Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Europe, North America and the United States of America. The aim of this trial is to compare two different titration algorithms of insulin degludec/liraglutide.
Interventions
DRUGinsulin degludec/liraglutide
For subcutaneous (s.c., under the skin) injection, once daily. Subjects will be instructed to continue with the same dose of OADs (metformin alone or in combination with pioglitazone), as prior to the trial.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus * Male or female equal to or above 18 years of age * HbA1c (glycosylated haemoglobin) 7.0 - 10.0% \[53 mmol/mol - 86 mmol/mol\] (both inclusive), confirmed by the central laboratory * Stable daily treatment with metformin (above or equal to 1500 mg or max tolerated dose) with or without pioglitazone (above orequal to 30 mg) for at least 90 days prior to screening * Body Mass Index (BMI) below or equal to 40 kg/m\^2
Exclusion criteria
* Current use of any anti-diabetic drugs (except for metformin and pioglitazone) or anticipated change in concomitant medication, which, in the opinion of the investigator, could interfere with the glucose metabolism (e.g. systemic corticosteroids) * Previous and / or current treatment with insulin (short term treatment due to intercurrent illness, including gestational diabetes, is allowed at the discretion of the investigator) * Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists, sulpfonylurea, glinides, dipeptidyl peptidase 4 (DPP-4) inhibitors or sodium-glucose co-transporter 2 (SGLT2) inhibitors within 90 days prior to the screening visit * Impaired liver function, defined as alanine aminotransferase (ALAT) above or equal to 2.5 times upper normal range (UNR) * Impaired renal function defined as serum-creatinine above or equal to 133 micromol/L (above or equal to 1.5 mg/dL) for males and above or equal to 125 micromol/L (above or equal to 1.4 mg/dL) for females, or as defined according to local contraindications for metformin * Screening calcitonin above or equal to 50 ng/L * Proliferative retinopathy or maculopathy (macular oedema) requiring acute treatment, according to investigator's clinical judgment * Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2) * History of pancreatitis (acute or chronic)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c | Week 0, week 32 | Change in glycosylated haemoglobin A1c (HbA1c) (%) from baseline after 32 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Below 7.0% | Week 0, week 32 | Responders to HbA1c below 7% after 32 weeks of treatment. |
| HbA1c Below or Equal to 6.5% | Week 0, week 32 | Responders to HbA1c below or equal to 6.5% after 32 weeks of treatment. |
| Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | Week 0-32 | An episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. |
Countries
Austria, Bulgaria, Canada, Czechia, Hungary, Russia, Serbia, Slovakia, United States
Participant flow
Recruitment details
The trial was conducted at 80 sites in 9 countries as follows:Austria: 6 sites; Bulgaria: 5 sites; Canada: 7 sites, Czech Republic:5 sites; Hungary: 4 sites, Russian Federation: 6 sites; Serbia: 4sites, Slovakia: 7 sites; United States: 36 sites.
Pre-assignment details
Stable daily treatment with metformin (≥1500 mg or max tolerated dose) ± pioglitazone (≥30 mg) for at least 90 days prior to screening
Participants by arm
| Arm | Count |
|---|---|
| IDegLira (1WT) Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira once weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 2 fasting SMPG values measured pre-breakfast in the morning of two consecutive days corresponding to one obtained on the day before titration and one obtained on titration day. | 210 |
| IDegLira Subjects inadequately controlled on metformin either alone or in combination with pioglitazone were randomized in a 1:1 manner to receive IDegLira once daily. The subjects were stratified by their OAD treatment prior to entering the trial. The starting dose of IDegLira was 10 dose steps (10 units IDeg/0.36mg liraglutide), and the maximum dose was 50 dose steps (50units/1.8mg liraglutide) The daily dose for metformin was ≥ 1500mg or max tolerated dose and ≥ 30mg for pioglitazone. In the IDegLira twice weekly titration group (1WT), the dose of IDegLira was adjusted based on the mean of 3 fasting SMPG values measured pre-breakfast in the morning of three consecutive days corresponding to one obtained on each of two days before titration and one obtained on titration day. | 210 |
| Total | 420 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Unclassified | 3 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 1 |
| Overall Study | Withdrawal criteria | 2 | 0 |
Baseline characteristics
| Characteristic | IDegLira (1WT) | IDegLira | Total |
|---|---|---|---|
| Age, Continuous | 56.6 years STANDARD_DEVIATION 10.3 | 57.0 years STANDARD_DEVIATION 9.6 | 56.8 years STANDARD_DEVIATION 9.9 |
| HbA1c | 8.2 percentage STANDARD_DEVIATION 0.9 | 8.1 percentage STANDARD_DEVIATION 0.9 | 8.1 percentage STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 99 Participants | 98 Participants | 197 Participants |
| Sex: Female, Male Male | 111 Participants | 112 Participants | 223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 209 | 19 / 210 |
| serious Total, serious adverse events | 7 / 209 | 14 / 210 |
Outcome results
Primary
Change From Baseline in HbA1c
Change in glycosylated haemoglobin A1c (HbA1c) (%) from baseline after 32 weeks of treatment.
Time frame: Week 0, week 32
Population: Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IDegLira (1WT) | Change From Baseline in HbA1c | -2.01 percentage | Standard Deviation 1.09 |
| IDegLira | Change From Baseline in HbA1c | -2.02 percentage | Standard Deviation 0.98 |
Comparison: The null hypothesis was tested against the alternative hypothesis of non-inferiority as given by H0: D ≥0.30% against HA: D \<0.30%.p-value: 0.01295% CI: [-0.04, 0.28]Mixed Models Analysis
Secondary
HbA1c Below 7.0%
Responders to HbA1c below 7% after 32 weeks of treatment.
Time frame: Week 0, week 32
Population: Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDegLira (1WT) | HbA1c Below 7.0% | yes | 170 participants |
| IDegLira (1WT) | HbA1c Below 7.0% | No | 19 participants |
| IDegLira | HbA1c Below 7.0% | yes | 179 participants |
| IDegLira | HbA1c Below 7.0% | No | 21 participants |
Secondary
HbA1c Below or Equal to 6.5%
Responders to HbA1c below or equal to 6.5% after 32 weeks of treatment.
Time frame: Week 0, week 32
Population: Full analysis set (FAS) included all randomised subjects. 20 subjects in the IDegLira (1WT) and 10 subjects in the IDegLira arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IDegLira (1WT) | HbA1c Below or Equal to 6.5% | No | 31 particpants |
| IDegLira (1WT) | HbA1c Below or Equal to 6.5% | yes | 158 particpants |
| IDegLira | HbA1c Below or Equal to 6.5% | yes | 170 particpants |
| IDegLira | HbA1c Below or Equal to 6.5% | No | 30 particpants |
Secondary
Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes
An episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Time frame: Week 0-32
Population: Safety Analysis Set (SAS): Included all subjects receiving at least one dose of trial product. Subjects contributed to the evaluation as treated. One subject in the IDegLira (1WT) arm did not contribute to the analysis for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IDegLira (1WT) | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 20 Number of episodes |
| IDegLira | Number of Treatment Emergent Severe or Blood Glucose (BG) Confirmed Symptomatic Hypoglycaemic Episodes | 97 Number of episodes |