14 CLINICAL STUDIES

14.1 Cardiovascular Outcomes Trial in Adult Patients with Cardiovascular Disease and Either Obesity or Overweight

Overview of Clinical Trial
Study 1 (NCT03574597) was a multi-national, multi-center, placebo-controlled, double-blind trial to determine the effect of WEGOVY relative to placebo on major adverse cardiovascular events (MACE) when added to current standard of care, which included management of CV risk factors and individualized healthy lifestyle counseling (including diet and physical activity). The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

All patients were 45 years or older, with an initial BMI of 27 kg/m2 or greater and established cardiovascular disease (prior myocardial infarction, prior stroke, or peripheral arterial disease). Patients with a history of type 1 or type 2 diabetes were excluded. Concomitant CV therapies could be adjusted, at the discretion of the investigator, to ensure participants were treated according to the current standard of care for patients with established cardiovascular disease.

In this trial, 17,604 patients were randomized to WEGOVY or placebo. At baseline, the mean age was 62 years (range 45 - 93), 72% were male, 84% were White, 4% were Black or African American, and 8% were Asian, and 10% were Hispanic or Latino. Mean baseline body weight was 97 kg and mean BMI was 33 kg/m2. At baseline, prior myocardial infarction was reported in 76% of randomized individuals, prior stroke in 23%, and peripheral arterial disease in 9%. Heart failure was reported in 24% of patients. At baseline, cardiovascular disease and risk factors were managed with lipid-lowering therapy (90%), platelet aggregation inhibitors (86%), angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (74%), and beta blockers (70%). A total of 10% had moderate renal impairment (eGFR 30 to <60 mL/min/1.73m2) and 0.4% had severe renal impairment eGFR <30 mL/min/1.73m2.

Results

In total, 96.9% of patients completed the trial, and vital status was available for 99.4% of patients. The median follow-up duration was 41.8 months. A total of 31% of WEGOVY-treated patients and 27% of placebo-treated patients permanently discontinued study drug.

For the primary analysis, a Cox proportional hazards model was used to test for superiority. Type 1 error was controlled across multiple tests.

WEGOVY significantly reduced the risk for first occurrence of MACE. The estimated hazard ratio (95% CI) was 0.80 (0.72, 0.90) (see Figure 4 and Table 4).

Figure 4. Cumulative Incidence Function: Time to First Occurrence of MACE in Study 1

Data from the in-trial period. Cumulative incidence estimates are based on time from randomization to first EAC-confirmed cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke with non-CV death modeled as competing risk using the Aalen-Johansen estimator. Patients without events of interest were censored at the end of their in-trial observation period. Time from randomization to first cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the group sequential design using the likelihood ratio ordering.

HR: Hazard ratio; CI: confidence interval; CV: cardiovascular

The treatment effect for the primary composite endpoint, its components, and other relevant endpoints in Study 1 are shown in Table 4.

Table 4. Treatment Effect for MACE and Other Events in Study 1

	Patients with events n (%)
	Placebo N=8,801	WEGOVY N=8,803	Hazard Ratio (95% CI)
Primary composite endpoint
Composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke1	701 (8%)	569 (6.5%)	0.80 (0.72; 0.90)*2
Key secondary endpoints
Cardiovascular death3	262 (3%)	223 (2.5%)	0.85 (0.71; 1.01)
All-cause death4	458 (5.2%)	375 (4.3%)	0.81 (0.71; 0.93)
Other secondary endpoints
Fatal or non-fatal myocardial infarction5	334 (3.8%)	243 (2.8%)	0.72 (0.61; 0.85)
Fatal or non-fatal stroke5	178 (2%)	160 (1.8%)	0.89 (0.72; 1.11)

*p-value <0.001, one-sided p-value

1Primary endpoint

2Adjusted for group sequential design using the likelihood ratio ordering.

3Cardiovascular death was the first confirmatory secondary endpoint in the testing hierarchy and superiority was not confirmed.

4Confirmatory secondary endpoint. Not statistically significant based on the prespecified testing hierarchy.

5Not included in the prespecified testing hierarchy for controlling type-I error.

