Weight Maintenance and Additional Weight Loss with Liraglutide after Low-calorie Dietinduced Weight Loss: the SCALE™ Maintenance Randomized Study
Thomas Wadden, Priscilla Hollander, Samuel Klein, Kevin Niswender, Vincent Woo, Paula M.
Hale, and Louis Aronne, on behalf of the NN8022-1923 Investigators
Non-thyroid related neoplasms reported during the trial
Three non-thyroid malignant neoplasms (reported as AEs) occurred in participants treated with liraglutide 3.0 mg; two
cases of breast cancer (ductal carcinoma in situ and bilateral breast cancer), and one case of ovarian cancer. Benign
neoplasms in 6 liraglutide-treated participants included benign breast neoplasm, fibroma, lipoma, papilloma,
prolactinoma and a uterine leiomyoma. Four participants in the placebo-treated group exhibited neoplasms. Two
malignancies were reported; one basal cell carcinoma and one case of metastases to the lung. Two benign neoplasms
were reported; one case of pseudolymphoma that had been a recurrence, and one report of a benign skin papilloma.
1
Supplementary Table 1 Complete list of inclusion and exclusion criteria
Inclusion criteria
1.
Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would
not have been performed during the normal management of the participant).
2.
BMI  30 kgm-2, or BMI  27 kgm-2 with presence of co-morbidities of treated or untreated dyslipidemia and/or
hypertension. Untreated dyslipidemia was defined as low-density lipoprotein (LDL) ≥160 mgdl-1, or triglycerides
≥150 mgdl-1, or high-density lipoprotein (HDL) < 40 mgdl-1 for men and < 50 mgdl-1 for women. Untreated
hypertension was defined as systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg.
3.
Stable body weight during the previous 3 months (<5 kg self-reported weight change)
4.
Age 18 years
5.
Previously undergone dietary weight loss and not able to maintain reduced weight
Exclusion criteria
1.
Any clinically significant disease which in the Investigators’ opinion could interfere with the safety of trial
participants or with the results of the trial
2.
Diagnosis of type 1 or type 2 diabetes per the judgment of the Investigator
3.
FPG  126 mgdl-1 (7 mmoll-1) at start of run-in period
4.
Previous treatment with GLP-1 receptor agonists (including liraglutide or exenatide) within the last 3 months
5.
Visit 1 thyroid-stimulatory hormone outside of the range of 0.4-6.0 mIUl-1.
6.
History of chronic pancreatitis or idiopathic acute pancreatitis
7.
Obesity induced by other endocrinological disorders (e.g., Cushing syndrome)
8.
Current or history of treatment with medications that may cause significant weight gain within 3 months prior to
screening visit, including systemic corticosteroids (except for a short course of treatment, i.e., 7-10 days), tri-cyclic
antidepressants, atypical antipsychotic and mood stabilisers (e.g., imipramine, amitriptyline, mirtazapin,
phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium)
9.
Current participation in an organized diet reduction program (or within the last 3 months)
10. Currently using or have used within the last 3 months before screening for this trial: pramlintide, sibutramine,
orlistat, zonisamide, topiramate, phentermine, or metformin (either by prescription or as part of a clinical trial)
11. Diet attempts using herbal supplements or over-the-counter medications within 3 months before screening for this
trial
12. Participation in a clinical trial of weight control within the last 3 months prior to screening for this trial
13. Previous surgical treatment for obesity (excluding liposuction if performed >1 year before study entry)
2
14. History of major depressive disorder or a PHQ-9 >15 within the last 2 years (completed at visit 1) or history of
other severe psychiatric disorders (e.g., schizophrenia or bipolar disorder) or diagnosis of an eating disorder such as
restrained eating, binge eating, or bulimia (based on Questionnaire for Diagnosing Binge Eating Disorder and
Bulimia Nervosa completed at visit 1)
15. Participants with a lifetime history of a suicide attempt or history of any suicidal behavior within the past month
before entry into the trial
16. Surgery scheduled for the trial duration period, except for minor surgical procedures, at the discretion of the
Investigator
17. Impaired liver function, defined as screening aspartate aminotransferase or alanine aminotransferase  2.5 times
upper normal range (one re-test analyzed at the central laboratory within 1 week is permitted with the last sample
being conclusive)
18. Impaired renal function defined as serum creatinine 152 moll-1 ( 1.72 mgdl-1) (one retest within one week
through the central laboratory is permitted with the result of the last sample conclusive)
