TRESIBA
®
(insulin degludec injection)
6
age and older. The efficacy of TRESIBA
®
administered once-daily either at the same time each
day or at any time each day in adult patients with type 2 diabetes and used in combination with a
mealtime insulin or in combination with common oral anti-diabetic agents was evaluated in six
randomized, open-label, treat-to-target active-controlled trials.
Adult patients treated with TRESIBA
®
achieved levels of glycemic control similar to those
achieved with LANTUS
®
(insulin glargine 100 units/mL) and LEVEMIR
®
(insulin detemir) and
achieved statistically significant improvements compared to sitagliptin.
14.1 Type 1 Diabetes – Adult
TRESIBA
®
Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin
Analog at Mealtimes in Adult Patients
Study A
The efficacy of TRESIBA
®
was evaluated in a 52-week randomized, open-label, multicenter trial
in 629 patients with type 1 diabetes mellitus (Study A). Patients were randomized to TRESIBA
®
once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved
labeling. Insulin aspart was administered before each meal in both treatment arms.
The mean age of the trial population was 43 years and mean duration of diabetes was 18.9 years.
58.5% were male. 93% were White, 1.9% Black or African American. 5.1% were Hispanic. 8.6%
of patients had eGFR<60 mL/min/1.73m
2
. The mean BMI was approximately 26.3 kg/m
2
.
At week 52, the difference in HbA
1c
reduction from baseline between TRESIBA
®
and insulin
glargine U-100 was -0.01% with a 95% confidence interval of [-0.14%; 0.11%] and met the
pre-specified non-inferiority margin (0.4%). See Table 6, Study A.
Study B
The efficacy of TRESIBA
®
was evaluated in a 26-week randomized, open-label, multicenter trial
in 455 patients with type 1 diabetes mellitus (Study B). Patients were randomized to TRESIBA
®
or insulin detemir once-daily in the evening. After 8 weeks, insulin detemir could be dosed twice-
daily. 67.1% used insulin detemir once daily at end of trial. 32.9% used insulin detemir twice
daily at end of trial. Insulin aspart was administered before each meal in both treatment arms.
The mean age of the trial population was 41.3 years and mean duration of diabetes was 13.9 years.
51.9% were male. 44.6% were White, 0.4% Black or African American. 4.4% were Hispanic.
4.4% of patients had eGFR<60 mL/min/1.73m
2
. The mean BMI was approximately 23.9 kg/m
2
.
At week 26, the difference in HbA
1c
reduction from baseline between TRESIBA
®
and insulin
detemir was -0.09% with a 95% confidence interval of [-0.23%; 0.05%] and met the
pre-specified non-inferiority margin (0.4%). See Table 6, Study B.
Table 6: Results at Week 52 in a Trial Comparing TRESIBA
®
to Insulin Glargine
U-100 (Study A) and Week 26 in a Trial Comparing TRESIBA
®
to Insulin Detemir
(Study B) in Adult Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart
at Mealtimes
Study A
Study B
TRESIBA
®
+
Insulin aspart
Insulin
glargine
U-100 +
Insulin aspart
TRESIBA
®
+ Insulin
aspart
Insulin
detemir
+ Insulin
aspart
N
472
157
302
153
HbA
1c
(%)
Baseline
7.7
7.7
8.0
8.0
End of trial
7.3
7.3
7.3
7.3
Adjusted mean change from baseline*
-0.36
-0.34
-0.71
-0.61
Estimated treatment difference [95%CI]
TRESIBA
®
- basal insulin U-100
-0.01 [-0.14;0.11]
-0.09 [-0.23;0.05]
Proportion Achieving
HbA
1c
< 7% at Trial End
39.8%
42.7%
41.1%
37.3%
FPG (mg/dL)
Baseline
165
174
178
171
End of trial
141
149
131
161
Adjusted mean change from baseline
-27.6
-21.6
-43.3
-13.5
Daily basal insulin dose
Baseline mean
28 U
26 U
22 U
22 U
Mean dose at end of study
29 U
1
31 U
1
25 U
2
29 U
2
Daily bolus insulin dose
Baseline mean
29 U
29 U
28 U
31 U
Mean dose at end of study
32 U
1
35 U
1
36 U
2
41 U
2
1
At Week 52
2
At Week 26
*The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with treatment, region,
sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA
1c
as covariates.
In Study A, there were 14.8% of subjects in the TRESIBA
®
and 11.5% Insulin glargine arms for whom data was
missing at the time of the HbA
1c
measurement.
In Study B, there were 6.3% of subjects in the TRESIBA
®
and 9.8% Insulin detemir arms for whom data was
missing at the time of the HbA
1c
measurement.
Study C: TRESIBA
®
Administered at the Same Time Each Day or at Any Time Each Day in
Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients
The efficacy of TRESIBA
®
was evaluated in a 26-week randomized, open-label, multicenter trial
in 493 patients with type 1 diabetes mellitus. Patients were randomized to TRESIBA
®
injected
once-daily at the same time each day (with the main evening meal), to TRESIBA
®
injected once
daily at any time each day or to insulin glargine U-100 injected once-daily according to the
approved labeling. The any time each day TRESIBA
®
arm was designed to simulate a worst-case
scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e.,
alternating intervals of 8 to 40 hours between doses). TRESIBA
®
in this arm was dosed in the
morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday,
and Sunday. Insulin aspart was administered before each meal in all treatment arms.
