Insulin degludec in combination with bolus

insulin aspart is safe and effective in children

and adolescents with type 1 diabetes

Insulin degludec (IDeg) once-daily was compared with insulin detemir (IDet)
once- or twice-daily, with prandial insulin aspart in a treat-to-target,
randomized controlled trial in children 1–17 yr with type 1 diabetes, for 26 wk
(n=350), followed by a 26-wk extension (n=280). Participants were
randomized to receive either IDeg once daily at the same time each day or
IDet given once or twice daily according to local labeling. Aspart was titrated
according to a sliding scale or in accordance with an insulin:carbohydrate
ratio and a plasma glucose correction factor. Randomization was
age-stratified: 85 subjects 1–5 yr. (IDeg: 43), 138 6–11 yr (IDeg: 70) and 127
12–17 yr (IDeg: 61) were included. Baseline characteristics were generally
similar between groups overall and within each stratification. Non-inferiority
of IDeg vs. IDet was confirmed for HbA1c at 26 wk; estimated treatment
difference (ETD) 0.15% [−0.03; 0.32]95%CI. At 52wk, HbA1c was 7.9% (IDeg)
vs. 7.8% (IDet), NS; change in mean FPG was −1.29 mmol/L (IDeg) vs.
+1.10 mmol/L (IDet) (ETD −1.62 mmol/L [−2.84; −0.41]95%CI, p=0.0090)
and mean basal insulin dose was 0.38 U/kg (IDeg) vs. 0.55U/kg (IDet). The
majority of IDet treated patients (64%) required twice-daily administration to
achieve glycemic targets. Hypoglycemia rates did not differ significantly
between IDeg and IDet, but confirmed and severe hypoglycemia rates were
numerically higher with IDeg (57.7 vs. 54.1 patient-years of exposure (PYE)
[NS] and 0.51 vs. 0.33, PYE [NS], respectively) although nocturnal
hypoglycemia rates were numerically lower (6.0 vs. 7.6 PYE, NS). Rates of
hyperglycemia with ketosis were significantly lower for IDeg vs. IDet [0.7 vs.
1.1 PYE, treatment ratio 0.41 (0.22; 0.78)95%CI, p=0.0066]. Both treatments
were well tolerated with comparable rates of adverse events. IDeg achieved
equivalent long-term glycemic control, as measured by HbA1c with a
significant FPG reduction at a 30% lower basal insulin dose when compared
with IDet. Rates of hypoglycemia did not differ significantly between the two
treatment groups; however, hyperglycemia with ketosis was significantly
reduced in those treated with IDeg.