19. Known clinically significant active cardiovascular disease, including history of unstable angina, acute coronary
event, other significant cardiac events (including history of arrhythmias, myocardial infarction (MI), or conduction
delays on electrocardiogram [ECG]), or cerebral stroke within the past 6 months and/or heart failure (New York
Heart Association [NYHA] Class III or IV) at the discretion of the Investigator
20. Uncontrolled treated/untreated hypertension (systolic blood pressure 160 mmHg and/or diastolic blood pressure
100 mmHg). If white-coat hypertension is suspected at the screening visit a repeated measurement at run-in prior
to other trial-related activities is allowed
21. Cancer (past or present, except basal cell skin cancer or squamous cell skin cancer), which in the Investigator’s
opinion could interfere with the results of the trial
22. Known or suspected allergy to trial product(s) or related products
23. Previous participation in the run-in or randomized phase of this trial. Re-screening is allowed once within the limit
of the recruitment period
24. Known or suspected abuse of alcohol or narcotics
25. Language barrier, mental incapacity, unwillingness or ability to understand and being able to complete the mental
health questionnaire in the provided language
26. Participants from the same household participating in the trial
27. Women of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using
adequate contraceptive methods (abstinence and/or the following methods: diaphragm with spermicide, condom
3
with spermicide (by male partner), intrauterine device, sponge, spermicide, Norplant, Depo-Provera or oral
contraceptives)
28. Positive screening for hepatitis B antigen, hepatitis C antibodies, positive human immunodeficiency virus (HIV)
antibodies
29. The receipt of any investigational drug within four weeks prior to screening for this trial.
4
Supplementary Table 2 Supportive analyses for co-primary endpoints
Change from randomization to week 56
Estimated treatment differences (ETD) or odds
ratios (OR) for liraglutide vs. placebo (95% CI),
P value
Liraglutide 3.0 mg
Placebo
n=148
n=141
-6.7 (7.7)
-0.1 (7.6)
ETD = -6.8 (-8.5, -5.0), P<0.0001
80.4%
48.2%
OR = 4.9 (2.8, 8.5), P<0.0001
Proportion with >5% weight loss
52.7%
22.7%
OR = 4.2 (2.4, 7.0), P<0.0001
Repeated measures analysis
n=156
n=144
-6.8 (7.8)
0.0 (7.5)
ETD = -6.1 (-7.7, -4.6), P<0.0001
73.4%
42.7%
OR = 3.3 (2.2, 5.0), P<0.0001
Proportion with >5% weight loss
42.5%
18.0%
OR = 3·9 (2.4, 6.3), P<0.0001
Analysis with fasting and non-fasting
n=212
n=208
-5.2 (7.5)
0.1 (7.3)
ETD = -5.4 (-6.8, -3.9), P<0.0001
77.4%
47.1%
OR = 3.8 (2.5, 5.8), P<0.0001
42.9%
20.5%
OR = 3.0 (1.9, 4.7), P<0.0001
Per-protocol (completer) analysis
Body weight (% change)
Proportion maintaining
≥5% run-in weight loss
Body weight (% change)
Proportion maintaining
≥5% run-in weight loss
observations*
Body weight (% change)
Proportion maintaining
≥5% run-in weight loss
Proportion with >5% weight loss
Changes from randomization to week 56 are observed means (SD). Estimated treatment differences are from an analysis
of covariance, and odds ratios are from a logistic regression analysis.
The per-protocol analysis set included all participants from the full analysis set who did not significantly violate
inclusion, exclusion or randomization criteria, who had a valid assessment at week 56, where week 56 was at least 52
weeks (365 days) after first drug date, but who were allowed to be off drug for a total of 4 weeks during the trial, but at
most 2 consecutive weeks. No imputation was performed on the data. Body weight was measured in the fasting state.
The repeated measures analysis (linear mixed-effect model) was done using the full analysis set with no imputation.
Body weight was measured in the fasting state.
*This sensitivity analysis also included observations off drug, and was performed using the last observation carried
forward.
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Supplementary Table 3 Additional measures of body weight maintenance
Change from randomization to week 56
Proportion with ≥5% weight
Estimated odds ratios for
liraglutide vs. placebo (95% CI), P value
Liraglutide 3.0 mg
Placebo
n=207
n=208
1.9%
17.5%
0.09 (0.03, 0.26), P<0.0001
0.0%
2.9%
0.0 (0.0, non-estimable), P=1.0
93.2%
70.9%
5.9 (3.1, 11.0), P<0.0001
87.4%
54.4%
6.0 (3.7, 9.9), P<0.0001
regain
Proportion with ≥10% weight
regain
Proportion maintaining >50%
run-in weight loss
Proportion maintaining >75%
run-in weight loss
Changes from randomization to week 56 are observed means. Estimated odds ratios are from a logistic regression
analysis, using the full analysis set with the last observation carried forward.
