Liraglutide for Children 6 to <12 Years of Age with Obesity - A Randomized Trial

Design

Prospective, phase 3a, double-blind, randomized, multicenter, placebo-controlled trial

N= 82

Objective

To assess the efficacy and safety of liraglutide, as compared with placebo, as an adjunct treatment to lifestyle interventions, for the treatment of obesity in children 6 to younger than 12 years of age

Study Groups

Liraglutide (n= 56)

Placebo (n= 26)

Inclusion Criteria

Children (6 to <12 years of age) with obesity; pubertal development of Tanner stage 1 through 5

Exclusion Criteria

No type 1 diabetes or secondary causes of obesity

Methods

Patients completed a 12-week run-in period after a 2-week screening period, then were randomized 2:1 to subcutaneous liraglutide 3 mg once daily or matching placebo; randomization was stratified based on sex and Tanner stage. Lifestyle interventions were conducted from run-in until the end of trial. Subcutaneous liraglutide was initiated at 0.6 mg/day for 1 week for patients ≥45 kg and 0.3 mg/day for 1 week for patients <45 kg, with dosing increased by 0.6 mg per week over 8 weeks (body weight ≥45 kg) or 10 weeks (body weight <45 kg) until the maintenance 3 mg dose or maximum tolerated dose was achieved.

Duration

March 2021 to January 2024

Treatment: 56 weeks

Outcome Measures

Primary: percentage change in body mass index (BMI)

Secondary: percentage change in body weight, reduction in BMI of ≥5%

Baseline Characteristics

Liraglutide (n= 56)

Placebo (n= 26)

Age, years

Female

White

Tanner stage

1

2 or 3

4 or 5

43%

39%

18%

38%

50%

12%

BMI, kg/m2

30.9 ± 4.7

31.3 ± 7.0

Body weight, kg

69.8 ± 17.7

71.0 ± 23.2

Number of obesity-related complications*

0

1

2

≥3

46%

23%

18%

12%

42%

31%

15%

12%

Obesity-related complications*

Insulin resistance

Asthma

Impaired glucose tolerance

Precocious puberty

Type 2 diabetes

25%

12%

11%

12%

0

8%

27%

15%

12%

0

*Complications were confirmed by investigators, and included asthma, dyslipidemia, gastroesophageal reflux disease, impaired glucose tolerance, hepatic steatosis, hypertension, impaired fasting glucose, insulin resistance, sleep apnea syndrome, and precocious puberty

Results

Endpoint

Liraglutide (n= 56)

Placebo (n= 26)

Difference (95% CI)

Percentage change in BMI at week 56

Percentage change in body weight

BMI reduction of ≥5%

Abbreviations: CI= confidence interval

*Adjusted odds ratio

Results for all supportive secondary end points related to body weight also favored liraglutide at week 56, with the exception of change in mean waist circumference. Changes in diastolic blood pressure and glycated hemoglobin level favored liraglutide over placebo.

Adverse Events

Common Adverse Events (liraglutide vs placebo): 89% vs 89%; gastrointestinal disorders were most common (80% vs 54%), with a greater incidence of mild-to-moderate nausea and vomiting during dose escalation with liraglutide vs placebo

Serious Adverse Events: 12% vs 8%; three were considered possibly or probably related to treatment liraglutide (vomiting, n= 2; colitis, n= 1)

Percentage that Discontinued due to Adverse Events: 11% discontinued with liraglutide (gastrointestinal disorders, n= 3) vs 0 placebo

Study Author Conclusions

This trial showed that among children 6 to younger than 12 years of age with obesity, liraglutide at a dose of 3 mg plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions.

InpharmD Researcher Critique

Although BMI reduction was reported, whether the reduction was clinically meaningful is uncertain. Limited long-term follow-up may not properly capture more serious or rare adverse events, and long-term safety of liraglutide in this patient population requires further research to determine. Obesity-related complications may have been underestimated due to patient self-reporting. 