Introduction
The Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions and Complications
(DCCT/EDIC) study showed conclusively that
good glycemic control delays, and may even prevent,
the development of long-term complications in type
1 diabetes (T1D) (1–5). Management of T1D in children
and adolescents presents particular challenges.
Factors that increase the complexity of treating children
include hormonal changes during normal growth
and development (e.g., rapid growth, pubertal insulin
resistance, psychosocial and cognitive development),
family dynamics (including socioeconomic status, cultural
considerations and parent/caregiver viewpoints)
and the provision and quality of care and support
outside the home, for example at school/college (6).
In recognition of this, the American Diabetes Association
and the International Society for Pediatric and
Adolescent Diabetes (ISPAD) have published specific
guidance for children (7, 8).
Hypoglycemia is one of the main side effects of
insulin therapy and is often viewed as themajor barrier
to achieving good glycemic control by parents and
physicians alike. A number of studies have shown that
hypoglycemia has a detrimental effect on the cognitive
development of young children, and that episodes of
hypoglycemia, particularly nocturnal hypoglycemia,
can be extremely frightening both for children and
their parents/caregivers (9, 10). It can therefore be
tempting to set higher glycemic targets to minimize
hypoglycemia. In addition, fear of hypoglycemia can
lead to reluctance to titrate to appropriate glucose
targets, with resultant hyperglycemia and suboptimal
HbA1c. However, underinsulinization can place
children at-risk of hyperglycemia with ketosis, which,
if left untreated, can progress to diabetic ketoacidosis
(DKA) (11). The risk of DKA in children with
established T1D is up to 10% per patient per year (11).
Children who restrict or omit insulin intentionally, or
unintentionally due to unstable family circumstances or
limited access to supplies, are at greatly increased risk
(12, 13). Basal insulin can help reduce the risk of DKA
by providing a continual background level of insulin.
The long-acting analogs insulin glargine (IGlar) and
insulin detemir (IDet) can provide up to 24-h coverage
when administered once daily (OD) or twice-daily
(BID) in the case of IDet (14, 15). However, because
of their action profile, administration should ideally be
at the same time each day to prevent periods of insulin
insufficiency (14, 15). As children of all ages often have
highly variable daily schedules, a basal regimen that
provides flexibility in dosing time may be beneficial.
Insulin degludec (IDeg), a new basal insulin for
the treatment of T1D and type 2 diabetes (T2D), has
been showed to have an ultra-long duration of action
and low variability in adults, producing a consistent
glucose-lowering activity profile at steady state (16,
17). Pharmacokinetic data have shown that IDeg has
a terminal half-life of approximately 25 h, twice that
of IGlar, and a duration of action of more than 42 h
(18). A phase 3, randomized, controlled trial in adults
with T1D confirmed that IDeg OD effectively reduced
HbA1c and fasting plasma glucose (FPG), with a lower
risk of nocturnal confirmed hypoglycemia than IGlar
(19). Furthermore, studies in adults with T1D and
T2D have shown that the IDeg injection time may be
varied from day to day without compromising efficacy
or safety, offering patients greater convenience and
flexibility, when needed (20, 21).
The objective of this trial was to investigate
the efficacy and safety of IDeg vs. IDet, both in
combination with bolus insulin aspart (IAsp), in
children and adolescents with T1D (Fig. 1).
Materials and methods
Trial conduct
This was a 26-wk, phase 3b, randomized, controlled,
open-label, multinational, parallel-group, treat-totarget
non-inferiority trial with a 26-wk extension,
comparing the efficacy and safety of IDeg administered
OD with that of IDet administered OD or BID, both
in combination with mealtime IAsp. The study was
conducted at 72 sites in 12 countries (Bulgaria, Finland,
France, Germany, Italy, Japan, the Netherlands,
Republic of Macedonia, Russian Federation, South
Africa, UK and USA). Of these, South Africa did not
participate in the 26-wk extension phase as regulatory
approval was not granted. The protocol, protocol
amendments, consent form, child assent form, subject
information sheet and other information provided to
the participants and parents/participants’ legal representatives
were approved by the relevant independent
ethics committees or institutional review boards (written
informed consent was obtained prior to participant
enrolment) and the trial was conducted according
to the Declaration of Helsinki (22) and ICH Good
Clinical Practice (23). In some countries assent from
children themselves (≤17 yr of age, where appropriate)
was required in addition to parental consent. Ongoing
safety surveillance was performed by a blinded internal
Novo Nordisk safety committee and an unblinded
independent Data Monitoring Committee (comprising
pediatric and endocrine experts). This trial is registered
at www.clinicaltrials.gov: NCT01513473.
Children and adolescents (1–17 yr of age) with T1D
who had been receiving insulin treatment (any regimen)
for at least 3 months, without concomitant oral antidiabetic
drugs andwithHbA1clevels of≤11%, were eligible
for inclusion (Fig. S1, Supporting Information).

Randomization
Following screening, eligible participants were randomized
1:1, using a central interactive voice/web
response system, to receive either IDeg (100 U/mL,
Penfill® 3-mL cartridge, Novo Nordisk, Bagsværd,
Denmark) or IDet (100 U/mL, Penfill®3-mL cartridge;
Novo Nordisk). Randomization was also stratified
by age group: 1–5, 6–11 and 12–17 yr, to ensure
an approximately equal distribution of participants
between treatment arms within each age group.
Procedures
To ensure treatment uniformity between clinics,
and to ensure that the patients received optimal
treatment, insulin treatment algorithms were developed
specifying recommended dose adjustments at different
PG levels. Clinical judgment had to be applied to avoid
increased risks for the patients. Thus the investigators
could overrule the guidelines when necessary. Eligible
participants were switched to either IDeg OD or IDet
OD or BID with mealtime IAsp at randomization
(wk 0). Participants switching to IDet received their
dose OD or BID in accordance with local labeling.
Participants switching to IDeg received a single dose
at the same time each day. The total daily insulin
dose was calculated and used to derive the trial bolus
and basal doses using the initiation table provided
(Table S1), aiming for a basal:bolus ratio of between
50:50 and 30:70 with no basal dose reduction, as this
range was generally considered to be appropriate for
children with T1D. For example, if the participant’s
total daily insulin dose prior to the trial was 28U, the
participant would receive a total of 8U of IDeg or
IDet and 20U of insulin aspart at the ratio of 30:70.
The choice of basal:bolus split for each individual was
made at the discretion of the investigator. At 26wk,
for those participants not continuing in the extension
study, basal insulin was switched to neutral protamine
Hagedorn insulin for 7 days to minimize interference
with antibody detection at a follow-up visit performed
1wk later. For those entering the extension study, this
was done at 52 wk.
The overall trial duration was approximately 53 wk,
including two 26-wk treatment periods and one 7-day
basal insulin washout period (Fig. S1).Atreat-to-target
approach was used to optimize glycemic control and