NOTE: Time to first event was analyzed in a Cox proportional hazards model with treatment as factor. For patients with multiple events, only the first event contributed to the composite endpoint.

Table 5. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 104 in Study 11,2

		PLACEBO		WEGOVY
		Baseline	Change from Baseline (LSMean)	Baseline	Change from Baseline (LSMean)	Difference from Placebo (LSMean)
Body Weight (kg)		96.8	-0.93	96.5	-9.43	-8.53
Waist Circumference (cm)		111.4	-1	111.3	-7.6	-6.5
Systolic Blood Pressure (mmHg)		131	-0.5	131	-3.8	-3.3
Diastolic Blood Pressure (mmHg)		79	-0.5	79	-1	-0.5
Heart Rate		69	0.7	69	3.8	3.1
HbA1c (%)		5.8	0	5.8	-0.3	-0.3
	Baseline		% Change from Baseline (LSMean)	Baseline	% Change from Baseline (LSMean)	Relative difference from placebo (%) (LSMean)
Total Cholesterol (mg/dL)4	156		-1.9	155.5	-4.6	-2.8
LDL Cholesterol (mg/dL)4	78.5		-3.1	78.5	-5.3	-2.2
HDL Cholesterol (mg/dL)4	44.2		0.6	44.1	4.9	4.2
Triglycerides (mg/dL)4	139.5		-3.2	138.6	-18.3	-15.6

1Parameters listed in the table were not included in the pre-specified hierarchical testing.

2Responses were analyzed using an ANCOVA with treatment as fixed factor and baseline value as covariate. Before analysis, missing data were multiple imputed. The imputation model (linear regression) was done separately for each treatment arm and included baseline value as a covariate and was fitted to all subjects with a measurement regardless of treatment status at week 104.

3For body weight the ‘change from baseline’ and ‘difference to placebo’ the unit is percentage change from baseline.

4Baseline value is the geometric mean.

The reduction of MACE with WEGOVY was not impacted by age, sex, race, ethnicity, BMI at baseline, or level of renal function impairment.

14.2 Weight Reduction and Long-term Maintenance Studies in Adults with Obesity or Overweight

Overview of Clinical Studies in Adults
The safety and efficacy of WEGOVY for weight reduction and long-term maintenance of body weight in conjunction with a reduced calorie diet and increased physical activity were studied in three 68-week, randomized, double-blind, placebo-controlled trials; one 68-week, randomized, double-blind, placebo withdrawal trial; and one 68-week, randomized, double-blind trial that investigated 2 different doses of WEGOVY versus placebo. In Studies 2 (NCT#03548935), 3 (NCT#03552757), and 4 (NCT#03611582), WEGOVY or matching placebo was escalated to 2.4 mg subcutaneous weekly during a 16-week period followed by 52 weeks on maintenance dose. In Study 5 (NCT#03548987), WEGOVY was escalated during a 20-week run-in period, and patients who reached a WEGOVY 2.4 mg subcutaneous weekly dosage after the run-in period were randomized to either continued treatment with WEGOVY or placebo for 48 weeks. In Study 6 (NCT#03811574), WEGOVY was escalated to 1.7 mg or 2.4 mg subcutaneous weekly dosages or placebo over 12 to 16 weeks followed by 52 weeks on either maintenance dose.

In Studies 2, 3 and 5, all patients received instruction for a reduced calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week) that began with the first dose of study medication or placebo and continued throughout the trial. In Study 4, patients received an initial 8-week low-calorie diet (total energy intake 1,000 to 1,200 kcal/day) followed by 60 weeks of a reduced calorie diet (1200-1800 kcal/day) and increased physical activity (100 mins/week with gradual increase to 200 mins/week).

Study 2 was a 68-week trial that enrolled 1,961 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 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 WEGOVY or placebo. At baseline, mean age was 46 years (range 18 to 86), 74% were female, 75% were White, 13% were Asian and 6% were Black or African American. A total of 12% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.3 kg and mean BMI was 37.9 kg/m2.

