nn9068-4229

Novo Nordisk A/S

Novo Allé, Bagsvaerd, Denmark, 2880

Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com

No

No

No

Final

29 Mar 2018

Yes

26 Sep 2017

Yes

23 Oct 2017

No

To confirm the effect of insulin degludec/liraglutide (IDegLira) in terms of glycaemic control in subjects with type 2 diabetes mellitus (T2DM) on previous treatment with sodium-glucose co-transporter 2 inhibitors (SGLT2i) ± oral anti-diabetic drug (OAD) therapy. This is done by comparing the difference in change from baseline in HbA1c after 26 weeks to a non-inferiority margin of 0.3% for IDegLira versus insulin glargine (IGlar), both in combination with SGLT2i ± OAD.

The trial was conducted in accordance with the Declaration of Helsinki (64th WMA Assembly, October 2013) and ICH Good Clinical Practice, including archiving of essential documents (June 1996) and 21 CFR 312.120.

23 May 2016

No

No

Argentina: 45

Canada: 30

Finland: 25

Hungary: 37

India: 58

Russian Federation: 49

Slovakia: 38

Slovenia: 24

Spain: 47

Switzerland: 8

United States: 59

420

171

0

0

0

0

0

0

322

98

0

Overall study (overall period)

Randomised - controlled

Not applicable

Yes

Insulin degludec liraglutide

Xultophy®

Solution for injection

Subcutaneous use

IDegLira was supplied in a 3 mL prefilled PDS290 pen-injector with a fixed IDeg/liraglutide ratio of 100 units/3.6 mg per mL solution subcutaneously in the thigh, upper arm (deltoid) or abdomen approximately at the same time every day throughout the trial. IDegLira treatment was initiated at 10 dose steps (containing 10 units IDeg /0.36 mg liraglutide). Dose was adjusted individually twice weekly on fixed days based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured on the days of the titration and the two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72- 90 mg/dL]). The maximum daily dose for IDegLira was 50 dose steps.

Insulin Glargine

Solution for injection

Subcutaneous use

IGlar was supplied in a 3 mL pre-filled Solostar® pen at 100 U/mL solution and administered subcutaneously according to the local labelling. Dose adjustment was based on the mean of three pre-breakfast self-measured plasma glucose (SMPG) values measured individually on the days of the titration and two days prior to the titration (target SMPG: 4.0-5.0 mmol/L [72 - 90 mg/dL]). There was no maximum dose specified for IGlar.

IDegLira

IGlar

IDegLira

IGlar

The mean change from baseline (week 0) in HbA1c values evaluated after 26 weeks of randomised treatment. The full analysis set (FAS) included all randomised subjects. The statistical evaluation of the FAS followed the intent-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. Number analysed = Number of subjects contributed to the analysis at week 26. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product.

Primary

After 26 weeks

Analysis was based on ANCOVA model with treatment, pre-trial OAD, region as factors and baseline HbA1c as covariate. Missing data were imputed using unconditional reference based multiple imputation including data obtained after premature treatment discontinuation. The non-inferiority margin of 0.3 % was added to the end-of-treatment value for prematurely discontinued and withdrawn from trial IDegLira subjects. Number of subjects contributed to the analysis included all randomised subjects (420)

IDegLira v IGlar

399

Pre-specified

-0.34

2-sided

This endpoint was analysed using an ANCOVA model with treatment, pre-trial OAD and region as factors and corresponding baseline value as covariate. Data obtained after premature treatment discontinuation were included in the analysis. Missing data were imputed using unconditional reference based multiple imputation including data obtained after premature treatment discontinuation. Number of subjects contributed to the analysis included all randomised subjects (420).

IDegLira v IGlar

399

Pre-specified

-0.36

2-sided

The mean change from baseline (week 0) in body weight evaluated after 26 weeks of randomised treatment. The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intent-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. Number analysed = Number of subjects contributed to the analysis at week 26. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product.

Secondary

After 26 weeks

This endpoint was analysed using an ANCOVA model with treatment, pre-trial OAD and region as factors and corresponding baseline weight as covariate. Data obtained after premature treatment discontinuation were included in the analysis. Missing data were imputed using unconditional reference based multiple imputation including data obtained after premature treatment discontinuation. Number of subjects contributed to the analysis included all randomised subjects (420).

IDegLira v IGlar

403

Pre-specified

-1.92

2-sided

Severe or BG confirmed symptomatic hypoglycaemic episodes were defined as episodes that were severe (subjects who were not able to self-treat) and/or BG confirmed by a plasma glucose values <3.1 mmol/L (56 mg/dL) with accompanied symptoms consistent with hypoglycaemia. The safety analysis set (SAS) included all subjects who received at least one dose of the investigational product or comparator.

Secondary

During 26 weeks

This endpoint was analysed using a negative binomial regression model with a log link and the logarithm of the exposure time as offset. The model included treatment and pre-trial OAD as fixed factors. Missing data were imputed using multiple imputations (conditioning on expected event rate before premature treatment discontinuation or withdrawal from trial as if treated with IGlar).

IDegLira v IGlar

419

Pre-specified

0.42

2-sided

Actual daily total insulin dose (Units) was evaluated after 26 weeks of randomised treatment. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product. The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intent-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. Number analysed = Number of subjects contributed to the analysis at week 26.

Secondary

After 26 weeks

The endpoint was analysed using an ANCOVA model with treatment, pre-trial OAD and region as factors and corresponding baseline HbA1c as covariate. Missing data were imputed using unconditional reference based multiple imputation including data obtained after premature treatment discontinuation. Number of subjects contributed to the analysis included all randomised subjects receiving at least one dose of the investigational product or comparator (419).

IDegLira v IGlar

397

Pre-specified

-15.37

2-sided

The proportion of subjects achieving pre-defined HbA1c targets <7.0% after 26 weeks of randomised treatment. The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intent-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. Number analysed = Number of subjects contributed to the analysis at week 26. The results presented included retrieved data at week 26 for subjects who prematurely discontinued the trial product.

Secondary

After 26 weeks

Change from baseline (week 0) in FPG was evaluated after 26 weeks of randomised treatment. The FAS included all randomised subjects. The statistical evaluation of the FAS followed the intent-to-treat (ITT) principle and subjects contributed to the evaluation “as randomised”. Number analysed = Number of subjects contributed to the analysis at week 26.

Secondary

After 26 weeks

Treatment emergent adverse events (TEAEs) were recorded from week 0-week 26. A TEAE was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. If the event had onset date before the first day of exposure on randomised treatment and increased in severity during the treatment period and until 7 days after the last drug date, then this event should also be considered as a TEAE. Major cardiovascular events (MACEs) were considered treatment-emergent until 30 calendar days after the last day of randomised treatment. The safety analysis set included all subjects who received at least one dose of the investigational product or comparator.

Secondary

During 26 weeks

From the first day of exposure until the end of treatment (week 0 to week 26) plus 7 days after last dose of trial product or 30 days for major cardiovascular events.

TEAE: An event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days (30 days for MACEs) after the last day of randomised treatment (or an event that increased in severity during this period but had an onset date before first day of exposure).

20

IDegLira

IGlar