achieve a pre-breakfast self-measured plasma glucose

(SMPG) target of 5–8 mmol/L, in accordance with
ISPAD guidelines (7). IDeg OD and IDet OD titration
was based on the lowest pre-breakfast SMPG value,
using glucose meters calibrated to plasma values, on
the 3 days prior to each weekly visit/phone contact, and
adjusted using a standard titration algorithm (Table 1).
Participants receiving IDet OD whose mean prebreakfast
SMPG had reached target but whose mean
pre-dinner plasmas glucose (PG) was >8.0 mmol/L
(145 mg/dL) commenced an additional morning dose
of IDet at 2–4 U, with a pre-dinner titration target of
5–8 mmol/L. If using IDet BID, morning dose titration
was based on the lowest pre-dinner SMPGand evening
dose titration on the lowest pre-breakfastSMPGon the
3 days prior to visit/phone contact. Titration of IAsp
was performed either by use of PG correction factors
and insulin:carbohydrate ratios or once weekly,
based on the lowest of three SMPG values measured
3 days before a visit/phone contact; pre-meal doses were
adjusted according to the lowest post-meal increment
observed over the preceding 3 days (Table 1). Carbohydrate
counting was only used by those participants and
caregivers that had prior experience with this method.
The primary endpoint was change from baseline in
HbA1c after 26wk of treatment. Other efficacy endpoints
assessed at both wk 26 and wk 52 included FPG,
analyzed by central laboratory, and 4- and 8-point
SMPG profiles. Self-measured glucose measurements
were performed with capillary blood automatically
calibrated to plasma-equivalent glucose values, using
a glucose monitor able to capture both blood glucose
and blood ketones, which was centrally supplied.
Four-point profiles were performed weekly and 8-point
profiles were performed at wk 0 (randomization),
12, 26, 38 and 52. Safety variables included adverse
events (AEs), hypoglycemic episodes, hyperglycemia,
incidence of hyperglycemia with elevated ketones
(>1.5 mmol/L), insulin dose, body weight, antibodies
and standard laboratory safety assessments.
Confirmed hypoglycemia was defined as SMPG
<3.1 mmol/L (56mg/dL) and/or severe episodes as
defined by ISPAD [the child has altered mental status
and cannot assist in their own care, is semiconscious
or unconscious, or in a coma±convulsions and may
require parenteral therapy (glucagon or i.v. glucose)].
The ISPAD definition is very broad and includes a subjective
element: ‘The child has altered mental status and
cannot assist in his own care’, and determining whether
an episode fulfills the definition can be challenging,
especially in young children. Therefore, all reported
episodes of severe hypoglycemia were reviewed in a
blinded manner by an independent, external pediatric
endocrinologist, in order to determine whether the
episodes fulfilled the criteria for severe hypoglycemia.
Hypoglycemic episodes occurring between 11pm and
7 am inclusive were classified as nocturnal.
Hyperglycemia was defined as PG values
>11.1 mmol/L (200 mg/dL). Hyperglycemia with ketosis
was defined when PG exceeded 14.0 mmol/L
(252 mg/dL) and the capillary blood ketones exceeded
1.5 mmol/L (27mg/dL).
Laboratory analyses were conducted at central laboratories
(Quintiles Laboratories Europe, Livingston,
UK; Quintiles Laboratories South Africa, Centurion,
South Africa; Quintiles Laboratories Limited, Marietta,
Georgia; Quintiles Laboratories Japan, Tokyo,
Japan), with the exception of FPG, whichwas analyzed
at Laboratorium f ¨ur Klinische Forschung GmbH
(Schwentinental, Germany). Antibody analyses were
conducted at Celerion Switzerland AG (Fehraltorf,
Switzerland), using a validated radioimmunoassay
method (24, 25).
Continuous glucose monitoring
Continuous glucose monitoring (CGM) was conducted
in a subset of participants in the IDeg group
(74 participants) and IDet group (75 participants) at
selected sites in Bulgaria, Finland, France, Germany,
Italy, the Netherlands, UK, South Africa, Russia
and US during the main trial period only. Interstitial
glucose (IG) profiles obtained by CGM were performed
over a period of 3–6 continuous days. The
CGM system (MedTronic International, Switzerland)
recorded IG values every fifth minute. CGM was
measured between screening and randomization, and
again after at least 5 months of treatment.
Statistical methods
The primary objective was to confirm the noninferiority
of IDeg OD to IDet, both with mealtime