Study 3 was a 68-week trial that enrolled 807 patients with type 2 diabetes and BMI greater than or equal to 27 kg/m2. Patients included in the trial had HbA1c 7-10% and were treated with either: diet and exercise alone or 1 to 3 oral anti‑diabetic drugs (metformin, sulfonylurea, glitazone or sodium-glucose co-transporter 2 inhibitor). Patients were randomized in a 1:1 ratio to receive either WEGOVY or placebo. At baseline, the mean age was 55 years (range 19 to 84), 51% were female, 62% were White, 26% were Asian and 8% were Black or African American. A total of 13% were Hispanic or Latino ethnicity. Mean baseline body weight was 99.8 kg and mean BMI was 35.7 kg/m2.

Study 4 was a 68-week trial that enrolled 611 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 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. The patients were randomized in a 2:1 ratio to receive either WEGOVY or placebo. At baseline, the mean age was 46 years, 81% were female, 76% were White, 19% were Black or African American and 2% were Asian. A total of 20% were Hispanic or Latino ethnicity. Mean baseline body weight was 105.8 kg and mean BMI was 38 kg/m2.

Study 5 was a 68-week trial that enrolled 902 patients with obesity (BMI greater than or equal to 30 kg/m2) or with overweight (BMI 27 to 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. Mean body weight at baseline for the 902 patients was 106.8 kg and mean BMI was 38.3 kg/m². All patients received WEGOVY during the run-in period of 20 weeks that included 16 weeks of dose escalation. Trial product was permanently discontinued before randomization in 99 of 902 patients (11%); the most common reason was adverse reactions (n=48, 5.3%); 803 patients reached WEGOVY 2.4 mg and were then randomized in a 2:1 ratio to either continue on WEGOVY or receive placebo. Among the 803 randomized patients, the mean age was 46 years, 79% were female, 84% were White, 13% were Black or African American, and 2% Asian. A total of 8% were Hispanic or Latino ethnicity. Mean body weight at randomization (week 20) was 96.1 kg and mean BMI at randomization (week 20) was 34.4 kg/m2.

Study 6 was a 68-week trial that enrolled 401 East-Asian patients (Japan and South Korea) with BMI greater than or equal to 35 kg/m2 and at least one weight-related comorbid condition or with BMI 27 to 34.9 kg/m2 and at least two weight-related comorbid conditions. The patients were randomized 2:1:1 to receive WEGOVY 2.4 mg, WEGOVY 1.7 mg, or placebo. At baseline, the mean age was 51 years, 63% were male, and all patients were Asian. Mean baseline body weight was 87.5 kg and mean BMI was 31.9 kg/m2. At baseline, 24.7% of patients had type 2 diabetes mellitus.

Results
The proportions of patients who discontinued study drug in Studies 2, 3, and 4 was 16% for the WEGOVY-treated group and 19.1% for the placebo-treated group, and 6.8% of patients treated with WEGOVY and 3.2% of patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions (6.1)]. In Study 5, the proportions of patients who discontinued study drug were 5.8% and 11.6% for WEGOVY and placebo, respectively. In Study 6, the proportions of patients who discontinued study drug were 7.9%, 6.5%, and 3% for WEGOVY 1.7 mg, WEGOVY 2.4 mg, and placebo, respectively.

For Studies 2, 3 and 4, the primary efficacy parameters were mean percent change in body weight and the percentages of patients achieving greater than or equal to 5% weight loss from baseline to week 68.

After 68 weeks, treatment with WEGOVY resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY achieved 5%, 10% and 15% weight loss than those treated with placebo as shown in Table 6.