Liraglutide effects in a paediatric (7-11 y) population with obesity: A randomized, double-blind, placebo-controlled, short-term trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics

Design

Randomized, double‐blind, placebo‐controlled, short‐term trial

N= 24

Objective

To assess safety, tolerability, pharmacokinetics, and pharmacodynamics during short‐term treatment with liraglutide in children (7‐11 y) with obesity

Study Groups

Liraglutide (n= 16)

Placebo (n= 8)

Inclusion Criteria

Male or female children (7‐11 years); Tanner stage 1 (including children with premature adrenarche); BMI corresponding to ≥ 30 kg/m² for adults by international cut‐off points; and BMI ≤ 45 kg/m² as well as BMI ≥ 95th percentile for age and sex

Exclusion Criteria

Secondary causes of childhood obesity; confirmed bulimia nervosa disorder; diagnosis of type 1 or 2 diabetes mellitus as defined by glycated hemoglobin (HbA1c) ≥ 6.5%; pubertal development—Tanner stages 2 to 5 (participants with premature adrenarche were included) at the time of screening; history of pancreatitis (acute or chronic); presence of severe comorbidities as judged by the investigator; family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma; and history of major depressive disorder within 2 years of randomization

Methods

Patients were randomized 2:1 to once‐daily subcutaneous injections of liraglutide or placebo to be administered via a prefilled syringe once daily (qAM). Liraglutide was initiated at doses of 0.3 mg, then escalated from 0.3 to 1.2 mg in weekly increments of 0.3 mg, and then followed with 0.6‐mg weekly increments to a maximum dose of 3.0 mg or maximum tolerated dose. Treatment duration extended for at least 7 weeks, with up to six optional treatment weeks, up to a maximum of 13 weeks. 

Duration

Intervention: up to 13 weeks

Patients screened between March 2016 and April 2017

Outcome Measures

Primary: adverse events from the time of first dosing until completion of the follow‐up visit 

Secondary: hypoglycemic episodes

Baseline Characteristics

Liraglutide (n= 16)

Placebo (n= 8)

Age, years

Female

Race

White

Black

56.3%

43.8%

62.5%

37.5% 

Body weight, kg (range)

66.6 ± 12.6

81.4 ± 16.6

Fasting plasma glucose, mg/dL

HbA1c, %

Results

Adverse events

Liraglutide (n= 16)

Placebo (n= 8)

Number of adverse events (n patients)

Severity, events (n patients)

Mild

Moderate

35 (9 [56.3%])

2 (1 [6.3%])

11 (5 [62.5%])

1 (1 [12.5%])

Relationship to trial product (events)

Probable

Possible

Unlikely

15 of 37

6 of 37

16 of 37

1 of 12

1 of 12

10 of 12

Outcome (events)

Recovered

Recovering

36 of 37

1 of 37

10 of 12

2 of 12

Number of hypoglycemic episodes

All hypoglycemic episodes were asymptomatic. Four episodes (all in liraglutide group) occurred following an overnight fast.

No clinically relevant safety findings were identified in relation to physical exam, vital signs, ECG, hematology, biochemistry, hormones, lipids, or calcitonin.

Pharmacokinetics

Trial population

Liraglutide C_trough concentrations were consistent with dose proportionality as a doubling of the liraglutide dose

Abbreviations: AUC_0‐24,ss, area under the concentration‐time curve from 0 to 24 h following last dose; C _avg, estimated average plasma liraglutide concentration in a dosing interval; CL/F, apparent clearance following last dose

Pharmacokinetic analysis conducted by comparing current data to data from other trials.

Adverse Events

Study Author Conclusions

Short‐term treatment with liraglutide in children with obesity revealed a safety and tolerability profile similar to trials in adults and adolescents with obesity, with no new safety issues.

InpharmD Researcher Critique

The current trial included a limited sample size and incorporated a short treatment duration, hindering long-term assessment of safety. 

Relevant Ongoing Comparative Trials in Pediatric Patients <12 years-old

Comparator(s)^(reference)

Indication(s)

Age range included

Study Design

Status

ClinicalTrials.gov Trial identifier(s) 

Updated

Bydureon vs Placebo¹

Obesity

Liraglutide vs Placebo²

Wegovy vs Placebo³

SUBQ semaglutide [Brand Unspecified] vs Placebo⁴

Abbreviations:

RCT: randomized control trial; T2DM: type 2 diabetes mellitus; yo: year(s)-old

A Phase 3 Randomized Clinical Trial Using a Once‐weekly Glucagon‐like Peptide‐1 Receptor Agonist in Adolescents and Young Adults with Hypothalamic Obesity