IAsp, in controlling glycaemia with respect to change

from baseline in HbA1c after 26wk of treatment. Noninferiority
was confirmed if the upper limit of the
two-sided confidence interval (CI) for the treatment
difference for mean change in HbA1c was ≤0.4%,
in accordance with regulatory guidelines (26). The
sample size was determined using a t-statistic under
the assumption of a one-sided test of size 2.5%, a zero
mean treatment difference and standard deviation (SD)
of 1.25% for HbA1c. A total of 346 participants had to
be randomized to achieve at least 80% or greater power
in the evaluation of the per protocol (PP) analysis set,
after adjustment for a 10% dropout rate.
Statistical analyses of all efficacy and safety
endpoints included all randomized participants [full
analysis set (FAS)], following the intention-to-treat
principle. No statistical analyses were performed at
the stratified age-group data level as the numbers
were too low. Descriptive tables and figures were
based on FAS for efficacy endpoints and on the
safety analysis set (SAS), consisting of all randomized
participants exposed to at least one dose of the
investigational product, for safety endpoints. Missing
values were imputed using last observation carried
forward. Comparisons between IDeg and IDet were
analyzed at 26 and 52wk.
Baseline characteristics, demographics, AEs and
number of hypoglycemic episodes (including CGM
measurements) are presented using descriptive statistics.
Treatment differences in change in HbA1c, FPG,
body weight and duration of low/high IG measurements
by CGM were estimated using analysis of
variance (ANOVA), adjusted by treatment, sex, region,
age group and baseline value of the respective endpoint.
The robustness of the analysis of change in HbA1c from
baseline to wk 26 was explored by additional analyses,
including analysis of the PP set. Hypoglycemic
events and number of low/high IG readings according
to CGM were modeled using negative binomial
regression, adjusted by treatment, sex, region and age
group as fixed factors and with the logarithm of the
time period for which a hypoglycemic episode is considered
treatment emergent as offset. This time period
was defined as the time elapsed from the first day of
treatment with investigational product to 7 days after
last day of treatment, both inclusive.Apost hoc analysis
examined hypoglycemia rates during the maintenance
period (from wk 16 to end of trial), when the majority
of participants were anticipated to have achieved
stable glycemic control and insulin dose. Analyses
were repeated for HbA1c, FPG, SMPG, hypoglycemic
episodes, antibodies and central laboratory parameters
at 52 wk using the extension trial set (ETS; participants
who attended the first visit of the extension period) to
assess stability of key results. Data were reported using
a 95% CI and p-values for two-sided testing at α=0.05.
Results
Patient characteristics
Of the 350 randomized participants, 349 (99.7%) were
exposed and most [170/174 (97.7%) for IDeg, 165/175
(93.7%) for IDet] completed the main trial period.
The percentage of participants withdrawn during the
main period from the IDet group was higher than
from the IDeg group (6.3 vs. 2.3%, respectively); see
Fig. 1. The majority of withdrawals were because of
participants meeting pre-specified withdrawal criteria
including withdrawal of consent (Table S2). Of 170
main trial completers in the IDeg group, 152 (87.4%)
continued into the extension and 151 (86.8%) of those
randomized in the main trial completed the extension
period. In contrast, of 165 main trial completers
in the IDet group, only 128 (72.7% of participants
randomized to IDet) continued into the extension
and 122 (69.3% of participants randomized to IDet)
completed the extension period (Fig. 1). Baseline
characteristics overall and in the stratified age groups
were representative for a pediatric population with
T1D and both groups were well matched at baseline,
with the exception of HbA1c and FPG which were
slightly higher in the IDeg arm; Table 2. The pretrial
regimen of most participants (95.7%) comprised
basal–bolus therapy. Of those on alternative regimens,
4% were using premix insulin (alone or combined
with either basal or bolus insulin), 0.3% were using
basal insulin alone and 1.4% were using bolus insulin
alone.
Glycemic control
Non-inferiority of IDeg to IDet with respect to change
in HbA1c from baseline to wk 26 was confirmed
[estimated treatment difference (ETD) IDeg–IDet:
0.15%-points, (0.03; 0.32)95% CI (1.6 mmol/mol, (0.3;
3.5)95% CI)]. The robustness of the primary analysis was
supported by analysis of the PP set [ETD IDeg–IDet:
0.19%-points, (0.01; 0.37)95% CI (2.0 mmol/mol, (0.1;
4.0)95% CI)] and other sensitivity analyses (data not
shown). The observed mean decrease in HbA1c
from baseline to wk 52 was similar between IDeg
[−0.27%-points (3 mmol/mol)] and IDet [−0.22%-
points (2.4 mmol/mol)] groups and the trend over time
in HbA1c was also similar (Fig. 2A). Similar betweentreatment
reductions in HbA1c were also observed in
children 1–5 yr of age [−0.36 %-points (3.9 mmol/mol)
for IDeg1–5 and −0.16%-points (1.7 mmol/mol)
for IDet1–5,], children 6–11 yr of age [−0.35%-
points (3.8 mmol/mol) for IDeg6–11, −0.33%-points
(3.6 mmol/mol) for IDet6–11] and adolescents 11–17 yr
of age [−0.10%-points (1.1 mmol/mol) for IDeg11–17
and −0.14%-points (1.5 mmol/mol) for IDet11–17],
respectively, at 52 wk.

