Multicenter, placebo-controlled trial of lorcaserin for weight management.

Abstract

Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight.
In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed.
At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar.
In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.)

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The new england journal of medicine
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245
original article
Multicenter, Placebo-Controlled Trial
of Lorcaserin for Weight Management
Steven R. Smith, M.D., Neil J. Weissman, M.D., Christen M. Anderson, M.D.,
Ph.D., Matilde Sanchez, Ph.D., Emil Chuang, M.D., Scott Stubbe, M.B.A.,
Harold Bays, M.D., William R. Shanahan, M.D., and the Behavioral Modification
and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group
From the Translational Research Institute
for Metabolism and Diabetes, Florida Hos-
pital and the Sanford–Burnham Institute,
Winter Park, FL (S.R.S.); MedStar Health
Research Institute at Washington Hospital
Center and Georgetown University, Wash-
ington, DC (N.J.W.); Arena Pharmaceuti-
cals, San Diego, CA (C.M.A., M.S., E.C.,
S.S., W.R.S.); and the Louisville Metabol-
ic and Atherosclerosis Research Center,
Louisville, KY (H.B.). Address reprint re-
quests to Dr. Smith at the Translational
Research Institute for Metabolism and
Diabetes, Florida Hospital and the San-
ford–Burnham Institute, 2566 Lee Rd.,
Winter Park, FL 32789, or at steven.r.smith
.MD@flhosp.org.
N Engl J Med 2010;363:245-56.
Copyright © 2010 Massachusetts Medical Society.
Abstract
BACKGROUND
Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reduc-
ing body weight.
METHODS
In this double-blind clinical trial, we randomly assigned 3182 obese or overweight
adults (mean body-mass index [the weight in kilograms divided by the square of the
height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice
daily for 52 weeks. All patients also underwent diet and exercise counseling. At
week 52, patients in the placebo group continued to receive placebo but patients in
the lorcaserin group were randomly reassigned to receive either placebo or lorca-
serin. Primary outcomes were weight loss at 1 year and maintenance of weight loss
at 2 years. Serial echocardiography was used to identify patients in whom valvul-
opathy (as defined by the Food and Drug Administration) developed.
RESULTS
At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients
(716 of 1587) receiving placebo remained in the trial; 1553 patients continued into
year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo
group had lost 5% or more of their body weight (P<0.001), corresponding to an aver-
age loss of 5.8±0.2 kg with lorcaserin and 2.2±0.1 kg with placebo during year 1
(P<0.001). Among the patients who received lorcaserin during year 1 and who had
lost 5% or more of their baseline weight at 1 year, the loss was maintained in more
patients who continued to receive lorcaserin during year 2 (67.9%) than in patients
who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evalu-
ated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not
increased with the use of lorcaserin. Among the most frequent adverse events re-
ported with lorcaserin were headache, dizziness, and nausea. The rates of serious ad-
verse events in the two groups were similar.
CONCLUSIONS
In conjunction with behavioral modification, lorcaserin was associated with signifi-
cant weight loss and improved maintenance of weight loss, as compared with placebo.
(Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.)
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A
opiomelanocortin system of neurons.1-3 Lorcaser-
in is a small-molecule agonist of the serotonin
2C (5-HT2c) receptor designed to promote weight
loss. Study of the nonselective serotonergic ago-
nists fenfluramine and dexfenfluramine, which
enhance presynaptic serotonin release and block
its reuptake, validated serotonin receptors as
pharmacologic targets for weight loss.4 Unfortu-
nately, use of these agents increases the risk of
serotonin-associated valvulopathy,5-8 which is
thought to occur through agonism of 5-HT2b re-
ceptors expressed on cardiac valvular interstitial
cells.9-11 Lorcaserin was designed to selectively ac-
tivate central 5-HT2c receptors, with a functional
selectivity of approximately 15 times that for
5-HT2a receptors and 100 times that for 5-HT2b
receptors.12,13 In a 12-week clinical trial involving
obese patients, the use of lorcaserin was associat-
ed with dose-dependent weight loss without ap-
parent effects on heart valves.14
The present report describes the Behavioral
Modification and Lorcaserin for Overweight and
Obesity Management (BLOOM) trial, a 2-year, ran-
domized, placebo-controlled, double-blind clini-
cal trial designed to evaluate the efficacy and
safety, including safety regarding cardiac valves,
of lorcaserin used for weight management.
