ProceduresEach glucagon-dosing visit was con-ducted after an overnight fast of at least8 h. On arrival to the research center, anintravenous catheter was inserted inan arm vein for blood sampling. For par-ticipants using an insulin pump for dia-betes management, the basal insulininfusion rate was increased by 25–50%to cause a gradual decline in plasma glu-cose in a procedure previously de-scribed by the Diabetes Research inChildren Network (DirecNet) (20). Bolusdoses of insulin equal to ;1 h of theparticipant’s basal rate and further in-creases in basal insulin rate were admin-istered, as needed, to achieve the targetglucose of ,80 mg/dL. Participants oninjection therapy received their usualdose of long-acting insulin analog inthe 24 h prior to the visit. Insulin was ad-ministered at a rate of 1 mU/kg/min i.v.to reach the target glucose of,80mg/dL.A priming dose of 2–4 units i.v. insulinalso was given if needed. For partici-pants who arrived to the center with aplasma glucose ,80 mg/dL, no addi-tional insulin was administered andthe randomized glucagon preparationwas given immediately after intravenousaccess was obtained and baseline bloodsamples were collected.Plasma glucose concentrations were

measured every 5–10min after the startof the study procedures using an FDA-approved glucose analyzer (YSI 2300,Yellow Springs Instruments, YellowSprings, OH; Analox GM9, Analox Instru-ments, Lunenburg, MA; or HemoCueGlucose 201 Analyzer, Angelholm, Swe-den). Once the glucose concentrationwas ,80 mg/dL, basal rates were re-turned to normal settings on the insulinpump or the intravenous insulin infusionwas stopped. Five minutes later, bloodsamples for glucose and glucagon werecollected and glucagon was adminis-tered (t = 0). Glucagon was deliveredwith the participant lying in a lateral re-cumbent position in the quadricepsmuscle for the intramuscular adminis-tration or in a nare for the intranasaladministration. Serial blood samples

for glucose and glucagon were collectedat t = 5, 10, 15, 20, 30, 40, 60, and 90min.A reduced blood draw schedule waspermitted for those participants of in-sufficient weight to accommodate thevolume of blood required. Nasal andnonnasal symptom scores were ascer-tained at baseline and at t = 15, 30,60, and 90 min after glucagon admin-istration in all participants.

Biochemical AnalysisAll samples for analysis of glucose andglucagon were collected on ice intotubes containing EDTA with the prote-ase inhibitor aprotinin immediatelyadded, centrifuged at 48C, separated,and frozen at 2808C until subsequentanalysis. Plasma glucose concentrationswere measured by the glucose hexoki-nase method using an automated glu-cose analyzer (Roche Module P; RocheDiagnostics, Indianapolis, IN) and gluca-gon by a commercially available radioim-munoassay (Millipore, Billerica, MA) atthe Northwest Lipid Research Labora-tory (University of Washington, Seattle,WA).

Statistical AnalysisSeparate analyses were conducted foreach age cohort (4 to ,8, 8 to ,12,and 12 to,17 years old). All dosing vis-its in which glucagon was received wereincluded in the analyses. One partici-pant in the 12 to ,17 year old cohorthad the 3-mg intranasal dosing visit re-peated owing to a device malfunctionleading to insufficient administrationof glucagon during the initial dosing visit(maximum glucagon concentration 327pg/mL, which is 8% of the average glu-cagon concentration achieved in thisdosing cohort). The results from thisparticipant’s initial 3-mg intranasal dos-ing visit were not included in the efficacyanalysis but were included in the safetyanalysis. The design defect that led tothe device malfunction was correctedto prevent future malfunction.

All reported glucose and glucagonvalues are from the central laboratory(Northwest Lipid Research Laboratory).If the central laboratory glucose mea-surement was missing, the local plasmaglucose measurement made using anFDA-approved glucose analyzer wasused (this occurred for 11 of 738 [1.5%]glucose measurements). Nadir glu-cose concentration was defined as the

minimum glucose measurement within10 min after glucagon administration.

