Efficacy and Safety of Switching From Sitagliptin to Lira... | NCT01907854

ID	Type	Description
2012-004931-22	EudraCT Number
U1111-1136-2073	Other Identifier	WHO
CTRI/2014/05/004623	Registry Identifier	Clinical Trial Registry India (CTRI)

Status Module

Oversight Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Liraglutide + metformin + sitagliptin placebo	Experimental		Drug: liraglutide Drug: placebo
Sitagliptin + metformin + liraglutide placebo	Experimental		Drug: sitagliptin Drug: placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
liraglutide	Drug	Starting dose of 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day is reached. Administered subcutaneously (s.c., under the skin) once daily + metformin tablets (at least 1000 mg/day)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change in HbA1c (Glycosylated Haemoglobin)	Change from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM).	From baseline to week 26

Secondary Outcomes

Measure	Description	Time Frame
Change in Body Weight	Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM.	From baseline to week 26
Change in Fasting Plasma Glucose

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
- Subjects diagnosed with type 2 diabetes and treated with metformin equal to or above 1500 mg/day (or maximum tolerated dose equal to or above 1000 mg/day) and sitagliptin 100 mg/day, both at a stable dose for at least 90 days prior to screening. Stable is defined as unchanged medication and dose
- HbA1c 7.5% - 9.5% (58 mmol/mol - 80 mmol/mol) (both inclusive)
- Body mass index equal to or above 20 kg/m^2

Exclusion Criteria:

- Any chronic disorder or severe disease which at the discretion of the investigator might jeopardise subject's safety or compliance with the protocol
- Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. An exception is short-term treatment (equal to or less than 7 days in total) with insulin in connection with intercurrent illness
- Female who is pregnant, breast-feeding, intends to become pregnant or of child-bearing potential not using adequate contraceptive methods (adequate contraceptive measures as required by local regulations or practice)
- History of chronic pancreatitis or idiopathic acute pancreatitis
- Screening calcitonin value equal to or above 50 ng/L
- Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
- Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer)
- Impaired liver function, defined as alanine aminotransferase equal to or above 2.5 times upper normal limit
- Impaired renal function defined as estimated glomerular filtration rate 60 mL/min/1.73 m^2 per modification of diet in renal disease formula
- Any episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack or other significant cardiovascular event as judged by the investigator within 90 days prior to screening
- Heart failure, New York Heart Association class IV
- Uncontrolled treated or untreated hypertension (systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg)

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		Phoenix	Arizona	85018	United States
Novo Nordisk Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
27381275	Result	Bailey TS, Takacs R, Tinahones FJ, Rao PV, Tsoukas GM, Thomsen AB, Kaltoft MS, Maislos M. Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial. Diabetes Obes Metab. 2016 Dec;18(12):1191-1198. doi: 10.1111/dom.12736. Epub 2016 Sep 14.

Label	URL
Clinical Trials at Novo Nordisk	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
BG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00056.3± 10.6 BG00156.5± 9.7 BG00256.4± 10.2

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00085 BG00179 BG002

HbA1c

Mean

Standard Deviation

percentage of glycosylated haemoglobin

Title

Denominators

Categories

Title	Measurements
	BG0008.3± 0.6 BG0018.2± 0.6 BG002

Body Weight

Mean

Standard Deviation

Title

Denominators

Categories

Title	Measurements
	BG00088.9± 19.8 BG00191.2± 19.6 BG002

Fasting Plasma Glucose

Mean

Standard Deviation

mmol/L

Title

Denominators

Categories

Title	Measurements
	BG00010.0± 2.7 BG0019.7± 2.5 BG002

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 from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM).

Full analysis set (FAS) -All randomised subjects receiving at least one dose of any of the trial product.

Posted

Mean

Standard Deviation

percentage of glycosylated haemoglobin

From baseline to week 26

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Units	Counts
Participants	OG000176 OG001182

Title

Denominators

Categories

Title	Measurements
	OG000-1.146± 0.9748 OG001-0.529± 1.0148

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	Changes in HbA1c from baseline to the 26 weeks measurements were analysed using MMRM, with treatment, baseline HbA1c level (≤8.5% and >8.5%), metformin dose (<1500 mg/day and ≥1500 mg/day), the interaction between baseline HbA1c level and metformin dose, and country as factors and the HbA1c value at baseline as a covariate, all variables nested within week as a factor.	Mixed Models Analysis	Superiority of liraglutide over sitagliptin was concluded if the 95% Confidence Interval for the treatment difference was entirely below 0%.	<0.0001		Treatment difference	-0.61			2-Sided	95	-0.82	-0.40

Secondary

Change in Body Weight

Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM.

FAS - All randomised subjects receiving at least one dose of any of the trial product.