ctivation of the 5-hydroxytryp-
tamine (5-HT, or serotonin) receptor 5-HT2c
decreases food intake through the pro-
Methods
Study Design
This study was conducted at 98 academic and pri-
vate trial sites from September 11, 2006, through
February 5, 2009, under the guidelines of the Dec-
laration of Helsinki. Institutional review boards
reviewed and approved the protocol for each site,
and all patients provided written informed con-
sent before participation.
The authors — both academic authors and in-
dustry authors, who were employees of the spon-
sor, Arena Pharmaceuticals — and a site investiga-
tor and other employees of the sponsor designed
the trial, planned the data analyses, reviewed the
data, wrote or revised the manuscript, and decided
to submit it for publication. An academic author
and an industry author wrote the initial draft of
the manuscript, which all the authors revised.
The authors planned the statistical analyses, and
a contract research organization performed them.
All authors assume responsibility for the integrity
and completeness of the data and the data analy-
ses. All authors had confidentiality agreements
with the sponsor during the planning and con-
duct of the study. The study was conducted in
accordance with the protocol (an abbreviated ver-
sion is available with the full text of this article at
NEJM.org).
Study End Points
The trial’s objective was to evaluate the safety and
efficacy of lorcaserin for weight loss and mainte-
nance of weight loss when administered in con-
junction with a lifestyle modification program.
The prespecified coprimary end points for year 1
were the proportion of patients with a reduction
in the baseline body weight of 5% or more at the
end of year 1, the change in weight between base-
line and the end of year 1, and the proportion of
patients with a reduction in the baseline body
weight of 10% or more at the end of year 1. The
primary end point for year 2 was the proportion
of patients who had had a reduction in the base-
line body weight of 5% or more at the end of year 1
and who maintained this reduction during year 2.
Key secondary end points included changes from
the baseline values for lipids (total cholesterol,
low-density lipoprotein [LDL] cholesterol, high-
density lipoprotein [HDL] cholesterol, and triglyc-
erides), glycemic variables (fasting glucose, fasting
insulin, glycated hemoglobin, and the homeosta-
sis model assessment of insulin resistance), physi-
cal measures (waist circumference, body-mass in-
dex [BMI], systolic blood pressure, and diastolic
blood pressure), inflammatory markers of cardio-
vascular risk (high-sensitivity C-reactive protein
and fibrinogen), and the quality of life (as assessed
by means of the Impact of Weight on Quality of
Life–Lite questionnaire, on which scores can range
from 0 to 100, with higher scores indicating a
better quality of life).
Study-Group Assignments
For year 1, on study day 1, patients were randomly
assigned, in a 1:1 ratio, to receive lorcaserin (at a
dose of 10 mg) or placebo twice daily, once before
breakfast and once before dinner. All patients who
remained in the trial at the end of year 1 were
eligible to continue in the study for a second year.
For year 2, patients who had been receiving placebo
continued to receive it, whereas patients who had
been receiving lorcaserin were again randomly as-
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247
signed, in a 2:1 ratio, either to continue to receive
lorcaserin or to begin to receive placebo.
Patients
Eligibility criteria included an age of 18 to 65 years
and a BMI (the weight in kilograms divided by the
square of the height in meters) of 30 to 45 or of
27 to 45 with at least 1 coexisting condition (hyper-
tension, dyslipidemia, cardiovascular disease, im-
paired glucose tolerance, or sleep apnea). Detailed
inclusion and exclusion criteria are provided in the
Supplementary Appendix (available at NEJM.org).