The proportion of participants ineach treatment arm achieving at leasta 25 mg/dL rise in central laboratoryglucose above the glucose nadir within20 min after receiving study glucagon,in the absence of additional actionsto increase the blood glucose level,was computed. The maximum centrallab glucose concentration after admin-istration of study glucagon was calcu-lated in each treatment arm. Summarystatistics for blood glucose concentra-tion at each time point across thedosing visit were computed withintreatment arm. Missing glucose valuesand glucose values after receipt of inter-vention treatment were imputed usingthe Rubin method based on availableglucose measurements, age cohort, andtreatment arm.

Peak central laboratory glucagon con-centration and time until administrationof study glucagon until peak glucagonconcentration (Tmax) were computed ineach treatment arm. Summary statisticsfor blood glucagon concentration ateach time point across the dosing visitwere computed within treatment arm.Missing glucagon values were imputedusing the Rubin method based on avail-able glucagon measurements, age co-hort, and treatment arm.

A treatment comparison of theoccurrence of nausea with or withoutvomiting was completed, pooling the2-mg intranasal and 3-mg intranasalstudy glucagon doses, using a general-ized linear mixed model with randomparticipant effect adjusting for age co-hort. Similarly, a treatment comparisonof the occurrence of head or facial painalso was completed using a general-ized linear mixed model with randomparticipant effect adjusting for agecohort.

Results are expressed as mean6 SD ormedian (interquartile range). Data analy-ses were performed using SAS software,version 9.4 (SAS Institute, Cary, NC).

RESULTS

ParticipantsForty-eight participants were enrolledin the study, and participant character-istics by age cohort are presented inTable 1. All but one participant com-pleted each planned dosing visit; a10-year-old withdrew from the study

care.diabetesjournals.org Sherr and Associates 557

after the first dosing visit of 3 mg in-tranasal glucagon (Fig. 1).

Plasma Glucose and GlucagonResponsesResults showed that at all dosing visitsthe insulin infusion successfully loweredmean nadir plasma glucose levels whenstratified by age and formulation used,as shown in Table 2, to a range of 67–75 mg/dL across age cohorts for the in-tranasal glucagon visits and 69–72 mg/dLacross age cohorts for the intramuscularglucagon visits. The primary outcomeof a $25 mg/dL rise in plasma glucosewithin 20 min after glucagon adminis-tration was achieved in all 24 intramus-cular dosing visits and in 58 of the 59intranasal dosing visits (Table 2). Theone exception was a 6-year-old boy

who blew his nose immediately after ad-ministration of the 2-mg intranasal dose.This resulted in a peak glucagon level of324 pg/mL, which was 10-fold less thanthe mean level detected with the 2-mgintranasal dose administered to otherparticipants in this age-group (Table 2).A 72 mg/dL increase in plasma glucoseafter 20 min was achieved in the samepatient after the 3-mg intranasal dose.The mean maximal glucose concentra-tions achieved in all successful intranasaldosing visits ranged between 178 and208 mg/dL across age cohorts, withmean maximal glucose in the intramus-cular dosing visits ranging between 194and 211 mg/dL across the age cohorts(Table 2).

Plasma glucagon levels increasedrapidly within 5 min of intranasal and

intramuscular glucagon administration(Fig. 2), and peak mean glucagon con-centrations across age cohorts ranged be-tween 2,952 and 5,832 pg/mL forthe intranasal cohort and 4,382 and6,343 pg/mL for the intramuscular co-hort. Further details regarding peakmean glucagon concentrations based onage and formulation of glucagon used arepresented in Table 2. Moreover, the me-dian time to the Tmax was #20 min forboth intramuscular and intranasal gluca-gon formulation and in all three age-groups.

Adverse EventsAdverse events stratified by age cohortand glucagon formulation and dosageare provided in Table 3, with full detailsavailable in Supplementary Table 1.