Design

Prospective, two‐arm, randomized, multicenter, double‐blind, placebo‐controlled trial

N= 42

Objective

To evaluate the efficacy, safety and tolerability of a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) in patients with hypothalamic obesity (HO)

Study Groups

ExQW (n= 23)

Placebo (n= 19)

Inclusion Criteria

Aged 10 to 25 years; hypothalamic injury following intracranial tumour and HO; age‐ and sex‐adjusted BMI ≥95 percentile or BMI ≥32 kg/m2 if aged 18 years or older; 6 months or longer postsurgical or radiation treatment; weight stable or increasing over 3 months; and stable hormone replacement for at least 3 months

Exclusion Criteria

History of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma; metabolic disorders, insulin‐treated diabetes, poorly controlled type 2 diabetes (HbA1c ≥ 10%); other chronic serious medical conditions; history of bariatric surgery or weight loss medication in the past 3 months; and pregnant, lactating or those expecting to conceive

Methods

Patients were randomized 1:1 to once‐weekly subcutaneous injections of a GLP‐1 RA exenatide 2 mg (Bydureon; ExQW) or placebo for 36 weeks, after a 2-week placebo run-in. Randomization was administered by the research pharmacist. After randomized treatment, patients also received an 18‐week open‐label extension, during which all patients recieved ExQW. HO was defined as rapid weight gain related to tumour onset or treatment. Patients were seen for study visits at 0, 6, 18, 36, and 54 weeks. Primary and secondary efficacy outcomes were analysed in the intention‐to‐treat (ITT) population.

Duration

Treatment: 36 weeks

Total study duration: 56 weeks

Outcome Measures

Primary: 36‐week % change in body mass index (BMI)

Secondary: change in body composition

Baseline Characteristics

ExQW (n= 23)

Placebo (n= 19)

Age, years

Female

White

Tumor type

Craniopharyngioma

Mixed germ cell tumour

Suprasellar ganglioglioma

Suprasellar germinoma

23 (100%)

0

0

0

15 (82%)

1 (6%)

1 (6%)

1 (6%)

Body mass index, kg/m²

35.8 ± 6.6

39.2 ± 7.3

Weight, kg

95.1 ± 27.9

103.7 ± 30.0

Concomitant medications

Growth hormone

Thyroid hormone

Hydrocortisone

DDAVP/desmopressin

Testosterone/estrogen

Dextroamphetamine

Methylphenidate

13 (57%)

19 (83%)

19 (83%)

19 (83%)

15 (65%)

5 (22%)

3 (13%)

11 (61%)

15 (83%)

15 (83%)

15 (83%)

15 (83%)

2 (11%)

1 (6%)

Due to low enrollment, three patients with HO following treatment for other suprasellar tumours were included.

Results

Endpoint

ExQW (n= 23)

Placebo (n= 19)

ETD (95% CI)

p-value

Estimated 36‐week change of outcomes

Body mass index, kg/m2

Waist circumference, cm

Waist/hip ratio

Waist/height ratio

Total adipose tissue, kg

% adipose tissue

0.6 ± 0.3

0.1 ± 0.7

-0.01 ± 0.01

-0.01 ± 0.004

1.5 ± 0.9

0.1 ± 0.4

1.4 ± 0.3

3.6 ± 0.7

-0.01 ± 0.01

0.01 ± 0.005

4.6 ± 1.0

1.3 ± 0.5

-0.80 (-1.60 to 0.10)

-3.50 (-5.50 to -1.60)

-0.01 (-0.03 to 0.02)

-0.02 (-0.03 to -0.01)

-3.10 (-5.70 to -0.40)

-1.20 (-2.50 to 0.00)

0.230

0.004

0.370

0.003

0.020

0.060

Abbreviations: CI= confidence interval; ETD= estimated treatment difference

Data are limited to individuals aged less than 20 years of age at start of study drug treatment.

No other outcomes were found to be significantly different between groups, with the exception of heart rate (5.7 ± 3.0 bpm vs -4.8 ± 3.4 bpm; ETD 10.5; 95% CI 1.5 to 19.4; p= 0.03).

