A Study to Compare Insulin Intensification of Biphasic In... | NCT02453685

ID	Type	Description	Link
2014-003708-62	EudraCT Number
U1111-1158-7280	Other Identifier	WHO

Label	Type	Description	Intervention Names
BIAsp	Experimental		Drug: biphasic insulin aspart 30
IGlar + IAsp	Active Comparator		Drug: insulin glargine Drug: insulin aspart

Name	Type	Description	Arm Group Labels	Other Names
biphasic insulin aspart 30	Drug	Injected s.c./subcutaneously once daily with the largest meal Subjects should continue their pre-trial metformin and sulfonylurea dosages all throughout the trial while other oral antidiabetic drugs will be discontinued.

Measure	Description	Time Frame
Change in HbA1c (Glycosylated Haemoglobin)	Change in HbA1c from baseline (week 0) to week 32.	Week 0, week 32

Measure	Description	Time Frame
HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes	Percentage of subjects with HbA1c below 7.0% after 32 weeks of randomised treatment without treatment emergent severe hypoglycaemic episodes during the last 12 weeks of treatment. Subjects withdrawn before 32 weeks were handled as non-responders. Severe hypoglycaemic episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
Male or female, age at least 18 years at the time of signing informed consent
Type 2 diabetes subjects clinically diagnosed at least 6 months prior to screening
Treatment with stable daily dose (for at least 90 days prior to screening) of: - Metformin (equal or above 1000 mg or maximum tolerated dose documented in the patient medical record) and - Sulfonylurea - and willing to discontinue any other oral antidiabetic drugs containing insulin secretagogues, DPP4i (dipeptidyl peptidase-4 inhibitor), SGLT2 (sodium glucose co-transporter 2), colesevelam, bromocriptin and/or combination products at randomisation
Insulin-naïve. Short term insulin treatment for acute illnesses for a total of 14 days or less is allowed as is prior insulin treatment for gestational diabetes
HbA1c (glycosylated haemoglobin) 7.0-9.5 % (both inclusive) analysed by central laboratory
Willing to consume 3 main meals daily (morning, mid-day and evening) throughout the entire trial. The definition for 'main meal' will be according to the investigator's discretion

Exclusion Criteria:

Anticipated initiation or change in concomitant medications known to affect weight or glucose metabolism, in excess of 14 days (i.e. sibutramine, orlistat, thyroid hormones, systemic corticosteroids and other weight loss/modifying agents)
Impaired liver function, defined as ALT (alanine aminotransferase) at least 2.5 times upper limit of normal (central laboratory value measured at screening visit)
Inadequately treated high blood pressure defined as Class 2 hypertension or higher (i.e. systolic blood pressure equal to or above 160 mm Hg or diastolic equal to or above 100 mm Hg) in accordance with the National High Blood Pressure Education Program, 7th Joint National Committee1 and ESH/ESC 2013 Guidelines2
Within the past 180 days prior to randomisation, any of the following: Myocardial Infarction, stroke or hospitalization for unstable angina and /or transient ischemic attack

Name	Affiliation	Role
Global Clinical Registry (GCR, 1452)	Novo Nordisk A/S	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novo Nordisk Investigational Site		Broadmeadow	New South Wales	2292	Australia
Novo Nordisk Investigational Site

PubMed Identifier	Type	Citation	Retractions
29129018	Result	Linjawi S, Lee BW, Tabak O, Lovdahl S, Werther S, Abusnana S. A 32-Week Randomized Comparison of Stepwise Insulin Intensification of Biphasic Insulin Aspart (BIAsp 30) Versus Basal-Bolus Therapy in Insulin-Naive Patients with Type 2 Diabetes. Diabetes Ther. 2018 Feb;9(1):1-11. doi: 10.1007/s13300-017-0334-8. Epub 2017 Nov 11.

Label	URL
Clinical Trials at Novo Nordisk	View source

ID	Title	Description
FG000	BIAsp 30	Subjects received subcutaneous (s.c.) injection of biphasic insulin aspart 30 (BIAsp 30-a mixture of soluble insulin aspart [IAsp] 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal self-measured plasma glucose (SMPG) target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (hemoglobin A1c [HbA1c] <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and sulphonylurea (SU) throughout the trial.

