Research Study to Look at How Well Semaglutide is at Lowering Weight When Taken Together With an Intensive Lifestyle Program (STEP 3)

Effect and Safety of Semaglutide 2.4 mg Once-weekly as Adjunct to Intensive Behavioural Therapy in Subjects With Overweight or Obesity

This study will look at the change in participant's body weight from the start to the end of the study. This is to compare the effect on body weight in people taking semaglutide (a new medicine) and people taking "dummy" medicine. Together with the medicine, the participant will also be part of an intensive lifestyle program where the participant will have talks with study staff about healthy food choices, what the participant can do to lose weight and be more physically active. The participant will either get semaglutide or "dummy" medicine - which treatment the participant gets is decided by chance. The participant will need to take 1 injection once a week. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. For the first 2 months the participant will be on a low calorie diet. The diet is made up of bars, shakes and 1 low calorie pre-prepared meal for each day. The study will last for about 1.5 years. The participant will have 32 clinic visits with the study doctor.

Study Overview

• Status: Completed
• Conditions: Obesity; Overweight
• Intervention / Treatment: Drug: Semaglutide; Drug: Placebo (semaglutide)

• Study Type: Interventional
• Enrollment (Actual): 611
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Novo Nordisk Investigational Site
    • Montgomery, Alabama, United States, 36106
      • Novo Nordisk Investigational Site
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Novo Nordisk Investigational Site
  • California
    • Anaheim, California, United States, 92801
      • Novo Nordisk Investigational Site
    • Escondido, California, United States, 92025
      • Novo Nordisk Investigational Site
    • Fresno, California, United States, 93720
      • Novo Nordisk Investigational Site
    • Fullerton, California, United States, 92835
      • Novo Nordisk Investigational Site
    • Huntington Beach, California, United States, 92648
      • Novo Nordisk Investigational Site
    • Los Angeles, California, United States, 90057
      • Novo Nordisk Investigational Site
    • Walnut Creek, California, United States, 94598
      • Novo Nordisk Investigational Site
  • Colorado
    • Golden, Colorado, United States, 80401
      • Novo Nordisk Investigational Site
  • Florida
    • Kissimmee, Florida, United States, 34744
      • Novo Nordisk Investigational Site
    • Panama City, Florida, United States, 32401
      • Novo Nordisk Investigational Site
    • Plantation, Florida, United States, 33324
      • Novo Nordisk Investigational Site
  • Georgia
    • Roswell, Georgia, United States, 30076
      • Novo Nordisk Investigational Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Novo Nordisk Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Novo Nordisk Investigational Site
    • Evanston, Illinois, United States, 60201-2477
      • Novo Nordisk Investigational Site
    • Skokie, Illinois, United States, 60077
      • Novo Nordisk Investigational Site
  • New York
    • Albany, New York, United States, 12203
      • Novo Nordisk Investigational Site
    • Endwell, New York, United States, 13760
      • Novo Nordisk Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • Novo Nordisk Investigational Site
    • Greensboro, North Carolina, United States, 27408
      • Novo Nordisk Investigational Site
    • Hickory, North Carolina, United States, 28601
      • Novo Nordisk Investigational Site
    • Raleigh, North Carolina, United States, 27609
      • Novo Nordisk Investigational Site
    • Wilmington, North Carolina, United States, 28401
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-3317
      • Novo Nordisk Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Novo Nordisk Investigational Site
    • Mount Pleasant, South Carolina, United States, 29464
      • Novo Nordisk Investigational Site
  • Tennessee
    • Knoxville, Tennessee, United States, 37912
      • Novo Nordisk Investigational Site
  • Texas
    • Austin, Texas, United States, 78731
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75230
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75226
      • Novo Nordisk Investigational Site
    • Dallas, Texas, United States, 75231
      • Novo Nordisk Investigational Site
    • Rockwall, Texas, United States, 75032
      • Novo Nordisk Investigational Site
    • Round Rock, Texas, United States, 78681
      • Novo Nordisk Investigational Site
  • Utah
    • Saint George, Utah, United States, 84790
      • Novo Nordisk Investigational Site
  • Virginia
    • Arlington, Virginia, United States, 22206
      • Novo Nordisk Investigational Site
    • Newport News, Virginia, United States, 23606
      • Novo Nordisk Investigational Site
    • Winchester, Virginia, United States, 22601-3834
      • Novo Nordisk Investigational Site
  • Washington
    • Olympia, Washington, United States, 98502
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, age more than or equal to 18 years at the time of signing informed consent
• Body mass index more than or equal to 30 kg/m^2 or more than or equal to 27 kg/m^2 with the presence of at least one of the following weight-related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease
• History of at least one self-reported unsuccessful dietary effort to lose body weight