: Table 6. Changes in Body Weight at Week 68 in Studies 2, 3, and 4

	Study 2 (Obesity or overweight with comorbidity)		Study 3 (Type 2 diabetes with obesity or overweight)		Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy)
Intention-to-Treat1	PLACEBO N=655	WEGOVY N=1306	PLACEBO N=403	WEGOVY N=404	PLACEBO N=204	WEGOVY N=407
Body Weight
Baseline mean (kg)	105.2	105.4	100.5	99.9	103.7	106.9
% change from baseline (LSMean)	-2.4	-14.9	-3.4	-9.6	-5.7	-16
% difference from placebo (LSMean) (95% CI)		-12.4 (‑13.3; ‑11.6)*		-6.2 (-7.3; -5.2)*		-10.3 (-11.8; -8.7)*
% of Patients losing greater than or equal to 5% body weight	31.1	83.5	30.2	67.4	47.8	84.8
% difference from placebo (LSMean) (95% CI)		52.4 (48.1; 56.7)*		37.2 (30.7; 43.8)*		37 (28.9; 45.2)*
% of Patients losing greater than or equal to 10% body weight	12	66.1	10.2	44.5	27.1	73
% difference from placebo (LSMean) (95% CI)		54.1 (50.4; 57.9)*		34.3 (28.4; 40.2)*		45.9 (38; 53.7)*
% of Patients losing greater than or equal to 15% body weight	4.8	47.9	4.3	25.1	13.2	53.4
% difference from placebo (LSMean) (95% CI)		43.1 (39.8; 46.3)*		20.7 (15.7; 25.8)*		40.2 (33.1; 47.3)*

LSMean = least squares mean; CI = confidence interval

1The intent-to-treat population includes all randomized patients. In Study 2, at week 68, the body weight was missing for 7.2% and 11.9% of patients randomized to WEGOVY and placebo, respectively. In Study 3, at week 68, the body weight was missing for 4% and 6.7% of patients randomized to WEGOVY and placebo, respectively. In Study 4, at week 68, the body weight was missing for 8.4% and 7.4% of patients randomized to WEGOVY and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

* p<0.0001 (unadjusted 2-sided) for superiority.

For Study 5, the primary efficacy parameter was mean percent change in body weight from randomization (week 20) to week 68.

From randomization (week 20) to week 68, treatment with WEGOVY resulted in a statistically significant reduction in body weight compared with placebo (Table 7). Because patients who discontinued WEGOVY during titration and those who did not reach the 2.4 mg weekly dose were not eligible for the randomized treatment period, the results may not reflect the experience of patients in the general population who are first starting WEGOVY.

: Table 7. Changes in Body Weight at Week 68 in Study 5 (Obesity or overweight with comorbidity after 20-week run-in)

	WEGOVY N=8031
Body Weight (only randomized patients)
Mean at week 0 (kg)	107.2
	PLACEBO N=268	WEGOVY N=535
Body Weight
Mean at week 20 (SD) (kg)	95.4 (22.7)	96.5 (22.5)
% change from week 20 at week 68 (LSMean)	6.9	-7.9
% difference from placebo (LSMean) (95% CI)		-14.8 (-16; -13.5)*

LSMean = least squares mean; CI = confidence interval

1902 patients were enrolled at week 0 with a mean baseline body weight of 106.8 kg. The intent-to-treat population includes all randomized patients. At week 68, the body weight was missing for 2.8% and 6.7% of patients randomized to WEGOVY and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

*p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

For Study 6, the primary efficacy parameters were mean percent change in body weight and the percentage of patients achieving greater than or equal to 5% weight loss from baseline to week 68.

After 68 weeks, treatment with WEGOVY 1.7 mg and 2.4 mg resulted in a statistically significant reduction in body weight compared with placebo. Greater proportions of patients treated with WEGOVY achieved 5%, 10%, and 15% weight loss than those treated with placebo as shown in Table 8.

Table 8. Changes in Body Weight at Week 68 in Study 6 in East-Asian Patients (WEGOVY 1.7 mg)

	Study 6 (BMI ≥35 kg/m2 with at least one comorbidity or BMI 27-34.9 kg/m2 with at least two comorbidities)
Intention-to-treat1	PLACEBO N=101	WEGOVY 1.7 mg N=101	WEGOVY 2.4 mg N=199
Body Weight
Baseline mean (kg)	90.2	86.1	86.9
% change from baseline (LSMean)	-2.1	-9.6	-13.2
% difference from placebo (LSMean) (95% CI)		-7.5 (-9.6; -5.4)*	-11.1 (-12.9; -9.2)*
% of Patients losing greater than or equal to 5% body weight	19.4	72.8	84
% difference from placebo (LSMean) (95% CI)		53.3 (41; 65.6)*	64.5 (54.8; 74.3)*
% of Patients losing greater than or equal to 10% body weight	4.5	39.1	59.9
% difference from placebo (LSMean) (95% CI)		34.5 (23.9; 45.1)*	55.4 (47.3; 63.6)*
% of Patients losing greater than or equal to 15% body weight	2.6	20.8	38.2
% difference from placebo (LSMean) (95% CI)		18.2 (9.8; 26.7)*	35.6 (27.9; 43.3)*