Table 1—Baseline demographic and clinical characteristics

4 to ,8 years old(N = 18)

8 to ,12 years old(N = 18)

12 to ,17 years old(N = 12)

Age (years) 6.5 6 1.2 11.1 6 0.8 14.6 6 1.6

Female 3 (17) 8 (44) 5 (42)

Non-Hispanic white 18 (100) 16 (89) 10 (83)

Weight (kg) 25.4 6 5.2 43.2 6 8.9 61.2 6 13.8

Duration of diabetes (years) 2.8 (2.1, 3.8) 4.6 (3.8, 6.7) 5.9 (3.5, 8.0)

HbA1c (%)a 8.1 6 0.8 7.9 6 0.9 8.2 6 1.5

HbA1c (mmol/mol)a 65 6 8.7 63 6 9.8 66 6 16.4

Insulin pump use 10 (56) 16 (89) 9 (75)

History of any prior severe hypoglycemic eventb 6 (33) 2 (11) 5 (42)

Data are mean6 SD, n (%), or median (25th, 75th percentile). aHbA1c test performed locally; bsevere hypoglycemic event defined as an episode thatrequired third-party assistance for treatment.

Figure 1—Study flowchart. aOne participant requested to withdraw prior to the second visit. IM, intramuscular; IN, intranasal; yrs, years.

558 Intranasal Glucagon in Pediatric T1D Diabetes Care Volume 39, April 2016

Nausea, with or without vomiting, oc-curred in 67% of participants who re-ceived intramuscular glucagon comparedwith 43% for the 3-mg intranasal doseand 39% for the 2-mg intranasal dose(P = 0.05 intramuscular vs. intranasal).Head/facial discomfort was reportedby 24% of participants receiving the3-mg intranasal dose, 17% receiving the2-mg intranasal dose, and 13% receivingintramuscular (P = 0.30 intramuscularvs. intranasal).

CONCLUSIONSThe current study was designed as aphase 1, pharmacokinetic, and pharma-codynamic dose-finding study of a new,needle-free, dry powder intranasal glu-cagon preparation for treatment of hy-poglycemia in youth with T1D. Plasmaglucagon concentrations rapidly in-creased to supraphysiologic levels in asimilar fashion after both intranasaland intramuscular glucagon dosing,accompanied by a rise in glucose of$25 mg/dL within 20 min of administra-tion in all of the intramuscular dosingvisits and 58 of 59 intranasal doses.The single failed 2-mg intranasal re-sponse observed is thought to have re-sulted from not receiving the intendeddose of glucagon, as the participantblew his nose immediately after theproduct was administered. In most situ-ations, it is highly unlikely that patientsrequiring emergency glucagon therapyfor treatment of severe hypoglycemiawill have such a problem. Importantly,as intranasal glucagon is absorbed pas-sively through the nasal mucosa, no co-operation from an individual requiringrescue glucagon therapy is required.

Another aim of the study was to eval-uate whether the intranasal dose of glu-cagon should be adjusted based on ageor body weight, as is recommended forintramuscular glucagon (18,21). In par-ticipants who were ,12 years old, theplasma glucose responses to the 2-mgand 3-mg intranasal doses of intranasalglucagon were similar. Moreover, theadverse effects of the two intranasalglucagon levels occurred at similar fre-quencies and were transient. Nauseawith or without vomiting tended to beless frequent with the two intranasaldoses than with weight-adjusted dosesof intramuscular glucagon.

Hypoglycemia was not intentionallyinduced in the current study for ethical

Table

2—Su

mmary

ofgluco

seandgluca

gonco

nce

ntra

tions

4to

,8years

old

8to

,12

yearsold

12to

,17

yearsold

IM2mgIN

3mgIN

IM2mgIN

3mgIN

IM3mgIN

N6

1212

611

1212

12

Plasm

aglu

cose

atnad

ir(m

g/dL) a

716

868

69

676

1072

612

756

771

66

696

1173

69

Plasm

aglu

cose

immed

iatelyprio

rto

glucago

nadministratio

n#70

mg/d

L3(50)