Exclusion Criteria:

• Hemoglobin A1c more than or equal to 48 mmol/mol (6.5%) as measured by the central laboratory at screening
• A self-reported change in body weight more than 5 kg (11 lbs) within 90 days before screening irrespective of medical records

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide; Participants will receive semaglutide 2.4 mg during 68-week treatment period in addition to intensive behavioural therapy.	Drug: Semaglutide; Subcutaneous (s.c., under the skin) injections of semaglutide once weekly at escalating doses (0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks.
Placebo Comparator: Semaglutide placebo; Participants will receive semaglutide placebo during 68-week treatment period in addition to intensive behavioural therapy.	Drug: Placebo (semaglutide); S.c. injections of placebo once weekly at a similar dose escalation manner as semaglutide (placebo matched to semaglutide 0.25 mg/week, 0.5 mg/week, 1.0 mg/week, 1.7 mg/week, 2.4 mg/week). The dose will be escalated to next level every 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Weight (%)	Change in body weight from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from both in-trial and on-treatment periods. In-trial observation period: the uninterrupted time interval from the start of randomisation (week 0) to last trial-related subject-site contact (week 75). On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 68
Participants Who Achieve (Yes/no): Body Weight Reduction More Than or Equal to 5%	Number of participants who achieved greater than or equal to (≥) 5% weight loss after 68 weeks is presented. In the reported data, 'Yes' infers the number of participants who have achieved ≥ 5% weight loss, whereas 'No' infers the number of participants who have not achieved ≥ 5% weight loss. The endpoint was evaluated based on the data from both in-trial and on-treatment observation periods. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75). On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 2 weeks of follow-up. It excludes any period of temporary treatment interruption.	After 68 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants Who Achieve (Yes/no): Body Weight Reduction More Than or Equal to 10%	Number of participants who achieved greater than or equal to (≥) 10% weight loss after 68 weeks is presented. In the reported data, 'Yes' infers number of participants who have achieved ≥ 10% weight loss whereas 'No' infers number of participants who have not achieved ≥ 10% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75).	After 68 weeks
Participants Who Achieve (Yes/no): Body Weight Reduction More Than or Equal to 15%	Number of participants who achieved greater than or equal to (≥) 15% weight loss after 68 weeks is presented. In the reported data, 'Yes' infers number of participants who have achieved ≥ 15% weight loss whereas 'No' infers number of participants who have not achieved ≥ 15% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75).	After 68 weeks
Participants Who Achieve (Yes/no): Body Weight Reduction More Than or Equal to 20%	Number of participants who achieved greater than or equal to (≥) 20% weight loss after 68 weeks is presented. In the reported data, 'Yes' infers number of participants who have achieved ≥ 20% weight loss whereas 'No' infers number of participants who have not achieved ≥ 20% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomization (week 0) to last trial-related subject-site contact (week 75).	After 68 weeks
Change in Waist Circumference	Change in waist circumference from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Systolic Blood Pressure	Change in systolic blood pressure from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Short Form-36 (SF-36) - Physical Functioning Score	SF-36 is a 36-item patient-reported survey of patient health that measures the participant's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured eight domains of functional health and well-being as well as two component summary scores (physical component summary and mental component summary). The 0-100 scale scores from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. In the metric of norm-based scores, 50 and 10 corresponds to the mean and standard deviation respectively. Change from week 0 in the domain scores and component summary scores were evaluated at week 68. A positive change score indicates an improvement since baseline. These endpoints were evaluated based on the data from in-trial observation period which is the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Body Weight (Kg)	Change in body weight from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Body Mass Index	Change in body mass index from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in HbA1c (%)	Change in glycosylated haemoglobin (HbA1c) from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in HbA1c (mmol/Mol)	Change in HbA1c from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Fasting Plasma Glucose	Change in fasting plasma glucose from week 0 to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Fasting Serum Insulin	Change in fasting serum insulin from week 0 to week 68 [measured as milli-international units per milliliter (mIU/mL)] is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Diastolic Blood Pressure	Change in diastolic blood pressure from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Total Cholesterol	Change in fasting total cholesterol from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in High-density Lipoproteins (HDL)	Change in fasting HDL from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline.The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Low-density Lipoproteins (LDL)	Change in fasting LDL from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Very Low Density Lipoprotein (VLDL)	Change in fasting VLDL from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Free Fatty Acids	Change in fasting free fatty acids from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Triglycerides	Change in fasting triglycerides from baseline (week 0) to week 68 (measured as mg/dL) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in High Sensitivity C-reactive Protein	Change in high sensitivity C-reactive protein from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Change in Plasminogen Activator Inhibitor-1 Activity	Change in plasminogen activator inhibitor-1 activity from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 68
Participants Who Achieve (Yes/no): Responder Definition Value for SF-36 Physical Functioning Score	The observed number of participants experiencing a meaningful within participant improvement in SF-36 Physical function after 68 weeks was determined based on two thresholds. The threshold of 4.3 is the default generic responder threshold defined in SF-36 manual for a general population. The threshold of 3.7 is specific for overweight or obese population included in the study and calculated using patient global rating anchor questionnaires to reflect participants' own perspective based on Food and Drug Administration (FDA) recommendations. In the reported data, "Yes" infers number of participants who have achieved an improvement in score greater than or equal to the threshold and "No" infers number of participants who have not achieved an improvement in score greater than or equal to the threshold. The endpoint was evaluated based on the in-trial observation period which is uninterrupted time interval from randomization (week 0) to last trial related subject-site contact (week 75).	After 68 weeks
Change in Body Weight	Change in body weight from baseline (week 0) to week 8 is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from start of randomisation (week 0) to last trial-related subject-site contact (week 75).	Baseline (week 0) to week 8
Number of Treatment-emergent Adverse Events (AEs)	An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product. All AEs mentioned here are treatment emergent adverse events (TEAE) defined as an event that had onset date (or increase in severity) on or after the first day of exposure to treatment. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 7 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 7 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 75
Number of Serious Adverse Events (SAEs)	A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity, or may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. The SAEs occurred from week 0 to week 75 is presented. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68), including 7 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 7 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 75
Change in Pulse	Change in pulse from baseline (week 0) to week 68 is presented. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 68
Change in Amylase	Change in amylase (measured as U/L) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 68
Change in Lipase	Change in lipase (measured as U/L) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 68
Change in Calcitonin	Change in calcitonin (measured as ng/L) is presented as ratio to baseline. The endpoint was evaluated based on the data from on-treatment observation period. On-treatment observation period: includes all time intervals in which participants are considered to be on treatment from the first (week 0) to last trial product administration (week 68) including 2 weeks of follow-up. It excludes any period of temporary treatment interruption. Temporary treatment interruption is defined as more than 2 consecutive missed doses (off-treatment period).	Baseline (week 0) to week 68