Posted

Mean

Standard Deviation

From baseline to week 26

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Units	Counts
Participants

Secondary

Change in Fasting Plasma Glucose

Change from baseline in fasting plasma glucose was analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

FAS - All randomised subjects receiving at least one dose of any of the trial product.

Posted

Mean

Standard Deviation

nmol/L

From baseline to week 26

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Units	Counts
Participants

Secondary

Change in Fasting Blood Lipids

Ratio to baseline in fasting blood lipids (total cholesterol, low density lipoprotein [LDL], very low density lipoprotein [VLDL], high density lipoprotein [HDL], triglycerides, and free fatty acids) were analysed after 26 weeks treatment. Missing values were imputed using MMRM. Here we are presenting ratio to baseline data.

FAS-All randomised subjects receiving at least one dose of any of the trial product. There were missing baseline values for free fatty acids in 1 subject in the liraglutide arm and 6 subjects in the sitagliptin arm.

Posted

Mean

Standard Deviation

ratio

From baseline to week 26

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Secondary

Change in Systolic Blood Pressure and Diastolic Blood Pressure

Change from baseline in systolic and diastolic blood pressure were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

FAS - All randomised subjects receiving at least one dose of any of the trial product

Posted

Mean

Standard Deviation

mmHg

From baseline to week 26

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Units	Counts
Participants

Secondary

Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n)

Number of subjects who achieve HbA1c <7.0% were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.

FAS-All randomised subjects receiving at least one dose of any of the trial product.

Posted

Number

percentage (%)

After 26 weeks of treatment

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

Units	Counts
Participants

Secondary

Number of Treatment Emergent Adverse Events (TEAEs)

A treatment emergent adverse event (TEAE) was defined as an event that had an onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. The number of TEAEs was recorded during 26 weeks of treatment plus one week follow-up period.

Safety analysis set-All randomised subjects receiving at least one dose of any of the trial product.

Posted

Number

number of events

During 26 weeks of treatment plus one week follow-up period.

ID	Title	Description
OG000	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.
OG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.

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	Liraglutide	Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., [under the skin] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD sitagliptin placebo tablets.			6	202	96	202
EG001	Sitagliptin	Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day [or documented maximum tolerated dose ≥1000 mg/day]) + OD s.c., injection of liraglutide placebo.			7	204	61	204

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute coronary syndrome	Cardiac disorders	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0010 events0 affected204 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0010 events0 affected204 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Prinzmetal angina	Cardiac disorders	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0010 events0 affected204 at risk
Non-cardiac chest pain	General disorders	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Pneumococcal sepsis	Infections and infestations	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Pneumonia	Infections and infestations	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0011 events1 affected204 at risk
Fall	Injury, poisoning and procedural complications	MedDRA version 18.0	Systematic Assessment	EG0002 events2 affected202 at risk EG0010 events0 affected204 at risk
Bladder cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Multiple sclerosis	Nervous system disorders	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Depression	Psychiatric disorders	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0010 events0 affected204 at risk
Acute febrile neutrophilic dermatosis	Skin and subcutaneous tissue disorders	MedDRA version 18.0	Systematic Assessment	EG0000 events0 affected202 at risk EG0011 events1 affected204 at risk
Joint arthroplasty	Surgical and medical procedures	MedDRA version 18.0	Systematic Assessment	EG0001 events1 affected202 at risk EG0010 events0 affected204 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA version 18.0	Systematic Assessment	EG00045 events33 affected202 at risk EG00121 events19 affected204 at risk
Nausea	Gastrointestinal disorders	MedDRA version 18.0	Systematic Assessment	EG00059 events44 affected202 at risk EG00121 events16 affected204 at risk
Vomiting	Gastrointestinal disorders	MedDRA version 18.0	Systematic Assessment	EG00018 events15 affected202 at risk EG00115 events10 affected204 at risk
Nasopharyngitis	Infections and infestations	MedDRA version 18.0	Systematic Assessment	EG00014 events12 affected202 at risk EG0017 events7 affected204 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA version 18.0	Systematic Assessment	EG00012 events12 affected202 at risk EG00115 events13 affected204 at risk
Lipase increased	Investigations	MedDRA version 18.0	Systematic Assessment	EG00012 events11 affected202 at risk EG0019 events9 affected204 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA version 18.0	Systematic Assessment	EG00018 events18 affected202 at risk EG0017 events7 affected204 at risk
Headache	Nervous system disorders	MedDRA version 18.0	Systematic Assessment	EG00016 events13 affected202 at risk EG00116 events12 affected204 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
D052216	Glucagon-Like Peptide 1
D004763	Glucagon-Like Peptides
D052336	Proglucagon
D005768	Gastrointestinal Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D014230	Triazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D011719	Pyrazines