Effect of Liraglutide in Obese Subjects With Moderate or Severe Obstructive Sleep Apnoea: SCALE™ - Sleep Apnoea

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01557166
• Collaborator: (none)
• Enrollment: 359
• Locations: 42
• Arms: 2
• Actual Duration (Months): 12.3
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This trial is conducted in North America. The aim of the trial is to investigate the effect of liraglutide in obese subjects with sleep apnoea.

Condition or Disease	Intervention/Treatment	Phase
Metabolism and Nutrition Disorder; Obesity; Obstructive Sleep Apnoea	Drug: liraglutide; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 359 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effect of Liraglutide in Obese Subjects With Moderate or Severe Obstructive Sleep Apnoea. A 32 Week Randomised, Double-blind, Placebo-controlled, Parallel Group, Multi-centre and Multinational Trial
• Actual Study Start Date: Jun 7, 2012
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 17, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Liraglutide 3.0 mg	Drug: liraglutide; 3.0 mg liraglutide administered subcutaneously (s.c., under the skin) once daily for 32 weeks + diet and exercise
Placebo Comparator: Placebo	Drug: placebo; Placebo administered subcutaneously (s.c., under the skin) once daily for 32 weeks + diet and exercise

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Apnoea-hypopnoea Index (AHI) [Week 0, Week 32]

   Observed mean change from baseline in AHI (events/hour) after 32 weeks of treatment. AHI (apnoea and hypopnoea events per hour of sleep) is a measure used for the diagnosis and severity classification of obstructive sleep apnoea. AHI severity category: none ≤4.9; mild 5.0-14.9; moderate 15.0-29.9; severe ≥30.0 events/hour.

Secondary Outcome Measures

1. Change From Baseline in Body Weight (kg) [Week 0, week 32]

   Observed mean change from baseline in fasting body weight (kg) after 32 weeks of treatment.

2. Change From Baseline in Fasting Plasma Glucose [Week 0, week 32]

   Observed mean change from baseline in fasting plasma glucose (mmol/L) after 32 weeks of treatment.

3. Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%) [Week 0, week 32]

   Observed mean change from baseline in glycosylated haemoglobin (HbA1c) (%) after 32 weeks of treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Informed consent

• Body mass index equal to or above 30 kg/m^2

• Stable body weight (less than 5% self-reported change during the previous 3 months)

• Diagnosis of moderate or severe obstructive sleep apnoea (OSA)

• Unwilling or unable to use continuous positive airway pressure (CPAP) (or other positive airway pressure) treatment. No CPAP (or other positive airway pressure) treatment for at least four weeks prior to screening

• Ability and willingness to comply with all protocol procedures e.g. correct handling of trial product, compliance to visit schedule and dietary advice and complete trial related questionnaires

Exclusion Criteria:

• Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors or insulin within the last 3 months prior to screening

• Diagnosis of type 1 or type 2 diabetes per judgement of the investigator

• Glycosylated haemoglobin (HbA1c) equal to or above 6.5%

• Significant craniofacial abnormalities that may cause OSA

• Respiratory and neuromuscular diseases that could interfere with the results of the trial in the opinion of the investigator

• Use of central stimulants, hypnotics, mirtazepine, opioids, trazodone within the previous 3 months prior to screening

• Obesity induced by drug treatment

• Treatment with pramlintide, sibutramine, orlistat, zonisamide, topiramate or phenteremine within the last 3 month prior to screening

• Previous surgical treatment for obesity

• Screening calcitonin equal to or above 50 ng/L

• Familial or personal history of Multiple Endocrine Neoplasia type 2 or familial Medullary Thyroid Carcinoma