LSMean = least squares mean; CI = confidence interval
1The intent-to-treat population includes all randomized patients. At baseline, 24.7% of patients had type 2 diabetes mellitus. At week 68, the body weight was missing for 3%, 3%, and 1% of patients randomized to WEGOVY 1.7 mg, WEGOVY 2.4 mg, and placebo, respectively. Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

*p<0.0001 (unadjusted 2-sided) for superiority.

A reduction in body weight was observed with WEGOVY irrespective of age, sex, race, ethnicity, BMI at baseline, body weight (kg) at baseline, and level of renal function impairment.

The cumulative frequency distributions of change in body weight are shown in Figure 5 and Figure 6 for Studies 2 and 3. 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 2 intersects the WEGOVY and placebo curves at approximately 66%, and 12%, respectively, which correspond to the values shown in Table 6.

: Figure 5.Change in body weight (%) from baseline to week 68 (Study 2)

Observed data from in-trial period including imputed data for missing observations (RD-MI).

: Figure 6. Change in body weight (%) from baseline to week 68 (Study 3)

Observed data from in-trial period including imputed data for missing observations (RD-MI).

The time courses of weight loss with WEGOVY and placebo from baseline through week 68 are depicted in Figure 7, Figure 8 and Figure 9.

: Figure 7.Change from baseline (%) in body weight (Study 2 on left and Study 3 on right)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI)

: Figure 8. Change from baseline (%) in body weight (Study 4 on left and Study 5a on right)

Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI)
aChange from week 0 was not a primary endpoint in study 5. Dotted line indicates time of randomization. Randomized patients (shown) do not include 99 patients that discontinued during the 20-week run-in period.

: Figure 9. Change in body weight (%) from baseline to week 68 (Study 6 in East-Asian Patients)

Observed values for patients completing each scheduled visit and estimates with multiple imputations from retrieved dropouts (RD-MI). At baseline, 24.7% of patients had type 2 diabetes mellitus.

Effect of WEGOVY on Anthropometry and Cardiometabolic Parameters in Adults

Changes in waist circumference and cardiometabolic parameters with WEGOVY are shown in Table 9 for Studies 2, 3, and 4; in Table 10 for Study 5; and in Table 11 for Study 6.

: Table 9. Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Studies 2, 3, and 4

Study 2 (Obesity or overweight with comorbidity)

Study 3 (Type 2 diabetes with obesity or overweight)

Study 4 (Obesity or overweight with comorbidity undergoing intensive lifestyle therapy)

Intention-to-Treat

PLACEBO
N=655

WEGOVY
N=1306

PLACEBO
N=403

WEGOVY
N=404

PLACEBO
N=204

WEGOVY
N=407

Waist Circumference (cm)

: Baseline
: Changes from baseline (LSMean1)
: Difference from placebo (LSMean)

114.8

-4.1

114.6

-13.5

-9.4

115.5

-4.5

114.5

-9.4

-4.9

111.8

-6.3

113.6

-14.6

-8.3

Systolic Blood Pressure (mmHg)

: Baseline
: Changes from baseline (LSMean1)
: Difference from placebo (LSMean)

127

-1.1

126

-6.2

-5.1

130

-0.5

130

-3.9

-3.4

124

-1.6

124

-5.6

-3.9

Diastolic Blood Pressure (mmHg)2

: Baseline
: Changes from baseline (LSMean1)
: Difference from placebo (LSMean)

80

-0.4

80

-2.8

-2.4

80

-0.9

80

-1.6

-0.7

81

-0.8

80

-3

-2.2

Heart Rate2,3

: Baseline
: Changes from baseline (LSMean)
: Difference from placebo (LSMean)