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Supplementary Table 4 Summary of adverse events
Liraglutide 3.0 mg (n=212)
Placebo (n=210)
N
(%)
E
N
(%)
E
194
(91.5)
1375
186
(88.6)
1067
Total serious adverse events
9
(4.2)
9
5
(2.4)
6
Total withdrawals
53
(25)
N/A
64
(30.5)
N/A
Total adverse events
a
Withdrawals due to adverse events
18
(8.5)
41
18
(8.6)
23b
Withdrawals due to serious adverse events
5
(2.4)
5
1
(0.5)
1
N=Number of participants with adverse event. %=proportion of participants in analysis set having adverse event.
E=number of adverse events. N/A=not applicable.
a
The 41 events that led to withdrawal in the 18 liraglutide-treated participants were: ovarian cancer; intermittent
diarrhea; diarrhea/intestinal gas/eructation; elevated blood creatine phosphokinase; papillary thyroid carcinoma; breast
cancer; nausea; diarrhea/nausea/vomiting; nausea/headache/constipation/blurred vision/dizziness; nausea/dizziness;
adjustment disorder; nausea/headache; nausea/constipation/back pain/dizziness/feeling abnormal/ageusia/urine flow
decreased; cholelithiasis; diarrhea; ischemic colitis; weight loss/general malaise/ hypoglycemia; and
diarrhea/nausea/flatulence/ abdominal pain/eructation/dysgeusia.
b
The 23 events that led to withdrawal in the 18 placebo-treated participants were: pruritus; dry throat; type 2 diabetes (5
people); palpitations; fatigue/agitation/blurred vision/confusion/alopecia; nephrotic syndrome; non-cardiac chest
pain/palpitations; lung metastases; diverticulum; drug intolerance; generalized anxiety disorder; stress; appendicitis;
tension headache.
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Supplementary Table 5 Psychiatric disorders (randomization to week 56)
Category/Preferred Term
Lira 3.0 mg
Placebo
n=212
n=210
N
%
E
R
N
%
E
R
24
11.3
31
15.9
26
12.4
30
16.3
Insomnia
5
2.4
7
3.6
7
3.3
7
3.8
Middle insomnia
1
0.5
1
0.5
1
0.5
1
0.5
Sleep disorder
–
–
–
–
2
1.0
2
1.1
Anxiety
9
4.2
9
4.6
2
1.0
2
1.1
Agitation
–
–
–
–
1
0.5
1
0.5
Anger
–
–
–
–
1
0.5
1
0.5
Generalized anxiety disorder
–
–
–
–
1
0.5
1
0.5
Stress
5
2.4
5
2.6
6
2.9
6
3.3
Adjustment disorder
1
0.5
1
0.5
–
–
–
–
Adjustment disorder with
1
0.5
1
0.5
–
–
–
–
Bipolar disorder
1
0.5
1
0.5
–
–
–
–
Decreased interest
1
0.5
1
0.5
–
–
–
–
Depression
4
1.9
4
2.1
3
1.4
3
1.6
Dysthymic disorder
–
–
–
–
1
0.5
1
0.5
Libido decreased
–
–
–
–
1
0.5
1
0.5
Major depression
–
–
–
–
1
0.5
1
0.5
Mood swings
–
–
–
–
1
0.5
1
0.5
Attention deficit/hyperactivity disorder
1
0.5
1
0.5
1
0.5
1
0.5
Confusional state
–
–
–
–
1
0.5
1
0.5
TOTAL
Sleep Disorders
Anxiety
Depression
depressed mood
Cognition
N = Number of participants with adverse event. % = proportion of participants in analysis set having adverse event.
E = number of adverse events. R = event rate per 100 exposure years.
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Supplementary Figure 1 Trial design
9
Supplementary Figure 2 Proportion of individuals with nausea
Observed mean data for the safety analysis set (n=422).
6 of the 7 events of nausea that led to participant withdrawal had onset in the first 4 weeks of the trial.
10
Supplementary Figure 3 Geometric mean changes in (a) calcitonin, (b) lipase and (c) amylase
Observed mean data for the safety analysis set (n=422).
a
b
c
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