Arm/Group Information

ID	Title	Description
BG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.
BG001	Basal-bolus	Subjects received s.c. injections of IGlar during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started with 1 daily injection of IGlar (administrated at same point of time every day) with starting dose of 10 units. Insulin titration: Subjects underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in a stepwise manner by adding an additional injection of IAsp depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving 1 daily injection of IGlar plus up to 3 daily injections of IAsp. Subjects continued their pre-trial treatment with metformin and SU throughout the trial.
BG002	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in HbA1c (Glycosylated Haemoglobin)

Change in HbA1c from baseline (week 0) to week 32.

Full analysis set. Week 32 data are presented after application of Last observation carried forward; 164 subjects contributed in each arm.

Posted

Mean

Standard Deviation

Percentage of HbA1c

Week 0, week 32

ID	Title	Description
OG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.
OG001	Basal-bolus	Subjects received s.c. injections of IGlar during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started with 1 daily injection of IGlar (administrated at same point of time every day) with starting dose of 10 units. Insulin titration: Subjects underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in a stepwise manner by adding an additional injection of IAsp depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving 1 daily injection of IGlar plus up to 3 daily injections of IAsp. Subjects continued their pre-trial treatment with metformin and SU throughout the trial.

Units	Counts
Participants	OG000164 OG001164

Title

Denominators

Categories

Title	Measurements
	OG000-1.16± 0.98 OG001-1.30± 0.90

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Analysis was performed using mixed model repeated measurements including treatment, region, and strata as fixed effects, HbA1c at baseline as covariate, interactions between all fixed effects and visit and using an unstructured residual covariance matrix.	Mixed Models Analysis		0.0435		Treatment difference at week 32	0.18			2-Sided	95	0.01	0.36			'Treatment difference' refers to "BIAsp 30 minus Basal-bolus		Superiority or Other

Secondary

HbA1c Below 7.0% Without Severe Hypoglycaemic Episodes

Percentage of subjects with HbA1c below 7.0% after 32 weeks of randomised treatment without treatment emergent severe hypoglycaemic episodes during the last 12 weeks of treatment. Subjects withdrawn before 32 weeks were handled as non-responders. Severe hypoglycaemic episode was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose (PG) concentrations may not be available during an event, but neurological recovery following the return of PG to normal is considered sufficient evidence that the event was induced by a low PG concentration.

Full analysis set.

Posted

Number

Percentage of subjects

After 32 weeks of treatment (yes/no)

ID	Title	Description
OG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.

Secondary

Number of Treatment Emergent Hypoglycaemic Episodes Classified According to the American Diabetes Association (ADA) and the Novo Nordisk Definitions

Hypoglycaemic episodes were classified as severe, Asymptomatic, Documented symptomatic, Pseudo, and Probable symptomatic as per ADA classification. As symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L, (56 mg/dL) Novo Nordisk classification included hypoglycaemia with plasma glucose (PG) levels below 3.1 mmol/L (56 mg/dL) in the definition of blood glucose confirmed hypoglycaemia. Hence, Novo Nordisk classification included following types of hypoglycaemia in addition to ADA classification: Severe hypoglycaemia, Symptomatic blood glucose confirmed hypoglycaemia, Asymptomatic blood glucose confirmed hypoglycaemia, Severe or blood glucose confirmed symptomatic hypoglycaemia, Blood glucose confirmed hypoglycaemia, and Severe or blood glucose confirmed hypoglycaemia. Reported data represents total of all hypoglycaemic episodes.

The safety analysis set included all subjects receiving at least one dose of the investigational product or its comparator.

Posted

Number

Hypoglycaemic episodes

Weeks 0-32

ID	Title	Description
OG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.

Secondary

Total Daily Insulin Dose

Total daily insulin dose in the basal bolus treatment group and in BIAsp 30 treatment group at each week of each treatment.

Safety analysis set. Number analysed=number of subjects with available data for individual timepoints.