Adverse Events

Common Adverse Events (ExQW vs placebo): similar between ExQW (91%) and placebo (83%); gastrointestinal tract‐related events were most common (abdominal pain, 39% vs 11%; nausea, 26% vs 17%; vomiting, 17% vs 22%; diarrhea, 30% vs 17%) as well as injection site reactions (30% vs 22%)

Serious Adverse Events: 6 requiring hospitalization, 4 ExQW (increased seizure activity, n= 1; altered mental status, hypernatremia, and suspicion of seizure activity, n= 1; migraine headache, n= 1; cellulitis requiring IV antibiotic therapy, n= 1) and 2 placebo (hypernatremic dehydration, n= 2); no significant differences observed between groups

Percentage that Discontinued due to Adverse Events: 1 ExQW patient (severe localized cutaneous sensitivity reaction)

Study Author Conclusions

In summary, this is the first randomized controlled clinical trial testing a GLP‐1 RA in adolescent and young adult subjects with HO because of hypothalamic injury. The shown GLP‐1 RA effects in patients with hypothalamic dysfunction not only open new avenues for intervention in a difficult‐to‐treat form of obesity but also contribute to a better understanding of GLP‐1 physiology. While the overall results are encouraging, as we observed relative reductions in body fat mass, the heterogeneity of response to ExQW therapy suggests that some patients are more probable to respond. More research is needed to understand the factors that have an impact on or may predict treatment success as well as strategies for identifying the optimal drug dose.

InpharmD Researcher Critique

The enrollment goal was not adequately reached, which resulted in the researchers expanding inclusion of patients to HO following treatment for other tumors. Extent of hypothalamic injury and how it may impact response to exenatide was not evaluated.

An Open-label 16-week Study of Liraglutide in Adolescents with Obesity Post-sleeve Gastrectomy

Design

Prospective, open-label, pilot study

N= 34

Objective

To determine whether liraglutide would significantly reduce body weight in adolescents and young adults who continued to have obesity after sleeve gastrectomy (SG) 

Study Groups

Study cohort (N= 34)

Inclusion Criteria

Adolescents aged 12–20 years old with BMI ≥30 kg/m² or ≥95th percentile for age and biological sex and a history of SG ≥1 year

Exclusion Criteria

Major medical illness, use of weight loss medications, positive pregnancy test, history of metabolic and bariatric surgery (MBS) other than SG, or significant weight-loss (>3% of body weight) within the last 2 months of screening

Methods

Patients were initiated on liraglutide at 0.6 mg/day, with weekly 0.6 mg escalations until 3 mg/day was reached over 16 weeks. Patients were seen monthly by a registered dietitian, and received individualized recommendations from their respective bariatric center; thus, there were no protocol-specified physical activity or nutrition targets.

Duration

June 2021 to September 2023

Treatment: 16 weeks

Outcome Measures

Primary: estimation of the required sample size for a subsequent randomized controlled trial through calculation of effect size for the change in BMI

Secondary: change in BMI, BMI standard deviation score for age and sex (BMIz), body weight, and fat mass

Baseline Characteristics

Study cohort (N= 34)

Age, years

Female

White

BMI, kg/m2

BMIz score

Weight, kg

Fat mass, kg

Most patients (94%) tolerated the maximum 3 g liraglutide dose, though 2 patients required dose reductions.

Results

Endpoint

End treatment

Change from baseline

p-value

BMI, kg/m2

BMIz score

Weight, kg

Fat mass, kg

Overall, 41.9% of participants reduced BMI by ≥5%, while 12.9% of participants reduced BMI by ≥10%.

Significant reductions in fat mass index, lean mass index, and systolic blood pressure were also observed after treatment with liraglutide.

Adverse Events

Common Adverse Events: 17/31 reported non-serious treatment-emergent adverse events; most common were gastrointestinal (emesis, nausea, constipation), dizziness, and low energy at 4 weeks of treatment, though all were reduced by week 16.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

In sum, liraglutide treatment for 16 weeks was associated with a mean BMI reduction of 4.3% in adolescents and young adults who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone bariatric surgery after 16 and 56 weeks of liraglutide. These data support the value of a randomized controlled trial to establish GLP-1 agonist efficacy and safety in adolescents who have undergone SG. Further research is needed to investigate potential reasons for variability in weight loss response to better characterize responders versus non-responders to GLP1-agonist therapy following MBS and to establish the optimal timing for initiation of post-SG obesity pharmacotherapy.

