14 CLINICAL STUDIES

14.1 Weight Management Trials in Adults with Overweight or Obesity

The safety and efficacy of SAXENDA for chronic weight management in conjunction with reduced caloric intake and increased physical activity were studied in three 56-week, randomized, double-blind, placebo-controlled trials. In all studies, SAXENDA was titrated to 3 mg daily during a 4-week period. All patients received instruction for a reduced-calorie diet (approximately 500 kcal/day deficit) and physical activity counseling (recommended increase in physical activity of minimum 150 mins/week) that began with the first dose of study medication or placebo and continued throughout the trial.

Study 1 enrolled 3731 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27-29.9 kg/m2) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either SAXENDA or placebo. Patients were stratified based on the presence or absence of abnormal blood glucose measurements at randomization. All patients were treated for up to 56 weeks. Those patients with abnormal glucose measurements at randomization (2254 of the 3731 patients) were treated for a total of 160 weeks. At baseline, mean age was 45 years (range 18-78), 79% were women, 85% were Caucasian, 10% were African American, and 11% were Hispanic/Latino. Mean baseline body weight was 106.3 kg and mean BMI was 38.3 kg/m2.

Study 2 was a 56-week trial that enrolled 635 patients with type 2 diabetes and with either overweight or obesity (as defined above). Patients were to have an HbA1c of 7-10% and be treated with metformin, a sulfonylurea, or a glitazone as single agent or in any combination, or with a reduced-calorie diet and physical activity alone. Patients were randomized in a 2:1 ratio to receive either SAXENDA or placebo. The mean age was 55 years (range 18-82), 50% were women, 83% were Caucasian, 12% were African American, and 10% were Hispanic/Latino. Mean baseline body weight was 105.9 kg and mean BMI was 37.1 kg/m2.

Study 3 was a 56-week trial that enrolled 422 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27-29.9 kg/m2) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. All patients were first treated with a low-calorie diet (total energy intake 1200-1400 kcal/day) in a run-in period lasting up to 12 weeks. Patients who lost at least 5% of their screening body weight after 4 to 12 weeks during the run-in were then randomized, with equal allocation, to receive either SAXENDA or placebo for 56 weeks. The mean age was 46 years (range 18-73), 81% were women, 84% were Caucasian, 13% were African American, and 7% were Hispanic/Latino. Mean baseline body weight was 99.6 kg and mean BMI was 35.6 kg/m2.

The proportions of patients who discontinued study drug in the 56-week trials were 27% for the SAXENDA-treated group and 35% for the placebo-treated group, and in the 160-week trial the proportions of patients who discontinued were 47% and 55%, respectively. In the 56-week trials, approximately 10% of patients treated with SAXENDA and 4% of patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions (6.1)]. The majority of patients who discontinued SAXENDA due to adverse reactions did so during the first few months of treatment. In the 160-week trial the proportions of patients who discontinued due to an adverse reaction was 13% and 6% for SAXENDA- and placebo-treated patients, respectively.

Effect of SAXENDA on Body Weight in 56-week Trials

For Study 1 and Study 2, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% and 10% weight loss from baseline to week 56. For Study 3, the primary efficacy parameters were mean percent change in body weight from randomization to week 56, the percentage of patients not gaining more than 0.5% body weight from randomization (i.e., after run-in) to week 56, and the percentage of patients achieving greater than or equal to 5% weight loss from randomization to week 56. Because losing at least 5% of fasting body weight through lifestyle intervention during the 4- to 12-week run-in was a condition for their continued participation in the randomized treatment period, the results may not reflect those expected in the general population.

Table 6 presents the results for the changes in weight observed in Studies 1, 2, and 3. After 56 weeks, treatment with SAXENDA resulted in a statistically significant reduction in weight compared with placebo. Statistically significantly greater proportions of patients treated with SAXENDA achieved 5% and 10% weight loss than those treated with placebo. In Study 3, statistically significantly more patients randomized to SAXENDA than placebo had not gained more than 0.5% of body weight from randomization to week 56.

