Transcript in the naltrexone 32 mg plus bupropion group

Journal Club
Cooper BA, Branley P, Bulfone L, Collins JF, Craig JC, Fraenkel MB, Harris A,
Johnson DW, Kesselhut J, Li JJ, Luxton G, Pilmore A, Tiller DJ, Harris DC, Pollock
CA; the IDEAL Study.
A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis.
N Engl J Med. 2010 Jun 27. [Epub ahead of print]
Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim
DD, Dunayevich E; for the COR-I Study Group.
Effect of naltrexone plus bupropion on weight loss in overweight and obese adults
(COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2010 Jul 29. [Epub ahead of print]
2010年8月12日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
the Initiating Dialysis Early and Late (IDEAL) Study
the Department of Renal Medicine, Royal North Shore Hospital, Sydney Medical School (B.A.C., J.K., C.A.P.), the Department of
Nephrology, Children’s Hospital at Westmead, Sydney School of Public Health (J.C.C.), the School of Rural Health, Sydney Medical
School (D.J.T.), the Centre for Transplantation and Renal Research, Westmead Millennium Institute, University of Sydney (D.C.H.),
and the Department of Nephrology, Prince of Wales Hospital, University of New South Wales (G.L.) — all in Sydney; Monash Medical
Centre and Eastern Health Renal Units, Melbourne (P.B.); the School of Health and Social Development, Deakin University, Burwood
(L.B.); the Department of Renal Medicine, Austin Hospital, Heidelberg (M.B.F.); the Centre for Health Economics, Monash University,
Clayton (A.H., J.J.L.); and the Centre for Kidney Disease Research, University of Queensland at Princess Alexandra Hospital,
Brisbane (D.W.J.) — all in Australia; and the Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand (J.F.C.,
A.P.).
10.1056/NEJMoa1000552 published on June 27, 2010, at NEJM.org
Background
In clinical practice, there is considerable
variation in the timing of the initiation of
maintenance dialysis for patients with stage
V chronic kidney disease, with a worldwide
trend toward early initiation. In this study,
conducted at 32 centers in Australia and
New Zealand, we examined whether the
timing of the initiation of maintenance
dialysis influenced survival among patients
with chronic kidney disease.
Methods
We randomly assigned patients 18 years of age
or older with progressive chronic kidney
disease and an estimated glomerular filtration
rate (GFR) between 10.0 and 15.0 ml per
minute per 1.73 m2 of body-surface area
(calculated with the use of the Cockcroft–Gault
equation) to planned initiation of dialysis when
the estimated GFR was 10.0 to 14.0 ml per
minute (early start) or when the estimated GFR
was 5.0 to 7.0 ml per minute (late start). The
primary outcome was death from any cause.
Figure 1. Enrollment, Randomization, and Follow-up. The reasons that 159 patients were registered but did not undergo randomization are
listed in Table 1 in the Supplementary Appendix. The reasons that patients randomly assigned to a group did not start dialysis were death (10 in
the early-start group and 22 in the late-start group) and the following other reasons (11 in the early-start group and 16 in the late-start group): the
GFR remained stable, the patient emigrated or transferred to a nonparticipating hospital, the patient withdrew consent, the patient underwent
transplantation, or the patient could not be contacted. Patients could have more than one reason for not completing follow-up.
6.05
5.98
1.8 months at 12.9ml/min
7.4 months at 9.8ml/min
for
asymptomatic
patients renalreplacement
therapy can be
delayed by an
average of 6
months
initiation of dialysis
when the estimated GFR was 10.0 to
14.0 ml per minute (early start)
or when the estimated GFR was 5.0 to
7.0 ml per minute (late start).
Figure 2. Kaplan–Meier Curves for Time to the Initiation of Dialysis and for
Time to Death. The data for time to the initiation of dialysis (Panel A) were censored
at the time of death, transplantation, or withdrawal of consent or at the time a patient
transferred to a nonparticipating hospital, emigrated, or could not be contacted.
The primary outcome was death from any cause.
Figure 2. Kaplan–Meier Curves for Time to the Initiation of Dialysis and for
Time to Death. The curves for time to death (Panel B) are truncated at 7 years of
follow-up and a cumulative hazard of 60%.
Results
Between July 2000 and November 2008, a total of 828 adults
(mean age, 60.4 years; 542 men and 286 women; 355 with
diabetes) underwent randomization, with a median time to the
initiation of dialysis of 1.80 months (95% confidence interval [CI],
1.60 to 2.23) in the early-start group and 7.40 months (95% CI,
6.23 to 8.27) in the late-start group. A total of 75.9% of the
patients in the late-start group initiated dialysis when the
estimated GFR was above the target of 7.0 ml per minute, owing
to the development of symptoms. During a median follow-up
period of 3.59 years, 152 of 404 patients in the early-start group
(37.6%) and 155 of 424 in the late-start group (36.6%) died
(hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P =
0.75). There was no significant difference between the groups in
the frequency of adverse events (cardiovascular events,
infections, or complications of dialysis).