InpharmD Researcher Critique

Lack of a comparator arm limits ability to evaluate liraglutide's effect against standard of care or other treatment regimens in patients with SG. Patients were also only treated for 16 weeks; longer treatment and follow-up may produce greater effect, as well as be able to capture more uncommon treatment-related adverse events.

The Effect of Glucagon-Like Peptide-1 Receptor Agonist Therapy on Body Mass Index in Adolescents with Severe Obesity: A Randomized, Placebo-Controlled, Clinical Trial

Design

Randomized, double-blind, placebo-controlled, multicenter clinical trial

N= 26

Objective

To evaluate the effects of exenatide on body mass index (BMI) and cardiometabolic risk factors in adolescents with severe obesity

Study Groups

Exenatide (n= 13)

Control (n= 13)

Inclusion Criteria

Adolescents aged 12-19 years with severe obesity, defined as having a BMI ≥ 1.2 times the 95th percentile or a BMI ≥ 35 kg/m²

Exclusion Criteria

History diabetes mellitus (type 1 or 2), use of medications associated with weight loss/gain within three-months of screening, history of bariatric surgery, initiation of a new drug therapy within 30-days of screening, psychiatric disorders, current pregnancy/plans to become pregnant, current tobacco use, renal or liver dysfunction, history of pancreatitis, obesity-associated genetic disorders (e.g., Prader-Willi), hypothyroidism, uncontrolled hypertriglyceridemia (≥300 mg/dL), and history of an eating disorder

Methods

Patients were randomly assigned to exenatide or placebo group. Exenatide was initiated at 5 mcg subcutaneously (SQ) BID for 1 month, then 10 mcg BID for 2 months. Following the first 3-month, double-blind period, an open-label extension was completed at which time active medication was offered to all patients.

Duration

January to November 2011

Trial phase: 3 months

Follow-up open-label extension: 3 months

Outcome Measures

Primary endpoint: mean percent change in BMI measured at baseline and three-months

Secondary endpoints: absolute change in BMI, body weight, body fat, hemoglobin A1c, fasting glucose, fasting insulin at three-months

Baseline Characteristics

Exenatide (n= 12)

Control (n= 10)

Age, years

Male

Race

White

Black

Other

83.3%

8.3%

8.3%

80%

20%

0%

BMI, kg/m²

Weight, kg

Waist, cm

Total tissue fat, kg

Visceral fat area, cm²

Glucose, mg/dL

Insulin, mU/L

HbA1c, %

Data is reported for only patients who completed 3-month follow-up

Of 26 patients, 1 exenatide patient and 3 patients placebo patients dropped out (1 discontinued due to lack of compliance with study protocol, 2 lost to follow-up due to lack of interest, and 1 due to diagnosis of pseudotumor cerebri)

Results

Endpoint (N=22)

Exenatide

Control

p-Value

BMI, kg/m²

39.64 ± 4.67

% Change in BMI

-2.90 ± 1.80

-0.15 ± 3.20

0.025

Change in weight, kg

Change in waist, cm

Change in total tissue fat, kg

Change in visceral fat area, cm²

Change in glucose, mg/dL

Insulin, mU/L

Change in HbA1c, %

Results comparing change in variables between baseline and at 3-month follow-up

Adverse Events

Common adverse events between baseline and 3 months (all mild-moderate and transient) were nausea (placebo 31%, exenatide 62%), abdominal pain (placebo 23%, exenatide 15%), diarrhea (placebo 31%, exenatide 8%), headache (placebo 46%, exenatide 23%), and vomiting (placebo 8%, exenatide 31%). No subjects experienced hypoglycemia or pancreatitis.

Study Author Conclusions

In conclusion, data from the current study provide evidence that GLP-1 receptor agonist treatment reduces BMI and elicits a potentially meaningful reduction in SBP in adolescents with severe obesity. Compliance with the required injection regimen was excellent and exenatide was generally well-tolerated. Future clinical trials with GLP-1 receptor agonists should extend treatment beyond six-months and evaluate changes in other health outcomes such as non-invasive measures of arterial health, insulin sensitivity, and pancreatic β-cell function. In addition, subsequent studies should be designed to evaluate predictors of response to therapy in an attempt to better identify which obese adolescents are most likely to benefit from treatment.

InpharmD Researcher Critique

Limitations of this study include small sample size and short treatment and follow-up period.