At 52 wk, there was a statistically significant difference

in laboratory-analyzed FPG, which decreased
from baseline in the IDeg group, but increased in
the IDet group. With IDeg, the mean FPG decreased
from 9.0 to 7.8 mmol/L, corresponding to a change
of −1.29 mmol/L. With IDet the mean FPG increased
from 8.4 to 9.5 mmol/L, corresponding to a change
of +1.10 mmol/L, ETD (IDeg–IDet): −1.62 mmol/L
[−2.84; −0.41]95%CI, p=0.0090, Fig. 2B. Similar
changes were observed for the three age groups and
for the ETS population, both overall (−1.67 mmol/L in
the IDeg group and +0.48 mmol/L in the IDet group)
and stratified by age group.
After 52wk, the change from baseline in the
mean of the 8-point SMPG profiles was significantly
different for the two treatments. The observed mean
change was −0.7 mmol/L with IDeg and +0.3 mmol/L
with IDet, ETD (IDeg–IDet): −0.79 mmol/L (−1.32;
−0.26)95%CI, p=0.0036 (Fig. 1C). Similar patterns
were seen between age groups. In the IDeg group,
post-prandial SMPG values at wk 12, 26, 38 and
52 decreased from baseline, whilst there was no
apparent reduction in the IDet group. After 52wk,
there was a statistically significant treatment difference
post-breakfast [IDeg–IDet: −1.57 mmol/L (−2.65;
−0.49)95%CI, p=0.0045], post-dinner [IDeg–IDet:

−1.85 mmol/L (−2.95; −0.75)95%CI, p=0.0011) and

pre-breakfast on the second day [IDeg–IDet:
−0.94 mmol/L (−1.77; −0.11)95%CI, p=0.0264]. There
were minor profile variations between age groups.
As with the 8-point profile data, pre-breakfast
SMPG (based on the 4-point profile) decreased
from baseline to wk 2 in the IDeg group and
subsequently remained lower than for the IDet group
throughout the trial. After 52 wk, the observed mean
pre-breakfast value was significantly lower with IDeg
compared with IDet [8.7 vs. 9.4 mmol/L, respectively;
ETD IDeg–IDet: −0.76 mmol/L (−1.46; −0.05)95%CI,
p=0.0354].Within-subject variability in pre-breakfast
SMPG after 52wk was similar for the two treatment
arms; ETD (IDeg–IDet): 1.04, (0.93; 1.16)95%CI.
Insulin dose
At baseline, the mean daily basal dose was slightly
lower in the IDeg group compared with the IDet group
(0.37 vs. 0.40 units/kg, respectively) and remained fairly
constant throughout the trial, reaching 0.38 U/kg by
wk 52. By contrast, the mean daily basal dose in the
IDet group increased over the study duration (Fig. 3).
The mean daily dose of IDeg remained lower than that
of IDet throughout the trial and across the three age
groups (Table 3). The overall pattern was similar in the
ETS, apart from a slightly lower basal insulin dose at
wk 1 in participants 6–11 yr of age in the IDet group
compared with the SAS (0.39 vs. 0.42 U/kg). After
52 wk, 112 (64%) participants were using IDet BID.
Mean daily IAsp dose increased gradually during the
trial in both treatment groups. After 52 wk, mean daily
IAsp dose was marginally lower in the IDeg group
compared with the IDet group (0.55 vs. 0.58 U/kg)
(Table 3). After 52 wk of treatment, participants
receiving IDeg required 30% less basal insulin, and
18% less insulin overall, and the basal:bolus ratios were
41:59 with IDeg vs. 48:52 with IDet. The mean basal
(IDeg:IDet) dose ratio (U/kg) was 0.70. In contrast, the
bolus insulin dose ratio (IAsp:IAsp) was∼1, indicating
that participants in both groups received comparable
doses of IAsp.