Key exclusion criteria included moderate or more
severe mitral regurgitation or mild or more severe
aortic regurgitation (i.e., valvulopathy, as defined
by the Food and Drug Administration [FDA]), dia-
betes mellitus, a systolic blood pressure exceeding
140 mm Hg or a diastolic blood pressure exceed-
ing 90 mm Hg, depression or other major psychi-
atric disease within 2 years before randomization
that necessitated treatment with prescription med-
ication, and pregnancy or lactation.
Study Procedures
Patients returned to the research site 2 and 4 weeks
after randomization and then on a monthly basis.
At each visit, a trained counselor at each site ad-
ministered standardized nutritional and exercise
counseling during individual sessions (lasting 15
minutes to 1 hour, depending on the study week).
Patients were instructed to exercise moderately for
30 minutes daily and to reduce the daily calorie
intake to 600 kcal below the individual estimate
for daily energy requirements. Energy requirements
were calculated with the use of equations pub-
lished by the World Health Organization15 and an
activity factor of 1.3, which assumes an average
activity level; a factor of 1.4 was used for patients
who reported performing an hour or more of aer-
obic exercise each day.
Research staff evaluated vital signs, concomi-
tant medication use, adverse events, study compli-
ance and results of physical examinations, routine
laboratory studies, pregnancy tests, and electro-
cardiography. Echocardiography was performed
at the screening visit and at weeks 24, 52, 76, and
104. The Beck Depression Inventory II (on which
scores can range from 0 to 63, with higher scores
indicating more severe depression), as adminis-
tered at the screening visit and at nine subse-
quent visits. Efficacy measures included fasting
insulin and fasting glucose levels (measured ev-
ery 4 months), high-sensitivity C-reactive protein
and fibrinogen levels, and the score on the Impact
of Weight on Quality of Life–Lite questionnaire.
Echocardiographic procedures and further study
details are listed in the Supplementary Appendix.
Statistical Analysis
The primary efficacy analyses involved data from
the intention-to-treat population and last-obser-
vation-carried-forward imputation for missing val-
ues. Sensitivity analyses were performed as de-
scribed in the Supplementary Appendix. The three
coprimary end points during year 1 were analyzed
by means of a closed hierarchical testing proce-
dure. Comparisons regarding categorical weight
loss were performed with the use of a logistic-
regression model with effects for treatment, sex,
and baseline body weight. Analysis of covariance
models for weight change used study group and
sex as factors and baseline body weight as a co-
variate. Key secondary efficacy end points were
categorized as relating to lipids, blood pressure,
or glycemic indicators; within each category, end
points were prioritized in a prespecified order.
The Supplementary Appendix provides further de-
tails concerning the statistical analyses.
The echocardiographic safety end point — the
proportion of patients in whom FDA-defined val-
vulopathy had developed by week 52 — was the
primary determinant of sample size. A noninferi-
ority analysis was used to establish that the rate of
FDA-defined valvulopathy among patients treated
with lorcaserin was no worse than the rate among
patients in the placebo group. On the basis of the
results of a 3-month phase 2 study of lorcaserin,14
we estimated that the proportion of patients in the
placebo group in whom FDA-defined valvulopathy
would develop was approximately 5% per year. On
the basis of a noninferiority margin of −0.025
(equivalent to a relative risk of valvulopathy with
lorcaserin of 1.5), a rate in the placebo group of
5%, and a one-sided test at the 5% level of signifi-
cance, we calculated that the total sample size re-
quired to provide 80% power was 1879 patients
(approximately 940 patients in each of the two
study groups). The analysis was performed on data
from a modified intention-to-treat population —
all patients with a screening echocardiogram and
at least one post-baseline echocardiogram — with
last-observation-carried-forward imputation. As-
suming a dropout rate as high as 40%, 3182 pa-
tients were randomly assigned to a study group.
