Liraglutide (Saxenda(R)) in Adolescents With Obesity After Sleeve Gastrectomy

Phase II Trial of Liraglutide (Saxenda(R), Novo Nordisk) in Adolescents With Obesity After Sleeve Gastrectomy: A Pilot Open-Label Study

Background:

Metabolic Bariatric Surgery, including a surgery called vertical sleeve gastrectomy, is the most effective weight loss treatment for severe obesity. However, many adolescents who have this surgery still have obesity 1 year later or regain weight. Researchers want to see if a drug can help.

Objective:

To learn if liraglutide can help adolescents who still have obesity 1 year or more after vertical sleeve gastrectomy lose additional weight.

Eligibility:

Healthy adolescents ages 12-20.99 years who are 1-10 years post vertical sleeve gastrectomy and have a BMI of 30 kg/m2 or >=95th percentile for age and sex.

Design:

Participants will be screened with:

Medical history

Physical exam

Questionnaires about their mood and feelings about their weight

Blood and urine tests

Nutrition counseling. They will keep a diet log.

A test where they view and respond to pictures of food

Wrist accelerometer set-up. They will wear an accelerometer (a device like a watch) on their wrist for 14 days. It will measure their physical activity.

Some screening tests will be repeated during the study.

Participants will have an oral glucose tolerance test. They will ingest a sweet liquid. Blood samples will be taken.

Participants will take liraglutide daily for 16 weeks. They will learn how to inject it under their skin.

Participants will have a body scan to measure muscle and fat.

Participants will be invited to eat as much as they want at a buffet meal at NIH. How much food they eat will be calculated. They will assess their appetite and mood before and after the meal.

Participation will last for 7 months. Participants will have 7 study visits....

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity; Status Post Sleeve Gastrectomy
• Intervention / Treatment: Drug: Liraglutide

Detailed Description

Study Description:

This trial is an open-label Phase II non-randomized pilot study conducted at the NIH Clinical Center to investigate the efficacy of daily subcutaneous injection of liraglutide, a glucagon-like peptide-1 (GLP1) analogue to promote reduction of body mass index (BMI) in adolescents who continue to have obesity (BMI (Bullet)30 or BMI >=95th percentile for age and sex) 1 year or more after vertical sleeve gastrectomy (SG). We hypothesize that administration of liraglutide will be associated with reduction in BMI in such adolescents.

Objectives:

Primary objective: To determine the effect size for the change in BMI of liraglutide 3.0 mg daily subcutaneously at 16 weeks in adolescents who have obesity after SG, in order to use the observed changes to determine the sample size of a subsequent randomized, controlled investigation.

Hypothesis:

The Primary Endpoint is estimation of required sample size for a later randomized controlled trial through calculation of effect size for change in body mass index (BMI) from baseline to 16 weeks of liraglutide. The hypothesis is: The data will be sufficient to calculate the effect size for change in BMI from baseline to 16 weeks for a 2-group experiment (placebo versus liraglutide).

Secondary objectives:

To study the effects of 16 weeks of liraglutide 3.0 mg subcutaneously on change in mean BMI and fat mass in adolescents who underwent vertical sleeve gastrectomy (SG) >=1y prior to study initiation but still have obesity or have a recrudescence of obesity despite surgery. To compare the effects of liraglutide on BMI and fat mass in enrolled participants who had a poor initial response to SG (<20% BMI reduction at BMI nadir) vs. those with a typical post-SG weight loss (>=20% BMI reduction at BMI nadir).

Additional Objectives:

To examine the effects of daily subcutaneous liraglutide in enrolled participants on changes in body composition, metabolic syndrome markers, energy intake, glucose tolerance, gastrointestinal (GI)

hormone concentrations, appetite, free living physical activity, mood, suicidality, weight related quality of life, self-perception of body image, and secretome.

Endpoints:

Primary Endpoint: Estimation of required sample size for a later RCT through calculation of effect size for change in body mass index (BMI) from baseline to 16 weeks of liraglutide.

Key Secondary Endpoints:

Changes in BMI and fat mass after 16 weeks of liraglutide Comparison of changes in BMI and fat mass after 16 weeks of liraglutide in participants who had a poor initial response to SG (<20% BMI reduction at BMI nadir) vs. those with a typical post-S weight loss (>=20% BMI reduction at BMI nadir) Tolerability and safety of liraglutide 3.0 mg.

