Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa and Asia. The aim of this trial is to compare efficacy and safety of insulin degludec/insulin aspart twice daily and biphasic insulin aspart twice daily in subjects with type 2 diabetes mellitus before, during and after Ramadan.
Interventions
DRUGinsulin degludec/insulin aspart
Injected subcutaneously (s.c., under the skin)twice daily. The pre-trial insulin will be discontinued.
DRUGbiphasic insulin aspart
Injected subcutaneously (s.c., under the skin)twice daily. The pre-trial insulin will be discontinued.
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
* Male or female, age at least 18 years at the time of signing informed consent. Algeria: Male or female, age at least 19 years at the time of signing informed consent * Subjects diagnosed (clinically) with type 2 diabetes mellitus prior to day of screening (Visit 1) * Treated with any pre-mix/self-mix or basal insulin regimen for at least 90 days prior to the day of screening (Visit 1) * Subjects not on any OAD(s) (oral anti-diabetic drug) prior to trial participation OR subjects on fixed daily dose(s) of OAD(s) for at least 90 days prior to screening (Visit 1). The OAD(s) include any of the following anti-diabetic drug(s)/regimen: Biguanides (metformin equal to or above 1500 mg or maximum tolerated dose documented in the subject medical record) Insulin secretagogues (sulfonylureas (SU) and glinides), Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), a-glucosidase inhibitors, Sodium-glucose co-transporter 2- inhibitors (SGLT2 Inhibitors ) (above or equal to half of the maximum approved dose according to local label or maximum tolerated dose as documented in subject medical record) * HbA1c 7.0%-10.0% (53-86 mmol/mol) (both inclusive, by central laboratory analysis) * Intention to fast (daytime, i.e., between dawn and sunset) during Ramadan after receiving medical counselling regarding the risk of fasting * Willing to give blood during Ramadan
Exclusion criteria
* Any contraindication for successful and sustained fasting from a medical perspective at the discretion of the investigator (such as acute illness, severe hypoglycaemia within 90 days prior to screening (Visit 1), hypoglycaemia unawareness, ketoacidosis within 90 days prior to screening (Visit), hyperosmolar hyperglycaemic coma within 90 days prior to screening (Visit 1), subjects performing intense physical labour)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (%) (Glycosylated Haemoglobin) | From week 0 to end of Ramadan (day 29 of Ramadan) | Mean change in HbA1c was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fructosamine | From week 0 to end of Ramadan (day 29 of Ramadan) | Mean change in fructosamine was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan). |
| Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target ) | End of Ramadan (day 29 of Ramadan) | Number of subjects who achieved HbA1c below 7% (53 mmol/mol; ADA target) at the end of Ramadan (day 29 of Ramadan). |
| Change in Fasting Plasma Glucose (FPG) | From week 0 to end of Ramadan (day 29 of Ramadan) | Mean change in FPG was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan). |
| Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic | From week 0 to 4 weeks post Ramadan | Treatment-emergent hypoglycaemic episodes: If the onset of the episode occurred on or after the first day of investigational medicinal product (IMP; IDegAsp/BIAsp 30) administration, and no later than 1 day after the last day on IMP, before switching to or being treated with another insulin product. The above mentioned definitions (in endpoint title) should read as the following: Novo Nordisk definition; severe or blood glucose (BG) confirmed symptomatic hypoglycaemia: An episode that was severe according to ADA classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. American Diabetes Association (ADA) definition; documented symptomatic hypoglycaemia: An episode, during which typical symptoms of hypoglycaemia were accompanied by a measured PG concentration ≤3.9 mmol/L (70 mg/dL). Due to character limitation, severe hypoglycaemia as per ADA classification is not defined here; see next outcome measure. |
| Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | From week 0 to 4 weeks post Ramadan | Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes, which occurred between 00:01 and 05:59 both inclusive. Novo Nordisk definition; severe or blood glucose (BG) confirmed symptomatic hypoglycaemia: An episode that was severe according to ADA classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA classification: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. |
| Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target) | End of Ramadan (day 29 of Ramadan) | Number of subjects who achieved FPG \<=7.2 mmol/L at the end of Ramadan (day 29 of Ramadan). The above written (in the endpoint title) 'ADA target' is not applicable for FPG. |