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Kushner RF, Calanna S, Davies M, Dicker D, Garvey WT, Goldman B, Lingvay I, Thomsen M, Wadden TA, Wharton S, Wilding JPH, Rubino D. Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5. Obesity (Silver Spring). 2020 Jun;28(6):1050-1061. doi: 10.1002/oby.22794.
• Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, Lingvay I, O'Neil PM, Rubino DM, Skovgaard D, Wallenstein SOR, Garvey WT; STEP 3 Investigators. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1403-1413. doi: 10.1001/jama.2021.1831.
• Perreault L, Davies M, Frias JP, Laursen PN, Lingvay I, Machineni S, Varbo A, Wilding JPH, Wallenstein SOR, le Roux CW. Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program. Diabetes Care. 2022 Oct 1;45(10):2396-2405. doi: 10.2337/dc21-1785.
• O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, Carson CG, Jepsen CH, Kabisch M, Wilding JPH. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018 Aug 25;392(10148):637-649. doi: 10.1016/S0140-6736(18)31773-2. Epub 2018 Aug 16.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2018
• Primary Completion (Actual): March 18, 2020
• Study Completion (Actual): April 28, 2020

Study Registration Dates

• First Submitted: July 17, 2018
• First Submitted That Met QC Criteria: August 1, 2018
• First Posted (Actual): August 2, 2018

Study Record Updates

• Last Update Posted (Actual): November 11, 2021
• Last Update Submitted That Met QC Criteria: November 10, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Body Weight; Obesity; Overweight
• Other Study ID Numbers: NN9536-4375; U1111-1200-8199 (Other Identifier: World Health Organization (WHO))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No