6(50)

7(58)

1(17)

3(27)

6(50)

7(58)

1(8)

$25

mg/d

Lrise

inglu

cose

by20

min

c6(100)

11(92)

12(100)

6(100)

11(100)

12(100)

12(100)

12(100)

Timeuntilallp

articipantsexp

erienced

risein

glucose

$25

mg/d

L(m

in) d

1020

1520

2015

2020

Mean

risein

plasm

aglu

cose

at20

min

(mg/d

L)77

610

606

3170

620

496

1364

611

676

1554

614

416

10

Maxim

um

plasm

aglu

cose

(mg/d

L) b211

627

1896

54208

644

2056

24201

628

2066

32194

633

1786

27

Cmaxglu

cagon(pg/m

L)6,343

62,029

3,5316

1,7624,033

62,435

4,8176

3,0862,952

61,024

5,8326

2,1064,382

63,771

3,1866

2,294

Tmaxglu

cagon(m

in)

17(5,30)

15(10,20)

17(10,60)

17(5,30)

15(10,20)

15(10,30)

17(5,30)

20(15,30)

Data

aremean

6SD

,n(%

),ormed

ian(25th

,75thpercen

tile).Oneparticip

antcompleted

onlyoneoftw

osch

eduled

dosin

gvisits:

a10-year-o

ldwhowith

drew

from

thestu

dyafter

thefirst

dosin

gvisit

of3mgintran

asalglucago

n.Cmax ,p

eakcen

trallaborato

ryglu

cagonconcen

tration;IM

,intram

uscu

lar;IN,in

tranasal.

aMinim

um

centrallab

orato

ryglu

cose

valuemeasu

redwith

in10

min

afterglu

cagon

administratio

n;bm

aximum

glucose

afteradministratio

nofglu

cagon;cth

eoneparticip

antwhofailed

toach

ievea$25

mg/d

Lrise

inglu

cose

blew

hisnose

immed

iatelyafter

2mgintran

asaldose

administratio

nandhad

apeak

glucago

nofonly324

pg/m

L;dexclu

des

theoneparticip

antwhoblew

hisnose

anddid

notexp

erience

a$25

mg/d

Lrise

inglu

cose.

care.diabetesjournals.org Sherr and Associates 559

reasons in the pediatric population,which may be viewed as a limitation instudy design. Yet, the demonstrationthat the patterns of plasma glucose

responses to intranasal and intramuscu-lar glucagon were similar over the first20 min and that the peak increment inplasma glucose levels was on average

126 mg/dL above nadir values in the58 successful intranasal glucagon dosingvisits supports the contention that theseresults can be extrapolated to what

Figure 2—A: Glucose and glucagon concentrations over time according to treatment arm: 4 to,8 years old. Solid black bars and line, 3mg intranasal;solid white bars and long dashed line, 2 mg intranasal; horizontal black-and-white striped bars and short dashed line, intramuscular. B: Glucose andglucagon concentrations over time according to treatment arm: 8 to,12 years old. Solid black bars and line, 3 mg intranasal; solid white bars andlong dashed line, 2 mg intranasal; horizontal black-and-white striped bars and short dashed line, intramuscular. C: Glucose and glucagon concen-trations over time according to treatment arm: 12 to,17 years old. Solid black bars and line, 3mg intranasal; horizontal black-and-white striped barsand short dashed line, intramuscular. Lab, laboratory.