Countries
Algeria, India, Lebanon, Malaysia, South Africa, United Arab Emirates
Participant flow
Recruitment details
The trial was conducted at 27 sites in 5 countries as follows: Algeria: 4 sites; India: 7 sites; Lebanon: 4 sites; Malaysia: 3 sites; South Africa: 9 sites.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Degludec/Insulin Aspart Subjects received IDegAsp s.c. in the thigh, upper arm or abdomen for a duration of 16-28 weeks (8-20 weeks treatment initiation period \[pre-Ramadan\], 4-week Ramadan treatment period, and 4 week post-Ramadan period). IDegAsp was administered BID during the entire treatment period with the breakfast/lunch meal and evening meal (during Ramadan Suhur and Iftar), with or without OADs. Subjects on pre-trial basal, premixed or self-mixed insulin therapy were converted unit-to-unit to trial insulin, BID IDegAsp at the same total insulin dose as the subject's pre-trial total daily insulin dose. Subjects used a fixed dose adjustment titration algorithm and there was no minimum or maximum dose for trial products. To optimise and maintain glycaemic control, IDegAsp dose was adjusted based on the subjects' SMPG values, measured twice daily during pre-Ramadan and post-Ramadan and 4 times daily during Ramadan. | 131 |
| Biphasic Insulin Aspart 30 Subjects received BIAsp 30 s.c. in the thigh, upper arm or abdomen for a duration of 16-28 weeks (8-20 weeks treatment initiation period \[pre-Ramadan\], 4-week Ramadan treatment period, and 4 week post-Ramadan period). BIAsp 30 was administered BID during the entire treatment period with the breakfast/lunch meal and evening meal (during Ramadan Suhur and Iftar), with or without OADs. Subjects on pre-trial basal, premixed or self-mixed insulin therapy were converted unit-to-unit to trial insulin, BID BIAsp 30 at the same total insulin dose as the subject's pre-trial total daily insulin dose. Subjects used a fixed dose adjustment titration algorithm and there was no minimum or maximum dose for trial products. To optimise and maintain glycaemic control, BIAsp 30 dose was adjusted based on the subjects' SMPG values, measured twice daily during pre-Ramadan and post-Ramadan, and 4 times daily during Ramadan. | 132 |
| Total | 263 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Unclassified | 5 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Insulin Degludec/Insulin Aspart | Biphasic Insulin Aspart 30 | Total |
|---|---|---|---|
| Age, Continuous | 54.9 Years STANDARD_DEVIATION 9.8 | 55.3 Years STANDARD_DEVIATION 9.2 | 55.1 Years STANDARD_DEVIATION 9.5 |
| Fasting plasma glucose (FPG) | 9.9 mmol/L STANDARD_DEVIATION 10.4 | 10.6 mmol/L STANDARD_DEVIATION 16.3 | 10.3 mmol/L STANDARD_DEVIATION 13.6 |
| Glycated haemoglobin (HbA1c) | 8.5 Percentage of HbA1c STANDARD_DEVIATION 0.9 | 8.5 Percentage of HbA1c STANDARD_DEVIATION 0.9 | 8.5 Percentage of HbA1c STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 67 Participants | 80 Participants | 147 Participants |
| Sex: Female, Male Male | 64 Participants | 52 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 130 | 47 / 132 |
| serious Total, serious adverse events | 5 / 130 | 3 / 132 |
Outcome results
Primary
Change in HbA1c (%) (Glycosylated Haemoglobin)
Mean change in HbA1c was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan).
Time frame: From week 0 to end of Ramadan (day 29 of Ramadan)
Population: Here, 'number of subjects analysed' specifies the number of subjects, who contributed to the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Change in HbA1c (%) (Glycosylated Haemoglobin) | -1.11 Percentage (%) of HbA1c | Standard Error 0.13 |
| Biphasic Insulin Aspart 30 | Change in HbA1c (%) (Glycosylated Haemoglobin) | -1.13 Percentage (%) of HbA1c | Standard Error 0.13 |
Comparison: The endpoint was analysed using mixed model for repeated measurements (MMRM) with an unstructured covariance matrix. The model included treatment, sex, region, previous OAD treatment, pre-Ramadan trial exposure and visit as factors and age and baseline value of the endpoint as covariates. Interactions between visit and all factors and covariates are included in the model.p-value: 0.842695% CI: [-0.2, 0.24]Mixed model for repeated measurements
Secondary
Change in Fasting Plasma Glucose (FPG)
Mean change in FPG was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan).
Time frame: From week 0 to end of Ramadan (day 29 of Ramadan)
Population: Analysis was based on the FAS, which included all randomised subjects. Here, 'number of subjects analysed' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Change in Fasting Plasma Glucose (FPG) | -2.0 mmol/L | Standard Deviation 12.4 |
| Biphasic Insulin Aspart 30 | Change in Fasting Plasma Glucose (FPG) | -4.4 mmol/L | Standard Deviation 18 |
Secondary
Change in Fructosamine
Mean change in fructosamine was evaluated from baseline (week 0) to end of Ramadan (day 29 of Ramadan).