At 52 wk, rates of confirmed hypoglycemia [i.e., PG

<3.1 mmol/L and/or severe (altered mental status,
cannot assist in own care, semiconscious/unconscious,
or in coma±convulsions)] were similar for IDeg
and IDet [57.7 vs. 54.1 events/exposure year, estimated
rate ratio (ERR): 1.11 (0.89; 1.38)95%CI, NS]
(Fig. 4A and Table 4), as were rates of nocturnal
hypoglycemia [6.0 vs. 7.6 events/exposure year, ERR
0.99 (0.72; 1.34)95% CI, NS; Fig. 4B and Table 4].
Incidence and rates of severe hypoglycemia were
numerically higher with IDeg than IDet, but the
difference was not statistically significant: 17.8 vs.
13.7%; 0.51 vs. 0.33 events/exposure year [ERR
1.30 (0.64; 2.64)95% CI, NS; Table 4]. Rates of severe
hypoglycemia, including only episodes of semi consciousness/
unconsciousness and coma±convulsions,
were 0.09 and 0.14 events/exposure year for IDeg and
IDet, respectively [ERR 0.62 (0.24; 1.60)95% CI, NS;
post hoc analysis based on external classification of
severe hypoglycemic episodes; Table 4].
Participants in the IDet group continuing in the
extension had markedly lower rates of both confirmed
(0.31 vs. 0.63 events/exposure year) and severe (50 vs.
80 events/exposure year), but not nocturnal confirmed
(7.3 vs. 6.9 events/exposure year) hypoglycemia at 26
wk compared with those discontinuing after the main
trial period. In the IDeg arm, those continuing into
the extension had higher rates of severe hypoglycemia
(0.48 vs. 0.11 events/exposure year) and lower rates
of nocturnal confirmed hypoglycemia (5.5 vs. 9.3
events/exposure year), whereas rates of confirmed
hypoglycemia were similar (58 vs. 55 events/exposure
year) at 26 wk irrespective of continuation or not (data
not shown).
Hyperglycemia with ketosis
The rate of hyperglycemic episodes (>14 mmol/L) with
ketosis (>1.5 mmol/L) was significantly lower for IDeg
vs. IDet [0.7 vs. 1.1 events/exposure year, treatment
ratio 0.41 (0.22; 0.78)95% CI, p=0.0066; Fig. 5], and
lower rates were observed for IDeg compared to
IDet for all age groups. The same pattern was also
observed in the ETS population. When stratified by
age, children 1–5 yr of age had a higher rate of episodes
of hyperglycemia with ketosis in both treatment groups
(1.34 vs. 1.61 events/exposure year for IDeg vs. IDet,
respectively) compared with the two older age groups

Other safety endpoints

At 52 wk, mean body weight SD scores had increased
in the IDeg group but remained relatively unchanged
in the IDet group [change: +0.11 vs. –0.06 kg, ETD:
0.17 (0.10; 0.25)95% CI, p<0.0001].
AE profiles were similar for IDeg and IDet (Table 5).
The majority of reported AEs for both groups were
mild or moderate in severity and considered unlikely
to be related to trial product. Of those considered
possibly or probably related to trial product, ∼97%
were resolved by the end of the trial. The observed
rates of serious AEs (SAEs) were also similar for
IDeg and IDet (Table 5) and the most common SAEs
were infections, hypoglycemia and hyperglycemia for
both groups. The rate of SAEs considered possibly
or probably related to the investigational medicinal
product was five events per 100 PYE with IDeg and
Table 5. Summary of AEs
IDeg IDet
All patients 174 175
Number of patients with events 161 157
Percentage of patients with events 92.5% 89.7%
Number of events 1462 1266
Adverse event rate per 100 PYE 906 859
Number of patients with serious AEs 18 16
Percentage of patients with serious AEs 10.3% 9.1%
Number of events 25 24
Serious adverse event rate per 100 PYE 15 16
Number of patients withdrawn due to
AEs
03
Percentage of patients withdrawn due to
AEs
0.0% 1.7%
AEs, adverse events; IDeg, Insulin degludec; IDet, insulin
detemir; PYE, patient-years of exposure.
3 events per 100PYEwith IDet, respectively. Only three
participants, all from the IDet group, withdrew from
the trial due to AEs (wrong trial drug administration,
hypoglycemic seizure and anxiety disorder). Two cases
of DKA were reported, both in the IDeg group, but
were considered unlikely to be related to trial product.
The mean level of insulin antibodies cross-reacting
between insulin analogs and human insulin decreased
slightly with IDeg and increased slightly with IDet
during the trial period (data not shown). No clinically
relevant differences either from baseline to end of
treatment or between the two treatment groups were
observed for vital signs, physical examination, electrocardiograms,
fundoscopy or laboratorymeasurements.
CGM subgroup analysis
In the subgroup of participants who performed CGM
assessment before and during treatment with IDeg
(74 participants) and IDet (75 participants) in the
main trial period, the event rates for low IG and
high IG generally reflected the pattern for hypo-