560 Intranasal Glucagon in Pediatric T1D Diabetes Care Volume 39, April 2016

would be observed in treating severehypoglycemia in an outpatient setting.Importantly, participantsweremaintainedon their usual basal insulin once the targetglucoseof,80mg/dLwas reached, allow-ing us to more closely approximate whatmay happen in a real-life, outpatient set-ting during a severe hypoglycemic episodewhere oftentimes basal insulin delivery isnot interrupted after glucagon administra-tion. It is also noteworthy that the subcu-taneous route of insulin administrationin insulin pump patients did not miti-gate against our ability to detect a rise inglucose with intranasal glucagon, eventhough the pharmacodynamic effects ofthe increased basal rates would have con-tinued after basal rates were returned totheir normal setting.All of the investigators involved in this

study believed that it would be unreal-istic and too much of a burden to re-quire each subject in the two youngerage-groups to undergo three sepa-rate studies. Therefore, subjects in the4- to,8- and 8- to,12-year old cohortswere randomized to either receive oneweight-adjusted dose of intramuscularglucagon or two visits using both the2-mg and3-mg intranasal glucagondoses.This precluded direct comparison ofthe intramuscular glucagon to the in-tranasal glucagon formulation in eachindividual studied and could be seen as alimitation of the current study. However,paired studies comparing the responsesto two different doses of intranasal

glucagon in the same subject providedgreater power to assess whether weight-or age-adjusted dosingwould be requiredwith the intranasal formulation.

Since this study was carried out incontrolled research center settings andboth intramuscular and intranasal gluca-gon were administered by trained pro-fessionals, it remains to be determinedwhether similar results will be seen inthe outpatient setting in a combativechild or one who is seizing. On the otherhand, recent studies have demonstratedthe difficulty with administration of cur-rently available injectable preparations.In one study, 94 of 136 parents had dif-ficulty handling the kit, 8 aborted theinjection entirely, and 5 injected onlyair or diluent (22). Another study com-pared the ability of trained caregivers ofinsulin-using persons with diabetes touse intramuscular and intranasal de-vices to treat a simulated episode ofsevere hypoglycemia (23). Intranasalglucagon was successfully administeredby 15 of 16 caregivers (average time16 s), while injectable glucagon was onlyadministered by 8 of 16 caregivers(average time .7 times that requiredfor intranasal administration). Impor-tantly, only two caregivers were able tocorrectly administer the full injectabledose, while two of the caregivers mistak-enly injected insulin rather than gluca-gon, highlighting the potential benefitof a glucagon rescue therapy that doesnot have the same mode of delivery as

insulin. Indeed, the first step to ensureglucagon can be administered is to as-sure that those who may need it haveit readily available. In a survey con-ducted by Glu, the T1D Exchange pa-tient/caregiver online community(myglu.org), nearly 75% of participants(n = 277) stated they never or rarelycarried a glucagon emergency kit (24).

Administration of intramuscular glu-cagon is thought to be so complex thatmany states allow only nurses or othertrained health professionals to give glu-cagon injections while youngsters withT1D are in school. Consequently, if clini-cians submit school orders for intramus-cular glucagon, youth with T1D may bebarred from school trips or after-schoolactivities in some states because of theabsence of adequately trained volun-teers. Even in states permissive to non-medical personnel providing assistanceto children during an episode of severehypoglycemia, only 25% of parents sur-veyed felt such individuals had beenidentified and adequately trained (25).

The problems in preparing and inject-ing the current intramuscular glucagonemergency kits stand in stark contrast tothe ease of using the single-dose, needle-free intranasal glucagon-dispensingdevice used in these studies. This study’sdata indicate that a single 3-mg intrana-sal dose of glucagon can be safely usedin pediatric patients 4 to ,18 years ofage. Indeed, we also have shown thatthe 3-mg intranasal dose of glucagon isas effective and safe as the administrationof a 1-mg intramuscular dose in adultswith T1D, which will simplify prescribingthis medication across the entire agerange of patients with T1D 4 years ofage or older.

Now that we have demonstrated thatneedle-free intranasal administration ofglucagon is a promising alternative tocurrently available injected glucagon inyouth with T1D, the next step will be todetermine its effectiveness when usedin the treatment of real-life outpatienthypoglycemic events in youth with T1D.