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248
At week 52, a total of 2472 patients had under-
gone echocardiography at both the screening visit
and at least one subsequent visit, and the observed
rate of FDA-defined valvulopathy in the placebo
group was 2.3%. Hence, our data provide a statis-
tical power of 60% to rule out a relative risk of
1.5 of valvulopathy having developed with lorca-
serin use at week 52, by means of last-observa-
tion-carried-forward analysis.
Results
Patients and Study Completion
In the trial, 3182 patients were randomly assigned
to receive one of the two study drugs; the two
groups had similar baseline characteristics (Ta-
ble 1). The rates of completion of year 1 of the
study were 55.4% in the lorcaserin group and 45.1%
in the placebo group, and 7.1% and 6.7% of pa-
tients, respectively, discontinued the study because
of adverse events (see the figure in the Supple-
mentary Appendix). More patients in the lorca-
serin group than in the placebo group withdrew
from the study owing to headache (2.0% vs. 0.8%)
and dizziness (0.8% vs. 0.1%). The overall rate of
completion of year 2 of the study was 72.6% of
patients who completed year 1, with a slightly
higher rate of discontinuation among patients
who received placebo in both years (27.3%) than
among patients who received lorcaserin in both
years (25.7%). The rates and reasons for discon-
tinuation during year 2 were similar among the
three groups present in that year: the group re-
ceiving placebo in both years, the group receiv-
ing lorcaserin in both years, and the group re-
ceiving lorcaserin in the first year and placebo in
the second.
Weight Loss
At the end of year 1, 47.5% of patients receiving
lorcaserin had lost 5% or more of their baseline
body weight, as compared with 20.3% of patients
receiving placebo (P<0.001) (Fig. 1A). Patients in
the lorcaserin group lost an average (±SE) of
5.81±0.16% of the baseline body weight, as com-
pared with 2.16±0.14% in the placebo group
(P<0.001) (Fig. 1B). More patients lost 10% or
more of their baseline body weight in the lorca-
serin group (22.6%) than in the placebo group
(7.7%, P<0.001). In a prespecified analysis of data
for patients who completed the protocol-defined
study visits (the per-protocol population), those
receiving lorcaserin also had greater weight loss
than those receiving placebo (Table 2). In the
population of all patients with weight data from
year 1 (including some who had discontinued the
study but returned at 1 year to be weighed), the
1015 patients in the lorcaserin group lost 7.0±
0.2% of their baseline body weight, whereas the
888 patients in the placebo group lost 3.0±0.2%
(P<0.001). A post hoc analysis of mean weight loss,
performed with the use of a repeated-measures
method, gave results similar to the last-observa-
tion-carried-forward analysis (Table 2).
Among patients in the lorcaserin group who
had weight loss of 5% or more at year 1, the loss
was maintained in a greater proportion of pa-
tients who continued to receive lorcaserin in year
2 than in those who were reassigned to receive
placebo (67.9% vs. 50.3%, P<0.001). The mean
body weight among patients who received lorca-
serin in both years was lower than that among
patients who received placebo in both years and
lower than that among patients who received lor-
caserin in year 1 and placebo in year 2 (Fig. 1C).
Waist circumference and insulin level
Lorcaserin was associated with significant de-
creases in waist circumference and BMI during year
1 as compared with placebo (Table 2). Fasting glu-
cose, insulin, and glycated hemoglobin levels and
the homeostasis model assessment of insulin re-
sistance decreased significantly more during year 1
in the lorcaserin group than in the placebo group
(Table 2). Glucose and insulin levels tended to
increase with body weight during year 2 (see the
table in the Supplementary Appendix).
Total cholesterol, LDL cholesterol, and triglyc-
eride levels at year 1 were significantly lower in
the lorcaserin group than in the placebo group but
had increased by year 2 in both groups. In patients
who received lorcaserin during year 1 and placebo
during year 2, levels of total cholesterol, LDL
cholesterol, and triglycerides tended to increase
to the levels seen in the placebo group by year 2
(see the table in the Supplementary Appendix).