72

-0.7

72

3.5

4.3

76

-0.2

75

2.5

2.7

71

2.1

71

3.1

1

HbA1c (%)2

: Baseline
: Changes from baseline (LSMean1)
: Difference from placebo (LSMean)

5.7

-0.2

5.7

-0.4

-0.3

8.1

-0.4

8.1

-1.6

-1.2

5.8

-0.3

5.7

-0.5

-0.2

Total Cholesterol (mg/dL)2,4

: Baseline
: Percent Change from baseline (LSMean1)
: Relative difference from placebo (LSMean)

192.1

0.1

189.6

-3.3

-3.3

170.8

-0.5

170.8

-1.4

-0.9

188.7

2.1

185.4

-3.9

-5.8

LDL Cholesterol (mg/dL)2,4

: Baseline
: Percent Change from baseline (LSMean1)
: Relative difference from placebo (LSMean)

112.5

1.3

110.3

-2.5

-3.8

90.1

0.1

90.1

0.5

0.4

111.8

2.6

107.7

-4.7

-7.1

HDL (mg/dL)2,4

: Baseline
: Percent Change from baseline (LSMean1)
: Relative difference from placebo (LSMean)

49.5

1.4

49.4

5.2

3.8

43.8

4.1

44.7

6.9

2.7

50.9

5

51.6

6.5

1.5

Triglycerides (mg/dL)2,4

: Baseline
: Percent Change from baseline (LSMean1)
: Relative difference from placebo (LSMean)

127.9

-7.3

126.2

-21.9

-15.8

159.5

-9.4

154.9

-22

-13.9

110.9

-6.5

107.9

-22.5

-17

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

1Model based estimates based on an analysis of covariance model including treatment (and stratification factors for Study 3 only) as a factor and baseline value as a covariate.

2Not included in the pre-specified hierarchical testing (except HbA1c for Study 3).

3Model based estimates based on a mixed model for repeated measures including treatment (and stratification factors for Study 3 only) as a factor and baseline values as a covariate.

4Baseline value is the geometric mean.

: Table 10. Mean Changes in Anthropometry and Cardiometabolic Parameters in Study 5 (Obesity or overweight with comorbidity after 20-week run-in)1

	PLACEBO N=268		WEGOVY N=535
	Randomization (week 20)	Change from Randomization (week 20) to week 68 (LSMean1)	Randomization (week 20)	Change from Randomization (week 20) to week 68 (LSMean1)	Difference from placebo (LSMean)
Waist Circumference (cm)	104.7	3.3	105.5	-6.4	-9.7
Systolic Blood Pressure (mmHg)	121	4.4	121	0.5	-3.9
Diastolic Blood Pressure (mmHg)2	78	0.9	78	0.3	-0.5
Heart Rate2,3	76	-5.3	76	-2	3.3
HbA1c (%)2	5.4	0.1	5.4	-0.1	-0.2
	Randomization (week 20)	% Change from Randomization (week 20) (LSMean1)	Randomization (week 20)	% Change from Randomization (week 20) (LSMean1)	Relative difference from placebo (LSMean)
Total Cholesterol (mg/dL)2,4	175.1	11.4	175.9	4.9	-5.8
LDL Cholesterol (mg/dL)2,4	109.1	7.6	108.7	1.1	-6.1
HDL Cholesterol (mg/dL)2,4	43.6	17.8	44.5	18.2	0.3
Triglycerides (mg/dL)2,4	95.3	14.8	98.1	-5.6	-17.8

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI).

1Model based estimates based on an analysis of covariance model including treatment as a factor and baseline value as a covariate.

2Not included in the pre-specified hierarchical testing.

3Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline values as a covariate.

4Baseline value is the geometric mean.