Table 6. Changes in Weight at Week 56 for Studies 1, 2, and 3

	Study 1 (Obesity or overweight with comorbidity)		Study 2 (Type 2 diabetes with obesity or overweight)		Study 3 (Obesity or overweight with comorbidity following at least 5% weight loss with diet)
	SAXENDA N=2487	Placebo N=1244	SAXENDA N=423	Placebo N=212	SAXENDA N=212	Placebo N=210
Weight
Baseline mean (SD) (kg)	106.2 (21.2)	106.2 (21.7)	105.7 (21.9)	106.5 (21.3)	100.4 (20.8)	98.7 (21.2)
Percent change from baseline (LSMean)	-7.4	-3.0	-5.4	-1.7	-4.9	0.3
Difference from placebo (LSMean) (95% CI)	-4.5* (-5.2;-3.8)		-3.7* (-4.7;-2.7)		-5.2* (-6.8;-3.5)
% of Patients losing greater than or equal to 5% body weight	62.3%	34.4%	49.0%	16.4%	44.2%	21.7%
Difference from placebo (LSMean) (95% CI)	27.9* (23.9;31.9)		32.6* (25.1;40.1)		22.6* (13.9;31.3)
% of Patients losing greater than 10% body weight	33.9%	15.4%	22.4%	5.5%	25.4%	6.9%
Difference from placebo (LSMean) (95% CI)	18.5* (15.2;21.7)		16.9* (11.7;22.1)		18.5* (11.7;25.3)

SD = Standard Deviation; CI = Confidence Interval

* p < 0.0001 compared to placebo. Type 1 error was controlled across the three endpoints.

Includes all randomized subjects who had a baseline body weight measurement. All available body weight data during the 56 week treatment period are included in the analysis. In Studies 1 and 2 missing values for week 56 were handled using multiple imputations analysis. In Study 3 missing values for week 56 were handled using weighted regression analysis.

The cumulative frequency distributions of change in body weight from baseline to week 56 are shown in Figure 2 for Studies 1 and 2. One way to interpret this figure is to select a change in body weight of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of weight loss. For example, note that the vertical line arising from ‑10% in Study 1 intersects the SAXENDA and placebo curves at approximately 34% and 15%, respectively, which correspond to the values shown in Table 6.

: Figure 2. Change in body weight (%) from baseline to week 56 (Study 1 on left and Study 2 on right)

The time courses of weight loss with SAXENDA and placebo from baseline through week 56 are depicted in Figures 3 and 4.

: Figure 3. Change from baseline (%) in body weight (Study 1 on left and Study 2 on right)

: Figure 4. Change from baseline (%) in body weight during Study 3

Effect of SAXENDA on Body Weight in a 160-week Trial (Study 1, Subset of Patients with Abnormal Blood Glucose at Randomization)

The numbers and percentages of patients known to have lost greater than or equal to 5% body weight at week 56 and/or week 160 in Study 1 (patients with abnormal glucose at randomization only) are summarized in Table 7 for descriptive purposes.

: Table 7. Changes in Weight at Week 56 and Week 160 for Study 1 (Subset of Patients with Abnormal Blood Glucose at Randomization)

	SAXENDA N=1505	Placebo N=749
Baseline mean body weight (SD) (kg)	107.5 (21.6)	107.9 (21.8)
Number (%) of patients known to lose greater than or equal to 5% body weight at 56 weeks	817 (56%)	182 (25%)
Number (%) of patients known to lose greater than or equal to 5% body weight at 160 weeks	424 (28%)	102 (14%)
Number (%) of patients known to lose greater than or equal to 5% body weight at both 56 weeks and 160 weeks	391 (26%)	74 (10%)
Number (%) of patients with weight assessment at 160 weeks	747 (50%)	322 (43%)

SD = Standard Deviation

Includes all randomized subjects who had a baseline body weight measurement. All available body weight data at 56 and 160 weeks are included in the analysis.

Effect of SAXENDA on Anthropometry and Cardiometabolic Parameters in 56-week Trials

Changes in waist circumference and cardiometabolic parameters with SAXENDA are shown in Table 8 for Study 1 (patients without diabetes mellitus) and Table 9 for Study 2 (patients with type 2 diabetes). Results from Study 3, which also enrolled patients without diabetes mellitus, were similar to Study 1.