and hyperglycemic episodes. At wk 26, there were

no significant differences between the IDeg and IDet
groups for either IG <3.1 mmol/L [IDeg:IDet ratio:
1.50 (0.97; 2.32)95%CI] or IG <3.9 mmol/L [IDeg:IDet
ratio: 1.29 (0.98; 1.71)95%CI]. Nocturnally, observed
rates with IDeg and IDet were 2.49 vs. 3.13 events
per 100 PYE for IG<3.1 mmol/L and 5.16 vs. 5.22
events per 100 PYE for IG ≤3.9 mmol/L. Owing to
the low number of nocturnal events, no statistical
analysis was conducted. The duration of low IGs
was not significantly different between IDeg and
IDet for either IG <3.1 mmol/L [IDeg–IDet contrast:
0.12 h (−0.33; 0.56)95%CI, NS] or IG <3.9 mmol/L
[IDeg–IDet contrast: 0.30 h (−0.37; 0.97)95%CI, NS].
The observed rate of high IGs after 26wk was
11.20 (IDeg) vs. 10.66 (IDet) events per 100 PYE,
respectively, with no significant difference between
treatments [IDeg–IDet contrast: 1.03 (0.91; 1.17)95%CI,
NS]. Nocturnal observed high IG rates after 26wk
were 12.05 (IDeg) vs. 10.61 (IDet) events per 100
PYE, respectively. There was no significant difference
between treatments in the observed duration of high
IGs overall [8.07 vs. 7.40 h; IDeg–IDet contrast: 0.47
(−0.69; 1.64)95%CI, NS] or nocturnally (2.92 vs. 2.12 h
for IDeg vs. IDet, respectively).
Discussion
Intensive insulin therapy is associated with reduced
long-term complications compared with non-intensive
therapy in people with T1D and as such has become
the standard of care. Treating intensively to reach
glycemic targets can be particularly challenging in
children, as their needs are in constant flux during their
growth and development toward adulthood. Although
a basal–bolus regimen containing basal insulin analogs
enables many patients to achieve their glycemic
targets, issues associated with variability of action,
and an action profile requiring strict administration
timing, can reduce the likelihood of attaining
good glycemic control, particularly for children and
adolescents, whose daily routine (and/or that of their
parent/caregiver) can vary substantially. Poor glycemic
control can result in persistent hyperglycemia and
increasing risk of DKA. IDeg has a duration of action
exceeding 42 h and a reduced intra-patient variability in
glucose-lowering effect, and thus may offer a desirable
alternative to other insulin analogs by enabling a degree
of flexibility in dosing time when needed (17, 27).
This study has showed that IDeg OD provides
effective long-term improvements in glycemic control,
when compared with IDet OD or BID, both with
mealtime IAsp in children with T1D as young as 1 yr of
age. In this study, the titration guideline recommended
that IDeg be dosed at the same time each day and IDet
in accordance with local labeling. Throughout the trial,
IDet doses were consistently higher than IDeg doses,
showing that improvements in FPG were achievedwith
lower daily insulin doses in the IDeg group.Onthe basis
of insulin dose ratios at 52 wk, the IDeg group required
less basal insulin and less insulin overall compared with
the IDet group. The higher IDet dose is probably in
part due to 64% of the group receiving IDet BID,
which is well-documented to increase basal doses (28,
29). The fact that IDeg ensures basal insulin coverage
with one daily injection for all is an important benefit,
particularly in children, as this reduces the burden of
insulin injections.
Furthermore, although not formally tested in this
study, flexibility in administration timing of IDeg was
shown to be possible without compromising glycemic
control in adults (20, 21). Owing to the preserved
pharmacokinetic properties of IDeg across pediatric
and adult populations (30), the potential for flexibility
in dosing time when needed may make IDeg a very
useful option for children and their caregivers.
In this trial, hypoglycemia was evaluated using
both ISPAD classifications and a Novo Nordisk
definition of confirmed hypoglycemic episodes PG
<3.1 mmol/L and/or severe hypoglycemia). Whereas
severe hypoglycemia in adults is defined based
on ability to self-treat (31), the ISPAD definition
contains a broader, more subjective component: ‘The
child is having altered mental status and cannot
assist in their care’ (10). On the basis of external
classification, the majority of hypoglycemic episodes
were deemed severe based on this most subjective
component. For severe episodes ‘accompanied by
either (semi) unconsciousness or coma±convulsion’,
post hoc analysis showed that the observed rates were
either numerically lower with IDeg compared with
IDet or similar between treatments, respectively. Thus,
rates of severe hypoglycemia in this trial cannot be
directly compared to rates of severe hypoglycemia
in other pediatric trials where a narrower definition
of severe hypoglycemia (e.g. episodes accompanied
by seizure/loss of consciousness/coma) may have
been used. Most severe episodes occurred during the
day and in most cases, bolus insulin was the last
insulin administered (results not shown). Moreover,
incidence of severe hypoglycemia was low with <1% of
hypoglycemic episodes classified as severe with either
treatment using the ISPAD criteria.
Nocturnal hypoglycemia represents a pivotal
parameter; as these episodes are usually independent
of bolus doses, exercise or food intake, they provide the
most relevant comparison standard for basal insulins.
IDeg has consistently been showed to be associated
with lower nocturnal hypoglycemia rates in adults
compared with other basal insulins (19, 32–35). In
this trial, there was a numerical reduction in nocturnal
hypoglycemia in favor of IDeg, although statistical