Table 11. Mean Changes in Anthropometry and Cardiometabolic Parameters at Week 68 in Study 6 in East-Asian Patients (WEGOVY 1.7 mg)

Study 6 (BMI ≥35 kg/m2 with at least one comorbidity or BMI 27 to 34.9 kg/m2 with at least two comorbidities)

Intention-to-treat

PLACEBO

N=101

WEGOVY 1.7 mg

N=101

WEGOVY 2.4 mg

N=199

Waist circumference (cm)

Baseline

Change from baseline (LSMean1)

Difference from placebo (LSMean)

103.8

-1.8

101.4

-7.7

-5.9

103.8

-11

-9.3

Systolic blood pressure (mmHg)2

Baseline

Change from baseline (LSMean1)

Difference from placebo (LSMean)

133

-5.3

135

-10.8

-5.4

133

-10.8

-5.5

Diastolic blood pressure (mmHg)2

Baseline

Change from baseline (LSMean1)

Difference from placebo (LSMean)

86

-2.2

85

-4.6

-2.4

83

-5.3

-3.1

Heart Rate2, 3

Baseline

Change from baseline (LSMean1)

Difference from placebo (LSMean)

73

2.4

73

4.4

2

73

6.3

3.9

HbA1c (%)2

Baseline

Change from baseline (LSMean1)

Difference from placebo (LSMean)

6.4

0

6.4

-0.9

-0.9

6.4

-0.9

-0.9

Total Cholesterol (mg/dL)2,4

Baseline

Percent change from baseline (LSMean1)

Relative difference from placebo (LSMean)

203.1

0.8

203.3

-6.6

-7.3

197.2

-8.7

-9.4

LDL Cholesterol (mg/dL)2,4

Baseline

Percent change from baseline (LSMean1)

Relative difference from placebo (LSMean)

123.3

-3.8

120.1

-10.1

-6.5

116.5

-14.6

-11.2

HDL Cholesterol (mg/dL)2,4

Baseline

Percent change from baseline (LSMean1)

Relative difference from placebo (LSMean)

48.7

5.9

50.2

6.7

0.7

50.8

9.2

3.1

Triglyceride (mg/dL)2,4

Baseline

Percent change from baseline (LSMean1)

Relative difference from placebo (LSMean)

134.2

5.5

138.8

-19.5

-23.7

127.1

-21.2

-25.3

Missing data were imputed from retrieved subjects of the same randomized treatment arm (RD-MI). At baseline, 24.7% of patients had type 2 diabetes mellitus.

1Model based estimates based on an analysis of covariance model including treatment and type 2 diabetes status as factors and baseline value as a covariate.

2Not included in the pre-specified hierarchical testing.

3Model based estimates based on a mixed model for repeated measures including treatment and type 2 diabetes status as factors and baseline values as a covariate.

4Baseline value is the geometric mean.

14.3 Weight Reduction and Long-Term Maintenance Study in Pediatric Patients Aged 12 Years and Older with Obesity

Overview of Clinical Trial in Pediatric Patients
WEGOVY was evaluated in a 68-week, double-blind, randomized, parallel group, placebo-controlled, multi-center trial in 201 pubertal pediatric patients aged 12 years and older with BMI corresponding to ≥95th percentile standardized for age and sex (Study 7) (NCT#04102189). After a 12-week lifestyle run-in period (including dietary recommendations and physical activity counseling), patients were randomized 2:1 to WEGOVY once weekly or placebo once weekly. WEGOVY or matching placebo was escalated to 2.4 mg or maximally tolerated dose during a 16-week period followed by 52 weeks on maintenance dose. Of WEGOVY-treated patients who completed the trial, 86.7% were on the 2.4 mg dosage at the end of the trial; for 5% of patients, 1.7 mg was the maximum tolerated dosage.

The mean age was 15 years; 38% of patients were male; 79% were White, 8% were Black or African American, 2% were Asian, and 11% were of other or unknown race; and 11% were of Hispanic or Latino ethnicity. The mean baseline body weight was 108 kg, and mean BMI was 37 kg/m2.

Results

The proportions of patients who discontinued study drug were 10% for the WEGOVY-treated group and 10% for the placebo-treated group.

The primary endpoint was percent change in BMI from baseline to week 68. After 68 weeks, treatment with WEGOVY resulted in a statistically significant reduction in percent BMI compared with placebo. Greater proportions of patients treated with WEGOVY achieved ≥5% reduction in baseline BMI than those treated with placebo as shown in Table 12.