: Table 8. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 1 (Patients without Diabetes)

	SAXENDA N = 2487		Placebo N = 1244
	Baseline	Change from Baseline (LSMean1)	Baseline	Change from Baseline (LSMean1)	SAXENDA minus Placebo (LSMean)
Waist Circumference (cm)	115.0	-8.2	114.5	-4.0	-4.2
Systolic Blood Pressure (mmHg)	123.0	-4.3	123.3	-1.5	-2.8
Diastolic Blood Pressure (mmHg)	78.7	-2.7	78.9	-1.8	-0.9
Heart Rate (bpm)2	71.4	2.6	71.3	0.1	2.5
HbA1c (%)	5.6	-0.3	5.6	-0.1	-0.2
	Baseline	% Change from Baseline (LSMean1)	Baseline	% Change from Baseline (LSMean1)	Relative Difference of SAXENDA to Placebo (LSMean)
Total Cholesterol (mg/dL)*	193.8	-3.2	194.4	-0.9	-2.3
LDL Cholesterol (mg/dL)*	111.8	-3.1	112.3	-0.7	-2.4
HDL Cholesterol (mg/dL)*	51.4	2.3	50.9	0.5	1.9
Triglycerides (mg/dL)†	125.7	-13.0	128.3	-4.1	-7.1

Based on last observation carried forward method while on study drug

1 Least squares mean adjusted for treatment, country, sex, pre-diabetes status at screening, baseline BMI stratum and an interaction between pre-diabetes status at screening and BMI stratum as fixed factors, and the baseline value as covariate.

2 See Warnings and Precautions (5.5)

* Baseline value is the geometric mean

†Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference.

: Table 9. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 2 (Patients with Diabetes Mellitus)

	SAXENDA N = 423		Placebo N = 212
	Baseline	Change from Baseline (LSMean1)	Baseline	Change from Baseline (LSMean1)	SAXENDA minus Placebo (LSMean)
Waist Circumference (cm)	118.1	-6.0	117.3	-2.8	-3.2
Systolic Blood Pressure (mmHg)	128.9	-3.0	129.2	-0.4	-2.6
Diastolic Blood Pressure (mmHg)	79.0	-1.0	79.3	-0.6	-0.4
Heart Rate (bpm)2	74.0	2.0	74.0	-1.5	3.4
HbA1c (%)	7.9	-1.3	7.9	-0.4	-0.9
	Baseline	% Change from Baseline (LSMean1)	Baseline	% Change from Baseline (LSMean1)	Relative Difference of SAXENDA to Placebo (LSMean)
Total Cholesterol (mg/dL)*	171.0	-1.4	169.4	2.4	-3.7
LDL Cholesterol (mg/dL)*	86.4	0.9	85.2	3.3	-2.3
HDL Cholesterol (mg/dL)*	45.2	4.8	45.4	1.9	2.9
Triglycerides (mg/dL)†	156.2	-14.5	155.8	-0.7	-13.5

Based on last observation carried forward method while on study drug

1 Least squares mean adjusted for treatment, country, sex, background treatment, baseline HbA1c stratum and an interaction between background treatment and HbA1c stratum as fixed factors, and the baseline value as covariate.

2 See Warnings and Precautions (5.5)

* Baseline value is the geometric mean

†Values are baseline median, median % change, and the Hodges-Lehmann estimate of the median treatment difference.

14.2 Weight Management Trial in Pediatric Patients Ages 12 and Older with Obesity

SAXENDA was evaluated in a 56-week, double-blind, randomized, parallel group, placebo controlled multi-center trial in 251 pubertal pediatric patients aged 12 to 17 years, with BMI corresponding to 30 kg/m2 or greater for adults by international cut-off points [see Dosage and Administration (2.1)] and BMI of 95th percentile or greater for age and sex (NCT02918279). After a 12-week lifestyle run-in period, patients were randomized 1:1 to SAXENDA once-daily or placebo once-daily. The SAXENDA dose was titrated to 3 mg over a 4- to 8-week period based on tolerability as judged by the investigator. Escalation of the trial product was not allowed if the subject had a self-monitored plasma glucose (SMPG) < 56 mg/dL or < 70 mg/dL in the presence of symptoms of hypoglycemia during the week prior to or during the dose escalation visits. The proportion of patients who reached the 3 mg dose was 82.4%; for 8.8% of patients 2.4 mg was the maximum tolerated dose.

The mean age was 14.5 years: 40.6% of patients were male, 87.6% were White, 0.8% were Asian, 8% were Black or African American; 22.3% were of Hispanic or Latino ethnicity. The mean baseline body weight was 100.8 kg, and mean Body Mass Index (BMI) was 35.6 kg/m2.

The proportions of patients who discontinued study drug were 19.2% for the SAXENDA-treated group and 20.6% for the placebo-treated group; 10.4% of patients treated with SAXENDA and no patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions (6.1)].