Markers of cardiovascular risk
High-sensitivity C-reactive protein levels de-
creased significantly between baseline and year 1
in the lorcaserin group, from 5.5±0.19 mg per
liter at baseline to 4.3±0.15 mg per liter, but not
in the placebo group. Fibrinogen levels decreased
significantly with lorcaserin as compared with
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Table 1. Baseline Characteristics of the Patients, According to Study Group.*
CharacteristicLorcaserin (N = 1595)Placebo (N = 1587)P Value†
Intention-to-treat population — no.
Race or ethnic group — no. (%)‡
White
Black
Hispanic
Asian
Native American
Pacific Islander
Other
Sex — no. (%)
Male
Female
Age — yr
Weight — kg
Height — cm
Body-mass index§
Waist circumference — cm
Blood pressure — mm Hg
Systolic
Diastolic
Heart rate — beats per min
PASP — mm Hg
Cholesterol — mg/dl
Total
LDL
HDL
Triglycerides — mg/dl
Fasting glucose — mg/dl
Fasting insulin — µU/ml
HOMA-IR
Glycated hemoglobin — %
High-sensitivity CRP — mg/liter
Fibrinogen — mg/dl
15381499
0.24
1081 (67.9)
298 (18.7)
181 (11.4)
12 (0.8)
11 (0.7)
1 (0.1)
9 (0.6)
1046 (66.0)
298 (18.8)
213 (13.4)
9 (0.6)
4 (0.3)
3 (0.2)
11 (0.7)
0.44
272 (17.1)
1321 (82.9)
43.8±0.3
100.4±0.4
166.4±0.2
36.2±0.1
109.6±0.3
253 (16.0)
1331 (84.0)
44.4±0.3
99.7±0.4
165.9±0.2
36.2±0.1
109.2±0.3
0.16
0.21
0.11
0.73
0.30
120.7±0.3
76.8±0.2
69.5±0.2
25.7±0.1
121.1±0.3
77.1±0.2
69.8±0.2
25.4±0.1
0.27
0.23
0.37
0.24
194.2±0.9
112.1±0.8
54.7±0.3
137.4±1.9
94.3±0.3
15.9±0.3
1.95±0.03
5.66±0.01
5.62±0.18
365.7±2.0
196.7±0.9
113.8±0.8
55.4±0.4
137.9±1.9
94.1±0.3
15.8±0.4
1.92±0.03
5.66±0.01
5.50±0.18
364.3±2.0
0.04
0.11
0.18
0.84
0.76
0.83
0.498
0.92
0.65
0.62
IWQOL-Lite score73.92±0.41 73.85±0.420.91
BDI-II score4.2±0.14.2±0.10.98
* Plus–minus values are means ±SE. Data for race or ethnic group, age, and sex are reported for the safety population
(all patients who received at least one dose of lorcaserin or placebo): 1593 patients in the lorcaserin group and 1584
patients in the placebo group; no missing-value imputation was used for safety analyses. Scores on the Impact of
Weight on Quality of Life–Lite (IWQOL-Lite) questionnaire can range from 0 to 100, with higher scores indicating a bet-
ter quality of life. Scores on the Beck Depression Inventory II (BDI-II) can range from 0 to 63, with higher scores indi-
cating more severe depression. To convert values for cholesterol to millimoles per liter, multiply by 0.02586. To convert
values for triglycerides to millimoles per liter, multiply by 0.01129. To convert values for glucose to millimoles per liter,
multiply by 0.05551. To convert values for insulin to picomoles per liter, multiply by 6.95. CRP denotes C-reactive pro-
tein, HDL high-density lipoprotein, HOMA-IR homeostasis model assessment of insulin resistance, LDL low-density li-
poprotein, and PASP pulmonary-artery systolic pressure.
† P values were calculated with the use of a two-sample t-test for continuous end points and a chi-square test for cate-
gorical end points.
‡ Race or ethnic group was self-reported.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
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