• Personal history of non-familial Medullary Thyroid Carcinoma

• History of chronic pancreatitis or idiopathic acute pancreatitis

• History of Major Depressive Disorder or suicide attempts

• Systolic blood pressure equal to or above 160 mmHg and/or diastolic blood pressure equal to or above 100 mmHg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Glendale	California	United States	91206
2	Novo Nordisk Investigational Site	Oceanside	California	United States	92054
3	Novo Nordisk Investigational Site	Orange	California	United States	92868
4	Novo Nordisk Investigational Site	Redwood City	California	United States	94063
5	Novo Nordisk Investigational Site	San Diego	California	United States	92103-5801
6	Novo Nordisk Investigational Site	Santa Monica	California	United States	90404
7	Novo Nordisk Investigational Site	Brandon	Florida	United States	33511
8	Novo Nordisk Investigational Site	Hollywood	Florida	United States	33024
9	Novo Nordisk Investigational Site	Miami	Florida	United States	33155
10	Novo Nordisk Investigational Site	Saint Petersburg	Florida	United States	33707
11	Novo Nordisk Investigational Site	South Miami	Florida	United States	33143
12	Novo Nordisk Investigational Site	Tampa	Florida	United States	33603
13	Novo Nordisk Investigational Site	West Palm Beach	Florida	United States	33409
14	Novo Nordisk Investigational Site	Atlanta	Georgia	United States	30342
15	Novo Nordisk Investigational Site	Macon	Georgia	United States	31201
16	Novo Nordisk Investigational Site	Chicago	Illinois	United States	60634
17	Novo Nordisk Investigational Site	Vernon Hills	Illinois	United States	60061
18	Novo Nordisk Investigational Site	Overland Park	Kansas	United States	66212
19	Novo Nordisk Investigational Site	Crestview Hills	Kentucky	United States	41017-3464
20	Novo Nordisk Investigational Site	Louisville	Kentucky	United States	40218
21	Novo Nordisk Investigational Site	Chevy Chase	Maryland	United States	20815-6905
22	Novo Nordisk Investigational Site	North Dartmouth	Massachusetts	United States	02747
23	Novo Nordisk Investigational Site	Portage	Michigan	United States	49024-4889
24	Novo Nordisk Investigational Site	Chesterfield	Missouri	United States	63017
25	Novo Nordisk Investigational Site	New York	New York	United States	10019
26	Novo Nordisk Investigational Site	New York	New York	United States	10065
27	Novo Nordisk Investigational Site	Wilmington	North Carolina	United States	28401
28	Novo Nordisk Investigational Site	Dublin	Ohio	United States	43017-3521
29	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19104-3317
30	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19118
31	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19140
32	Novo Nordisk Investigational Site	Warwick	Rhode Island	United States	02886
33	Novo Nordisk Investigational Site	Columbia	South Carolina	United States	29201-2951
34	Novo Nordisk Investigational Site	Dallas	Texas	United States	75231
35	Novo Nordisk Investigational Site	Dallas	Texas	United States	75234
36	Novo Nordisk Investigational Site	Fort Worth	Texas	United States	76135
37	Novo Nordisk Investigational Site	Vienna	Virginia	United States	22182
38	Novo Nordisk Investigational Site	Burlington	Ontario	Canada	L7R 1E2
39	Novo Nordisk Investigational Site	Hamilton	Ontario	Canada	L8L 5G8
40	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M4P 1P2
41	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5M 1C7
42	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5M1C7

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01557166
• Other Study ID Numbers: NN8022-3970; U1111-1126-6260
• First Posted: Mar 19, 2012
• Last Update Posted: Nov 1, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Novo Nordisk A/S: OSA
• Additional relevant MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Nutrition Disorders; Liraglutide

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 40 sites in 2 countries, as follows: United States: 35 sites; Canada: 5 sites.
Pre-assignment Detail	The trial consisted of a 2-week screening period before randomisation.

Arm/Group Title	Liraglutide 3.0 mg	Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Period Title: Overall Study
STARTED	180	179
Exposed	176	179
COMPLETED	134	142
NOT COMPLETED	46	37

Baseline Characteristics

Arm/Group Title	Liraglutide 3.0 mg	Placebo	Total
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Total of all reporting groups
Overall Participants	180	179	359
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.6 (9.9)	48.4 (9.5)	48.5 (9.7)
Sex: Female, Male (Count of Participants)
Female	51 28.3%	50 27.9%	101 28.1%
Male	129 71.7%	129 72.1%	258 71.9%
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	116.5 (23.0)	118.7 (25.4)	117.6 (24.2)
Body mass index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	38.9 (6.4)	39.4 (7.4)	39.1 (6.9)
Apnoea-hypopnoea index (AHI) (events/hour) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [events/hour]	49.0 (27.5)	49.3 (27.5)	49.2 (27.4)
Fasting plasma glucose (FPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	5.4 (0.6)	5.4 (0.9)	5.4 (0.8)
Glycosylated haemoglobin (HbA1c) (Percent (%) glycosylated haemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent (%) glycosylated haemoglobin]	5.7 (0.4)	5.6 (0.4)	5.7 (0.4)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Apnoea-hypopnoea Index (AHI)
Description	Observed mean change from baseline in AHI (events/hour) after 32 weeks of treatment. AHI (apnoea and hypopnoea events per hour of sleep) is a measure used for the diagnosis and severity classification of obstructive sleep apnoea. AHI severity category: none ≤4.9; mild 5.0-14.9; moderate 15.0-29.9; severe ≥30.0 events/hour.
Time Frame	Week 0, Week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - included all randomised subjects. 334 subjects contributed to the statistical analysis.

Arm/Group Title	Liraglutide 3.0 mg	Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Measure Participants	168	166
Mean (Standard Deviation) [events/hour]	-12.22 (23.34)	-6.08 (25.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Liraglutide 3.0 mg, Placebo
	Comments	Let μ liraglutide 3.0mg and μ placebo denote mean change in AHI for liraglutide 3.0 mg and placebo,respectively. The null-hypothesis and the alternative was H0: μliraglutide 3.0mg = μplacebo against the alternative HA: μliraglutide 3.0mg ≠ μplacebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	ANCOVA
	Comments	ANCOVA model was used with treatment, country and sex as fixed factors, and the baseline value of AHI, baseline BMI and baseline age as covariates.
Method of Estimation	Estimation Parameter	Estimated treatment difference
	Estimated Value	-6.10
	Confidence Interval	() 95%; -11.0 to -1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Body Weight (kg)
Description	Observed mean change from baseline in fasting body weight (kg) after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - included all randomised subjects. 353 subjects contributed to the statistical analysis.