Funding and Duality of Interest. Funding wasprovided by a grant from the Leona M. andHarry B. Helmsley Charitable Trust and by theNational Center for Research Resources and theNational Center for Advancing TranslationalSciences, National Institutes of Health, throughgrants UL1TR000003 (University of Pennsylva-nia), UL1TR000064 (University of Florida),

Table 3—Adverse events by treatment arm within age cohort

4 to ,8 years old 8 to ,12 years old 12 to ,17 years old

Adverse events IM 2mg IN 3mg IN IM 2mg IN 3mg IN IM IN

N 6 12 12 6 11 12 12 13

One or moreevents 5 (83) 6 (50) 5 (42) 6 (100) 5 (46) 6 (50) 7 (58) 9 (69)

Gastrointestinala,b 5 (83) 5 (42) 5 (42) 5 (83) 4 (36) 6 (50) 6 (50) 6 (46)

Headachea 0 2 (17) 1 (8) 2 (33) 2 (18) 4 (33) 1 (8) 4 (31)

Nasala,c 0 1(8) 2 (17) 0 0 1 (8) 0 3 (23)

Oculara,d 0 0 0 0 1(9) 0 0 2 (15)

Sensory/paina,e 2 (33) 1 (8) 0 3 (50) 0 0 0 0

Othera,f 1 (17) 1 (8) 0 1 (17) 0 0 0 0

One serious adverse event was reported in which a 7-year-old participant (intramusculartreatment) experienced a hypoglycemic event after receiving a bolus of insulin with lunch. Theparticipant received 90 g oral carbohydrates and made a full recovery. One participant in the12- to,17-year-old group had a repeat 3-mg intranasal glucagon dosing visit owing to a devicemalfunction leading to insufficient receipt of glucagon during the initial visit; both dosing visitswere included in the safety analysis. IM, intramuscular; IN, intranasal. aN (%) of participants withat least 1 occurrence of the adverse event group; bincludes abdominal pain (upper), diarrhea,nausea, and vomiting; cincludes nasal congestion, nasal discomfort, sneezing, and rhinalgia;dincludes eye irritation, lacrimation increase, and ocular discomfort; eincludes catheter site painand injection site discomfort; fincludes hypoglycemia, tachycardia, and dizziness.

care.diabetesjournals.org Sherr and Associates 561

UL1TR001108 (Indiana University), and LocemiaSolutions. Studies at the Barbara Davis Cen-ter for Childhood Diabetes were performedin their infusion center and not the hospitalClinical and Translational Research Center.Locemia Solutions provided the intranasal glu-cagon product. The nonprofit employer of J.L.S.has received grants for support of supplies forinvestigator-initiated studies from Medtronic.C.A.P. is an employee and member of the boardfor Locemia Solutions, one of the entities thatprovided financial support for the conduct ofthis study. H.D. is an employee for LocemiaSolutions. M.R.R. has received consultancypayments from Longevity Biotech, Janssen Re-search & Development, and Semma Thera-peutics and research support from Merck.The nonprofit employer of W.V.T. has receivedconsulting fees from Novo Nordisk and Locemia(Locemia consultancy for protocol develop-ment). R.P.W. reports receiving research sup-port from Novo Nordisk and serves as aconsultant for Novo Nordisk and Medtronic. E.R.and L.M. received payment for pharmacokinetic/pharmacodynamic analysis. The nonprofitemployer of R.W.B. has received consultantpayments on his behalf from Sanofi and Animasand a research grant from Novo Nordisk, withno personal compensation to R.W.B. No otherpotential conflicts of interest relevant to thisarticle were reported.Author Contributions. J.L.S. researched dataand wrote and edited the manuscript. K.J.R.researched data and wrote and edited themanuscript. N.C.F., E.R., and L.M. researcheddata, performed statistical analyses, and wroteand edited the manuscript. C.A.P., H.D., M.R.R.,W.V.T., K.E.B., L.A.D., L.A.F., R.P.W., D.A.S., B.M.N.,S.M.M., and R.W.B. researched data and re-viewed and edited the manuscript. N.C.F. andR.W.B. are the guarantors of this work and, assuch, had full access to all the data in the studyand take responsibility for the integrity of thedata and the accuracy of the data analysis.

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