Posted

Mean

Standard Deviation

U/kg

Weeks 0-32

ID	Title	Description
OG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.
OG001	Basal-bolus	Subjects received s.c. injections of IGlar during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started with 1 daily injection of IGlar (administrated at same point of time every day) with starting dose of 10 units. Insulin titration: Subjects underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in a stepwise manner by adding an additional injection of IAsp depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving 1 daily injection of IGlar plus up to 3 daily injections of IAsp. Subjects continued their pre-trial treatment with metformin and SU throughout the trial.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BIAsp 30	Subjects received s.c. injection of BIAsp 30 (a mixture of soluble IAsp 30% and protaminated IAsp 70%) during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started treatment with 1 daily injection of BIAsp 30 (starting dose 12 unit) with the largest meal. Insulin titration: Subjects underwent weekly insulin dose titration during entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in stepwise manner by adding an additional injection of BIAsp 30 depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving up to 3 daily injections of BIAsp 30. Subjects continued pre-trial treatment with metformin and SU throughout the trial.			14	166	37	166
EG001	Basal-bolus	Subjects received s.c. injections of IGlar during a 32-week treatment period (divided into 4 periods of 8 weeks each). Subjects started with 1 daily injection of IGlar (administrated at same point of time every day) with starting dose of 10 units. Insulin titration: Subjects underwent a weekly insulin dose titration during the entire treatment period in order to achieve the pre-meal SMPG target of 4.4-6.1 mmol/L (80-110 mg/dL). Insulin intensification: At the end of each 8-week period, insulin treatment was intensified in a stepwise manner by adding an additional injection of IAsp depending on whether subjects achieved the pre-defined glycaemic target (HbA1c <7.0%). Subjects had the possibility of receiving 1 daily injection of IGlar plus up to 3 daily injections of IAsp. Subjects continued their pre-trial treatment with metformin and SU throughout the trial.			12	166	40	166

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Anal abscess	Infections and infestations	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Angina pectoris	Cardiac disorders	MedDRA 19	Systematic Assessment	EG0002 events2 affected166 at risk EG0010 events0 affected166 at risk
Atrial fibrillation	Cardiac disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Cataract	Eye disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0011 events1 affected166 at risk
Cellulitis	Infections and infestations	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Cerebellar infarction	Nervous system disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Cholangitis	Hepatobiliary disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Diabetic foot	Skin and subcutaneous tissue disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0012 events2 affected166 at risk
Diabetic neuropathy	Nervous system disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Gastritis erosive	Gastrointestinal disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Hip fracture	Injury, poisoning and procedural complications	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0011 events1 affected166 at risk
Hypertension	Vascular disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 19	Systematic Assessment	EG0002 events2 affected166 at risk EG0010 events0 affected166 at risk
Hypoglycaemic seizure	Nervous system disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0018 events3 affected166 at risk
Hypoglycaemic unconsciousness	Nervous system disorders	MedDRA 19	Systematic Assessment	EG0000 events0 affected166 at risk EG0013 events2 affected166 at risk
Inguinal hernia	Gastrointestinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Invasive breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0011 events1 affected166 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Restrictive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Retinal detachment	Eye disorders	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk
Thermal burn	Injury, poisoning and procedural complications	MedDRA 19	Systematic Assessment	EG0001 events1 affected166 at risk EG0010 events0 affected166 at risk

ID	Term
D003920	Diabetes Mellitus
D003924	Diabetes Mellitus, Type 2

ID	Term
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
C557564	insulin aspart, insulin aspart protamine drug combination 30:70
D000069036	Insulin Glargine
D061267	Insulin Aspart

ID	Term
D049528	Insulin, Long-Acting
D061385	Insulins
D010187	Pancreatic Hormones
D036361	Peptide Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins
D061266	Insulin, Short-Acting

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 19	Systematic Assessment	EG00016 events11 affected166 at risk EG0017 events6 affected166 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 19	Systematic Assessment	EG00013 events11 affected166 at risk EG0019 events8 affected166 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 19	Systematic Assessment	EG00019 events10 affected166 at risk EG00112 events11 affected166 at risk
Headache	Nervous system disorders	MedDRA 19	Systematic Assessment	EG00024 events12 affected166 at risk EG00127 events15 affected166 at risk
Nasopharyngitis	Infections and infestations	MedDRA 19	Systematic Assessment	EG00031 events21 affected166 at risk EG00127 events18 affected166 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 19	Systematic Assessment	EG00015 events11 affected166 at risk EG00113 events11 affected166 at risk