Arm/Group Title	Liraglutide 3.0 mg	Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Measure Participants	175	178
Mean (Standard Deviation) [kg]	-6.73 (6.59)	-1.87 (5.44)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose
Description	Observed mean change from baseline in fasting plasma glucose (mmol/L) after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - included all randomised subjects. 355 subjects contributed to the statistical analysis.

Arm/Group Title	Liraglutide 3.0 mg	Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Measure Participants	178	177
Mean (Standard Deviation) [mmol/L]	-0.15 (0.69)	0.17 (0.96)

4. Secondary Outcome

Title	Change From Baseline in Glycosylated Haemoglobin (HbA1c) (%)
Description	Observed mean change from baseline in glycosylated haemoglobin (HbA1c) (%) after 32 weeks of treatment.
Time Frame	Week 0, week 32

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) - included all randomised subjects. 345 subjects contributed to the statistical analysis

Arm/Group Title	Liraglutide 3.0 mg	Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.	Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
Measure Participants	174	171
Mean (Standard Deviation) [percentage of glycosylated haemoglobin]	-0.36 (0.30)	-0.17 (0.29)

Adverse Events

Time Frame	Events that either occur before randomisation and increase in severity during the treatment period or have an onset date on or after the first day of randomised treatment and no later than 14 days after the last day of randomised treatment.
Adverse Event Reporting Description	Safety analysis set - included all randomised subjects exposed to trial drug.
Arm/Group Title	Liraglutide 3.0 mg		Placebo
Arm/Group Description	Subjects were administered 3.0 mg of liraglutide subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.		Subjects were administered placebo subcutaneously (s.c., under the skin) once daily for 32 weeks. Subjects were also prescribed a 500 kcal/day-deficit diet and exercise for a minimum of 150 min/week.
All Cause Mortality
	Liraglutide 3.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Liraglutide 3.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/176 (3.4%)		6/179 (3.4%)
Cardiac disorders
Angina pectoris	2/176 (1.1%)	3	0/179 (0%)	0
Angina unstable	0/176 (0%)	0	1/179 (0.6%)	1
Myocardial infarction	0/176 (0%)	0	1/179 (0.6%)	1
Sinus arrest	1/176 (0.6%)	1	0/179 (0%)	0
Gastrointestinal disorders
Gastrooesophageal reflux disease	0/176 (0%)	0	1/179 (0.6%)	1
Obstruction gastric	0/176 (0%)	0	1/179 (0.6%)	1
Hepatobiliary disorders
Cholecystitis	0/176 (0%)	0	1/179 (0.6%)	1
Cholelithiasis	1/176 (0.6%)	1	0/179 (0%)	0
Infections and infestations
Pneumonia	1/176 (0.6%)	1	0/179 (0%)	0
Injury, poisoning and procedural complications
Procedural pain	1/176 (0.6%)	1	0/179 (0%)	0
Spinal fracture	1/176 (0.6%)	1	0/179 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/176 (0.6%)	1	0/179 (0%)	0
Musculoskeletal and connective tissue disorders
Bone lesion	0/176 (0%)	0	1/179 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/176 (0%)	0	1/179 (0.6%)	1
Psychiatric disorders
Anxiety	1/176 (0.6%)	1	0/179 (0%)	0
Depression suicidal	1/176 (0.6%)	1	0/179 (0%)	0
Nightmare	0/176 (0%)	0	1/179 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal swelling	1/176 (0.6%)	1	0/179 (0%)	0
Sleep apnoea syndrome	1/176 (0.6%)	1	0/179 (0%)	0
Surgical and medical procedures
Coronary revascularisation	1/176 (0.6%)	1	1/179 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Liraglutide 3.0 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/176 (66.5%)		84/179 (46.9%)
Gastrointestinal disorders
Constipation	21/176 (11.9%)	26	6/179 (3.4%)	7
Diarrhoea	29/176 (16.5%)	38	14/179 (7.8%)	17
Dyspepsia	15/176 (8.5%)	20	2/179 (1.1%)	2
Gastrooesophageal reflux disease	10/176 (5.7%)	11	0/179 (0%)	0
Nausea	47/176 (26.7%)	59	12/179 (6.7%)	14
Vomiting	13/176 (7.4%)	16	5/179 (2.8%)	5
General disorders
Injection site haematoma	7/176 (4%)	8	13/179 (7.3%)	14
Infections and infestations
Influenza	9/176 (5.1%)	12	9/179 (5%)	9
Nasopharyngitis	15/176 (8.5%)	19	18/179 (10.1%)	20
Upper respiratory tract infection	18/176 (10.2%)	25	19/179 (10.6%)	25
Investigations
Lipase increased	9/176 (5.1%)	11	5/179 (2.8%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	7/176 (4%)	7	9/179 (5%)	9
Nervous system disorders
Headache	25/176 (14.2%)	26	20/179 (11.2%)	23

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to review any scientific paper, presentation, communication or other information concerning the investigation described in the protocol. Novo Nordisk reserves the right to prior review of such publications and to ask for deferment of publication of individual site results until after the primary manuscript is accepted for publication.