Additional (exploratory) Endpoints: Change from baseline to 16 weeks of liraglutide in:

1. Proportion reducing BMI by at least 5% and 10%
2. BMI standard deviation score for age and sex (BMIz)
3. Body weight
4. Percentage total body fat mass by DXA
5. Appetite score using visual analog scale (VAS)
6. Attention bias to highly palatable images
7. Energy intake at buffet meal
8. Free living physical activity by accelerometry
9. Metabolic syndrome markers (waist circumference, systolic and diastolic blood pressure, lipids, fasting plasma glucose level)
10. Fasting plasma insulin and HOMA-IR index
11. 2-hour oral glucose tolerance test (OGTT) insulin and glucose measurements
12. Hemoglobin A1C
13. Plasma GI hormones (GLP-1 and PYY) during OGTT
14. Weight related quality of life (QoL) score
15. Beck Depression Inventory total score
16. Body-Esteem Scale Score for Adolescents and Adults
17. Columbia Suicide Severity Rating Scale
18. Secretome analysis
19. Stool microbiome analysis

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jack A Yanovski, M.D.; Phone Number: (301) 496-0858; Email: jy15i@nih.gov
• Study Contact Backup: Name: Sheila M Brady, C.R.N.P.; Phone Number: (301) 451-3783; Email: sb575j@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Male or female, 12-20.999 years at screening visit
2. 12 months or more status-post vertical sleeve gastrectomy with a maximum of 10 years after surgery
3. BMI 30 kg/m2 or greater than or equal to 95th percentile for age and sex
4. In good general health as evidenced by medical history
5. Ability to take subcutaneous medication and be willing to adhere to the daily subcutaneous liraglutide regimen
6. Ability to provide consent/assent before any trial-related activities as required per protocol
7. Stated availability for the duration of the study

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Current or recent (within 3 months of start of study drug initiation) use of weight loss medications such as phentermine, topiramate, lisdexamfetamine (prescribed specifically for weight loss; when prescribed for ADHD and dose is stable for last 3 months this medication will be allowed), orlistat, and naltrexone HCl/bupropion HCl, or liraglutide
2. Weight of more than 450 lbs. (because Dual-Energy X-ray Absorptiometry (DXA) scanning cannot be done in those exceeding this weight)
3. Current use of insulin or sulfonylurea or other medication affecting insulin secretion or GLP1 clearance such as a DPPIV inhibitor
4. Weight loss of more than 3% of body weight in the past 2 months
5. Current pregnancy, desire to become pregnant within study period, current lactation or, if sexually active, not willing to use adequate contraceptive measures
6. History of recurrent pancreatitis (greater than 2 episodes)
7. History of chronic kidney disease (eGFR <60)
8. History of gastroparesis
9. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2
10. History of prior metabolic and bariatric surgery other than vertical sleeve gastrectomy
11. Current or prior use of any GLP-1 agonist medication during the 6 months before screening, including liraglutide.
12. Known or suspected allergy to trial medication, excipients, or related products
13. Treatment with another investigational drug or other experimental intervention within 3 months prior to enrollment in this trial
14. Individuals who have current substance abuse or a DSM 5 Axis I psychiatric disorder or DSM Axis II Mental Retardation diagnosis that in the opinion of the investigators would impede competence, compliance, or participation in the study
15. Suicidal ideation type 4 or 5, history of past suicide attempt, and suicidal behavior in the past month
16. Presence of a major medical illness not listed above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liraglutide; Treated with Liraglutide	Drug: Liraglutide; Liraglutide by subcutaneous injection administered daily. Dose will be initiated at 0.6mg per day and increased to a maximum of 3.0 mg per day as tolerated.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in BMI	The change in BMI (kg/m2) measured from the baseline visit to the week 16 visit will be used to inform a power calculation for a subsequent trial.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Fat Mass	Change in fat mass (in kg) from baseline to the week 16 visit	16 weeks
Change in BMI	The change in BMI (kg/m2) from baseline to the week 16 visit	16 weeks

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Jack A Yanovski, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015 Jul 2;373(1):11-22. doi: 10.1056/NEJMoa1411892.
• Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD, Prabhu N, Arslanian S; NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020 May 28;382(22):2117-2128. doi: 10.1056/NEJMoa1916038. Epub 2020 Mar 31.
• Inge TH, Courcoulas AP, Jenkins TM, Michalsky MP, Helmrath MA, Brandt ML, Harmon CM, Zeller MH, Chen MK, Xanthakos SA, Horlick M, Buncher CR; Teen-LABS Consortium. Weight Loss and Health Status 3 Years after Bariatric Surgery in Adolescents. N Engl J Med. 2016 Jan 14;374(2):113-23. doi: 10.1056/NEJMoa1506699. Epub 2015 Nov 6.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2021
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: May 11, 2021
• First Submitted That Met QC Criteria: May 11, 2021
• First Posted (Actual): May 12, 2021

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 22, 2024

More Information

Terms related to this study

• Keywords: Children; Weight Loss; Bariatric Surgery; glucagon-like peptide; pharmacotherapy for obesity
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: 10000241; 000241-CH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .Individual data for all IPD that underlie results in a publication will be made available.
• IPD Sharing Time Frame: Data will be available starting 6 months after publication or after 1 year following study closure.
• IPD Sharing Access Criteria: Data will be stored in NIH CTDB and will be made available to university-based researchers on reasonable request to the Principal Investigator following establishment of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

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