significance was not achieved. The ultra-long, flat

action profile and reduced intrapatient variability
of IDeg facilitate improvements in FPG without
increasing nocturnal hypoglycemic episodes. This
property is especially beneficial for young children,
where nocturnal hypoglycemia is of particular concern
(36, 37). It should be noted that in this trial participants
were transferred from pre-trial basal insulin to IDeg or
IDet without specific dose reduction recommendations.
However, evidence from the phase 3 trial program has
led to the recommendation that the dose of both basal
and bolus insulin should be reduced upon initiation
of IDeg (38), and a similar recommendation would
seem appropriate for children, based on the lower
pre-breakfast, post-breakfast and post-dinner glucose
levels observed in the IDeg arm in this trial. The
values for pre- and post-breakfast in particular reflect
the effect of greater basal control, which could be
explained by the ultra-long duration of IDeg; a lower
pre-breakfast, leading to a reduction in post-breakfast
by default, although bolus insulin certainly will also
play a role. The effect on post-lunch glucose values
may be confounded by the availability (or lack of)
medical assistance to administer bolus insulin during
school/nursery hours.
At the opposite end of the glycemic spectrum,
inadequate treatment can lead to hyperglycemia and
if left untreated, rising ketone levels may progress
to DKA, which is associated with increased morbidity
and mortality (11). Prevention of DKA is of
particular importance in children and adolescents,
whose continuous cognitive and physical development
place them at particular risk (11). In this trial, IDeg
treatment led to a significant reduction in the rates of
hyperglycemia with ketosis when compared with IDet.
This reduction may be attributed to the ultra-long and
flat pharmacokinetic profile of IDeg.
The CGM data from a subset of participants
generally confirmed the patterns of hypo- and
hyperglycemia (but not hyperglycemia with ketosis)
discussed above, and showed that the duration of low
IGs was not significantly longer for IDeg than IDet.
In general, IDeg and IDet were both well tolerated
and there were no clinically meaningful differences
in relation to AEs, antibodies and standard safety
parameters.
Limitations of this trial include the greater extent
of discontinuation following the main study of
participants in the IDet group compared with the IDeg
group. Those participants from the IDet group who
discontinued had a higher confirmed and severe hypoglycemia
rate than those who continued. Secondly,
this was an open-label trial and investigators may have
been more vigilant in their management of the IDeg
arm, including reporting of AEs. Furthermore, as 46%
of those enrolled received IDet as part of their prior
therapy, familiarity may have affected both the dosing
and hypoglycemia rates observed, especially during
the initial part of the trial.
The multinational nature of the trial population,
covering 12 countries and a range of racial backgrounds,
and the broad age range of participants
who were all characteristic of patients with T1D,
make these findings highly generalizable to the global
pediatric population with T1D. Moreover, this study
has provided a comprehensive assessment of severe
hypoglycemia in a pediatric population.
Conclusion
In conclusion, this trial has showed that IDeg offers
a valuable new addition to the treatment of T1D in
children, with the potential to deliver similar glycemic
control to IDet, achieved with comparable safety, but
reduced hyperglycemia with ketosis in a single daily
injection.
Acknowledgements
We thank the investigators, trial staff, and participants for their
participation. We also thank Gemma Rogers PhD and Mark
Nelson at Watermeadow Medical, funded by Novo Nordisk, for
providing medical writing and editorial assistance. This study
was funded by Novo Nordisk A/s; ClinicalTrials.gov number,
NCT01513473.
Author contributions
N. T. acts as guarantor for the contents of this article.
All authors (N. T., L. D., V. I., T. K., G. K., A. P., J.
S., S. T., A. M. O. F., O. K. and T. D.) were involved
in critical analysis and interpretation of the data,
drafting/critically revising the article, and shared in the
final responsibility for the content of the manuscript
and the decision to submit it for publication.
Conflict of interest
N. T. has participated in advisory boards for Novo
Nordisk, Eli Lilly and Lifescan. He has acted as
a paid consultant to Novo Nordisk in the capacity
of an external speaker at international meetings and
his institution has received financial support for the
delivery of clinical research trials from Novo Nordisk,
Sanofi Aventis and Eli Lilly. L. D. has participated
in advisory boards for Sanofi and received research
support from Novo Nordisk. G. K. has acted as a
consultant to Novo-Nordisk, providing consultation
on the definition of hypoglycemia in children. A. P. has
participated in advisory boards and speakers’ bureau
for Novo Nordisk and has also received research
support from Novo Nordisk. J. S. has received grant
funding from Daiichi Sankyo. S. T. has participated

in advisory boards for Novo Nordisk, Sanofi Aventis,

Eli Lilly and Lifescan. He has also received speaker
honoraria from Roche Diagnostics, Novo Nordisk and
Sanofi Aventis. A. M. O. F. and O. K. are employees
of Novo Nordisk and own stock in the company. T. D.
has received speakers’ honoraria, research support and
has consulted for Eli Lilly, Medtronic, Novo Nordisk,
Roche, Bristol-Myers Squibb (BMS)/AstraZeneca,
Boehringer, Bayer, Abbott, DexCom and Sanofi. V.
I. and T. K. have no conflicts of interest to disclose.
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Fig. S1. Trial design schematic.
Table S1. Titration guideline for insulin dose at
initiation.
Table S2. Withdrawals according to prespecified
criteria.