The primary endpoint was change in BMI SDS. At baseline, mean BMI SDS was 3.14 in the SAXENDA group and 3.20 in the placebo group. At week 56, treatment with SAXENDA resulted in statistically significant reduction in BMI SDS from baseline compared to placebo. The observed mean change in BMI SDS from baseline to week 56 was -0.23 in the SAXENDA group and -0.00 in the placebo group. The estimated treatment difference in BMI SDS reduction from baseline between SAXENDA and placebo was -0.22 with a 95% confidence interval of -0.37, -0.08; p=0.0022.

The time course of change in BMI SDS with SAXENDA and placebo from baseline through week 56 are depicted in Figure 5.

Figure 5. Change from Baseline in BMI SDS

Changes in weight and BMI with SAXENDA are shown in Table 10. Changes in waist circumference and cardiometabolic parameters with SAXENDA are shown in Table 11.

Table 10. Changes in Weight and BMI at Week 56 for Study 4 (Pediatric Patients Ages 12 to Less than 18)

	SAXENDA N=125	Placebo N=126	SAXENDA minus Placebo
Body Weight
Baseline mean Body Weight (kg)	99.3	102.2
Mean Change from Baseline (%)	-2.65	2.37	-5.01
BMI
Baseline mean BMI (kg/m2)	35.3	35.8
Mean Change from Baseline (%)	-4.29	0.35	-4.64
Proportion of patients with greater than or equal to 5% reduction in baseline BMI at week 56 (%)	43.3%	18.7%	24.6%
Proportion of patients with greater than or equal to 10% reduction in baseline BMI at week 56 (%)	26.1%	8.1%	18.0%

Full Analysis Set. For body weight and BMI, baseline values are means, changes from baseline at week 56 are estimated means (least-squares) and treatment contrasts at week 56 are estimated treatment differences. Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach.

Table 11. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 4 (Pediatric Patients Ages 12 to Less than 18)

	SAXENDA N = 125		Placebo N = 126
	Baseline	Change from Baseline	Baseline	Change from Baseline	SAXENDA minus Placebo
Waist Circumference (cm)	105	-4.35	107	-1.42	-2.93
Systolic Blood Pressure (mmHg)	116	-1.21	117	0.84	-2.05
Diastolic Blood Pressure (mmHg)	72	0.77	73	-0.46	1.24
Heart Rate (bpm)*	75	1.87	78	-0.14	2.01
HbA1c (%)	5.3	-0.10	5.3	-0.03	-0.06
	Baseline	% Change from Baseline	Baseline	% Change from Baseline	Relative Difference of SAXENDA to Placebo
Total Cholesterol (mg/dL)**	154.2	0.84	152.2	-0.03	0.88
LDL Cholesterol (mg/dL)**	85.5	1.74	82.5	3.01	-1.27
HDL Cholesterol (mg/dL)**	42.7	5.14	42.7	3.33	1.81
Triglycerides (mg/dL)**	109.1	-0.12	112.2	-1.35	1.23
* See Warnings and Precautions (5.5)

Full Analysis Set. Baseline values are means, changes from baseline at week 56 are estimated means (least-squares) and treatment contrasts at week 56 are estimated treatment differences. Missing observations were imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach.

: ** Baseline values are geometric means.

14.3 Cardiovascular Outcomes Trial of Liraglutide 1.8 mg in Adult Patients with Type 2 Diabetes and Cardiovascular Disease

Liraglutide 1.8 mg (Victoza) is used in the treatment of type 2 diabetes mellitus in adults. The efficacy of liraglutide at doses below 3 mg daily has not been established for chronic weight management.

The LEADER trial (NCT01179048) randomized 9340 patients with inadequately controlled type 2 diabetes and cardiovascular disease to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. Patients either were 50 years of age or older with established, stable cardiovascular, cerebrovascular, peripheral vascular disease, chronic renal failure or chronic heart failure (80% of patients), or were 60 years of age or older and had other specified risk factors of vascular disease (20% of patients).The population was 64% male, 78% Caucasian, 10% Asian and 8% Black; 12% of the population was Hispanic or Latino.

In total, 96.8% of the patients completed the trial; vital status was known at the end of the trial for 99.7%. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1302 (608 [13.0%] with liraglutide 1.8 mg and 694 [14.9%] with placebo).