The mean age of the trial population was 43.7 years and mean duration of diabetes was 18.5 years.
57.6% were male. 97.6% were White, 1.8% Black or African American. 3.4% were Hispanic. 7.4%
of patients had eGFR<60 mL/min/1.73m
2
. The mean BMI was approximately 26.7 kg/m
2
.
At week 26, the difference in HbA
1c
reduction from baseline between TRESIBA
®
administered
at alternating times and insulin glargine U-100 was 0.17% with a 95% confidence interval of
[0.04%; 0.30%] and met the pre-specified non-inferiority margin (0.4%). See Table 7.
Table 7: Results at Week 26 in a Trial Comparing TRESIBA
®
Dosed Once Daily at
the Same and at Alternating Times Each Day to Insulin Glargine U-100 in Adult
Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes
TRESIBA
®
at the
same time each
day + Insulin
aspart
TRESIBA
®
at
alternating times
+ Insulin aspart
Insulin
glargine U-100
+ Insulin aspart
N
165
164
164
HbA
1c
(%)
Baseline
7.7
7.7
7.7
End of trial
7.3
7.3
7.1
Adjusted mean change from baseline*
-0.41
-0.40
-0.57
Estimated treatment difference [95%CI]
TRESIBA
®
alternating - Insulin glargine U-100
0.17 [0.04;0.30]
Proportion Achieving HbA
1c
< 7% at
Trial End
37.0%
37.2%
40.9%
FPG (mg/dL)
Baseline
179
173
175
End of trial
133
149
151
Adjusted mean change from baseline
-41.8
-24.7
-23.9
Daily basal insulin dose
Baseline mean
28 U
29 U
29 U
Mean dose at end of study
32 U
36 U
35 U
Daily bolus insulin dose
Baseline mean
29 U
33 U
32 U
Mean dose at end of study
27 U
30 U
35 U
*The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with treatment, region,
sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA
1c
as covariates.
In Study C, there were 15.8% and 15.9% of subjects in the TRESIBA
®
(same time and alternating times
respectively) and 7.9% Insulin glargine arms for whom data was missing at the time of the HbA
1c
measurement.
14.2 Type 1 Diabetes – Pediatric Patients 1 Year of Age and Older
Study J: TRESIBA
®
Administered at the Same Time Each Day in Combination with a Rapid-Acting
Insulin Analog at Mealtimes in Pediatric Patients 1 Year of Age and Older
The efficacy of TRESIBA
®
was evaluated in a 26-week, randomized, open label, multicenter trial
in 350 patients with type 1 diabetes mellitus (Study J). Patients were randomized to TRESIBA
®
once-daily or insulin detemir once or twice-daily. Subjects on a twice-daily insulin detemir
regimen were dosed at breakfast and in the evening either with the main evening meal or at
bedtime. Insulin aspart was administered before each main meal in both treatment arms. At end
of trial, 36% used insulin detemir once daily and 64% used insulin detemir twice daily.
The mean age of the trial population was 10 years; 24% were ages 1-5 years; 39% were ages
6-11 years and 36% were ages 12-17 years. The mean duration of diabetes was 4 years. 55.4%
were male. 74.6% were White, 2.9% Black or African American. 2.9% were Hispanic. The mean
z-score for body weight was 0.31.
At week 26, the difference in HbA
1c
reduction from baseline between TRESIBA
®
and insulin
detemir was 0.15% with a 95% confidence interval of [-0.03%; 0.33%] and met the pre-specified
non-inferiority margin (0.4%). See Table 8.
Table 8: Results at Week 26 in a Trial Comparing TRESIBA
®
to Insulin Detemir
in Pediatric Patients 1 Year of Age and Older with Type 1 Diabetes Mellitus
Receiving Insulin Aspart at Mealtimes
TRESIBA
®
+ Insulin aspart
Insulin detemir
+ Insulin aspart
N
174
176
HbA
1c
(%)
Baseline
8.2
8.0
End of 26 weeks
8.0
7.7
Adjusted mean change from baseline after 26 weeks
±
-0.19
-0.34
Estimated treatment difference [95%CI]
TRESIBA
®
v. Insulin detemir
0.15 [-0.03; 0.33]
FPG (mg/dL)
Baseline
162
151
End of 26 weeks
150
160
Adjusted mean change from baseline after 26 weeks
52.0
59.6
Daily basal insulin dose
Baseline mean
15 U (0.37 U/kg)
16 U (0.41 U/kg)
Mean dose after 26 weeks
16 U (0.37 U/kg)
22 U (0.51 U/kg)
Daily bolus insulin dose
Baseline mean
20 U (0.50 U/kg)
20 U (0.52 U/kg)
Mean dose after 26 weeks
23 U (0.56 U/kg)
22 U (0.57 U/kg)
±
The change from baseline to end of treatment visit in HbA
1c
was analyzed using ANOVA with missing data
imputed by multiple imputation carrying forward the baseline value and adding the error term, with treatment,
region, sex, and age group as fixed factors, and baseline HbA
1c
as covariate.
In Study J, there were 2.9% of subjects in TRESIBA
®
and 6.3% Insulin detemir arms for whom data was missing
at the 26-week HbA
1c
measurement.