Time frame: From week 0 to end of Ramadan (day 29 of Ramadan)
Population: Analysis was based on the FAS, which included all randomised subjects. Here, 'number of subjects analysed' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Change in Fructosamine | -0.035 mmol/L | Standard Deviation 0.051 |
| Biphasic Insulin Aspart 30 | Change in Fructosamine | -0.035 mmol/L | Standard Deviation 0.048 |
Secondary
Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target)
Number of subjects who achieved FPG \<=7.2 mmol/L at the end of Ramadan (day 29 of Ramadan). The above written (in the endpoint title) 'ADA target' is not applicable for FPG.
Time frame: End of Ramadan (day 29 of Ramadan)
Population: Analysis was based on the FAS, which included all randomised subjects. Here, 'number of subjects analysed' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target) | Subjects with FPG <=7.2 mmol/L (Yes) | 65 Number of subjects. |
| Insulin Degludec/Insulin Aspart | Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target) | Subjects with FPG <=7.2 mmol/L (No) | 56 Number of subjects. |
| Biphasic Insulin Aspart 30 | Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target) | Subjects with FPG <=7.2 mmol/L (Yes) | 83 Number of subjects. |
| Biphasic Insulin Aspart 30 | Number of Subjects Who Achieve FPG Below or Equal to 7.2 mmol/L (ADA Target) | Subjects with FPG <=7.2 mmol/L (No) | 40 Number of subjects. |
Secondary
Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target )
Number of subjects who achieved HbA1c below 7% (53 mmol/mol; ADA target) at the end of Ramadan (day 29 of Ramadan).
Time frame: End of Ramadan (day 29 of Ramadan)
Population: Analysis was based on the FAS, which included all randomised subjects. Here, 'number of subjects analysed' specifies the number of subjects with available data at specified time-point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target ) | Subjects with HbA1c <7.0% (Yes) | 38 Number of subjects |
| Insulin Degludec/Insulin Aspart | Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target ) | Subjects with HbA1c <7.0% (No) | 83 Number of subjects |
| Biphasic Insulin Aspart 30 | Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target ) | Subjects with HbA1c <7.0% (Yes) | 42 Number of subjects |
| Biphasic Insulin Aspart 30 | Number of Subjects Who Achieve HbA1c Below 7% (53 mmol/Mol (American Diabetes Association (ADA) Target ) | Subjects with HbA1c <7.0% (No) | 81 Number of subjects |
Secondary
Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic
Treatment-emergent hypoglycaemic episodes: If the onset of the episode occurred on or after the first day of investigational medicinal product (IMP; IDegAsp/BIAsp 30) administration, and no later than 1 day after the last day on IMP, before switching to or being treated with another insulin product. The above mentioned definitions (in endpoint title) should read as the following: Novo Nordisk definition; severe or blood glucose (BG) confirmed symptomatic hypoglycaemia: An episode that was severe according to ADA classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. American Diabetes Association (ADA) definition; documented symptomatic hypoglycaemia: An episode, during which typical symptoms of hypoglycaemia were accompanied by a measured PG concentration ≤3.9 mmol/L (70 mg/dL). Due to character limitation, severe hypoglycaemia as per ADA classification is not defined here; see next outcome measure.
Time frame: From week 0 to 4 weeks post Ramadan
Population: Analysis was based on the safety analysis set (SAS), which included all subjects receiving at least 1 dose of the investigational product (IDegAsp) or its comparator (BIAsp 30).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Degludec/Insulin Aspart | Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic | Severe or BG confirmed symptomatic hypoglycaemia | 93 Number of episodes. |
| Insulin Degludec/Insulin Aspart | Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic | Documented symptomatic hypoglycaemia | 521 Number of episodes. |
| Biphasic Insulin Aspart 30 | Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic | Severe or BG confirmed symptomatic hypoglycaemia | 389 Number of episodes. |
| Biphasic Insulin Aspart 30 | Number of Treatment Emergent Hypoglycaemic Episodes Both According to the Novo Nordisk Definition for Hypoglycaemic Episodes (Severe or BG Hypoglycaemia) as Well as According to the ADA definition1 Confirmed Symptomatic | Documented symptomatic hypoglycaemia | 775 Number of episodes. |
Secondary
Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes, which occurred between 00:01 and 05:59 both inclusive. Novo Nordisk definition; severe or blood glucose (BG) confirmed symptomatic hypoglycaemia: An episode that was severe according to ADA classification or BG confirmed by a plasma glucose (PG) value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Severe hypoglycaemia as per ADA classification: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.
Time frame: From week 0 to 4 weeks post Ramadan
Population: Analysis was based on the SAS, which included all subjects receiving at least one dose of the investigational product or its comparator.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Degludec/Insulin Aspart | Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 18 Number of episodes. |
| Biphasic Insulin Aspart 30 | Number of Treatment Emergent Nocturnal (00:01-05:59 am) Severe or BG Confirmed Symptomatic Hypoglycaemic Episodes | 106 Number of episodes. |