Table 12. Changes in Weight and BMI at Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7

Intention-to-Treata	PLACEBO N=67	WEGOVY N=134
BMI
Baseline mean (kg/m2)	35.7	37.7
% change from baseline in BMI (LSMean)	0.6	-16.1
% difference from placebo (LSMean) (95% CI)		-16.7 (-20.3; -13.2)*
% of Patients with greater than or equal to 5% reduction in baseline BMIb	19.7	77.1
% difference from placebo (LSMean)		57.4
% of Patients with greater than or equal to 10% reduction in baseline BMIb	7.7	65.1
% difference from placebo (LSMean)		57.5
% of Patients with greater than or equal to 15% reduction in baseline BMIb	4	57.8
% difference from placebo (LSMean)		53.9
Body Weightb
Baseline mean (kg)	102.6	109.9
% change from baseline (LSMean)a	2.7	-14.7
% difference from placebo (LSMean)		-17.4

LSMean = least squares mean; CI = confidence interval

aThe intention-to-treat population includes all randomized patients. Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). At week 68, the BMI was missing for 2.2% and 7.5% of patients randomized to WEGOVY and placebo, respectively.

bParameters not included in the pre-specified hierarchical testing.

* p<0.0001 (unadjusted 2-sided) for superiority.

The time course of change in BMI with WEGOVY and placebo from baseline through week 68 is depicted in Figure 10. The cumulative frequency distribution of change in BMI is shown in Figure 11.

Figure 10.Change from Baseline (%) in BMI in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7

Observed values for patients completing each scheduled visit, and estimates with multiple imputations from retrieved dropouts (RD-MI).

Figure 11.Change in BMI (%) from Baseline to Week 68 in Pediatric Patients with Obesity Aged 12 Years and Older in Study 7

Observed data from in-trial period including imputed data for missing observations (RD-MI).

Effect of WEGOVY on Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older

Changes in waist circumference and cardiometabolic parameters with WEGOVY are shown in Table 13 for the study in pediatric patients aged 12 years and older.

Table 13. Mean Changes in Anthropometry and Cardiometabolic Parameters in Pediatric Patients with Obesity Aged 12 Years and Older in Study 71

	PLACEBO N=67		WEGOVY N=134
	Baseline	Change from Baseline (LSMean)	Baseline	Change from Baseline (LSMean)	Difference from placebo (LSMean)
Waist Circumference (cm)2	107.3	-0.6	111.9	-12.7	-12.1
Systolic Blood Pressure (mmHg)2	120	-0.8	120	-2.7	-1.9
Diastolic Blood Pressure (mmHg)2	73	-0.8	73	-1.4	-0.6
Heart Rate3	76	-2.3	79	1.2	3.5
HbA1c (%)2,4	5.4	-0.1	5.5	-0.4	-0.2
	Baseline	% Change from Baseline (LSMean)	Baseline	% Change from Baseline (LSMean)	Relative difference from placebo (LSMean)
Total Cholesterol (mg/dL)2,5	160.1	-1.3	159.4	-8.3	-7.1
LDL Cholesterol (mg/dL)2,5	91.7	-3.6	89.8	-9.9	-6.6
HDL Cholesterol (mg/dL)2,5	43.3	3.2	43.7	8	4.7
Triglycerides (mg/dL)2,5	108	2.6	111.3	-28.4	-30.2

1Parameters listed in the table were not included in the pre-specified hierarchical testing.

2Missing data were imputed using available data according to value and timing of last available observation on treatment and endpoint’s baseline value from retrieved subjects (RD-MI). Model based estimates based on an analysis of covariance model including treatment and stratification groups (gender, Tanner stage group) and the interaction between stratification groups as factors and baseline value as a covariate.

3Model based estimates based on a mixed model for repeated measures including treatment as a factor and baseline value as a covariate all nested within visit.

4For patients without type 2 diabetes at randomization (N=129 for WEGOVY-treated patients and N=64 for placebo-treated patients).

5Baseline value is the geometric mean.