Conclusion
In this study, planned early initiation of
dialysis in patients with stage V chronic
kidney disease was not associated
with an improvement in survival or
clinical outcomes.
(Australian New Zealand Clinical Trials
Registry number, 12609000266268.)
Editorial Comments
The Initiation of Renal-Replacement Therapy — Just-in-Time Delivery
Norbert Lameire, M.D., Ph.D., and Wim Van Biesen, M.D., Ph.D.
The important conclusion of the study is that
waiting to initiate dialysis until signs of uremia
appear does not jeopardize the patient and that
starting renal-replacement therapy on the basis
of a predefined estimated GFR value does not
improve the outcome.
10.1056/nejme1006669 nejm.org
Message/Comments
透析開始を急いでもそれほどメリットはな
いようだが，結局開始のeGFR自体は２群で
異なっておらず，症状を見ながら開始する
ことが必要。
Bupropion
Bupropion (also known as Wellbutrin,
Zyban, Voxra, Budeprion, or Aplenzin;
formerly known as amfebutamone) is an
atypical antidepressant and smoking
cessation aid.
Adverse effects
Seizure
Suicidality
Naltrexone
Naltrexone is an opioid receptor
antagonist used primarily in the
management of alcohol dependence
and opioid dependence
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
(Prof F L Greenway MD); Scripps Clinic, La Jolla, CA, USA (K Fujioka MD); University of Nevada School
of Medicine and Reno Veterans Aff airs Medical Center, Sierra Nevada Health Care System, Reno, NV,
USA (Prof R A Plodkowski MD); Veterans Aff airs San Diego Healthcare System and Department of
Medicine, University of California, San Diego, CA, USA (Prof S Mudaliar MD); MG Consulting, New York,
NY, USA (M Guttadauria MD); inVentiv Clinical Solutions, Baltimore, MD, USA (J Erickson PhD); and
Orexigen Therapeutics, La Jolla, CA, USA (D D Kim MD, E Dunayevich MD)
www.thelancet.com Published online July 30, 2010 DOI:10.1016/S0140-6736(10)60888-4
Background
Despite increasing public health concerns
regarding obesity, few safe and effective
drug treatments are available. Combination
treatment with sustained-release naltrexone
and bupropion was developed to produce
complementary actions in CNS pathways
regulating bodyweight. The Contrave
Obesity Research I (COR-I) study assessed
the effect of such treatment on bodyweight
in overweight and obese participants.
Methods
Men and women aged 18–65 years who had a body-mass index (BMI) of
30–45 kg/m2 and uncomplicated obesity or BMI 27–45 kg/m2 with
dyslipidaemia or hypertension were eligible for enrolment in this
randomised, double-blind, placebo-controlled, phase 3 trial undertaken
at 34 sites in the USA. Participants were prescribed mild hypocaloric
diet and exercise and were randomly assigned in a 1:1:1 ratio to receive
sustained-release naltrexone 32 mg per day plus sustained-release
bupropion 360 mg per day combined in fixed-dose tablets (also known
as NB32), sustained-release naltrexone 16 mg per day plus sustainedrelease bupropion 360 mg per day combined in fixed-dose tablets (also
known as NB16), or matching placebo twice a day, given orally for 56
weeks. The trial included a 3-week dose escalation. Randomisation was
done by use of a centralised, computer-generated, web-based system
and was stratified by study centre. Co-primary efficacy endpoints at 56
weeks were percentage change in bodyweight and proportion of
participants who achieved a decrease in bodyweight of 5% or more. The
primary analysis included all randomised participants with a baseline
weight measurement and a post-baseline weight measurement while on
study drug (last observation carried forward).
Table 2: Change in bodyweight at 56 weeks
Data are least squares mean (SE) or number
of participants (%). p<0・0001 for all
comparisons between naltrexone 32 mg plus
bupropion and placebo and between
naltrexone 16 mg plus bupropion and placebo
except where noted. *Primary analysis
population included all randomised
participants with a baseline weight
measurement and a post-baseline weight
measurement while on study drug. Missing
data was imputed by use of the last
observation carried forward method. †A
repeated-measures linear mixed-effects
model based upon type III sums of squares in
all randomised participants with a baseline
bodyweight measurement and at least one
post-baseline bodyweight measurement.
‡Includes all randomised participants with a
baseline bodyweight measurement in which
the baseline observation was carried forward
for participants who prematurely discontinued
study drug. §All randomised participants who
completed 56 weeks of treatment. ¶p=0・0079
and ||p=0・0099 for naltrexone 32 mg plus
bupropion compared with naltrexone 16 mg
plus bupropion (exploratory analysis
performed for primary analysis population
only).
www.thelancet.com Published online October 23, 2009 DOI:10.1016/S0140-6736(09)61375-1
Table 4: Adverse events and safety endpoints*
Adverse event data are number of
participants (%); safety analysis
population. Baseline values are mean
(SD), change values are least squares
mean (SE) for change from baseline to
week 56. No participants in any of the
groups had an adverse event related to
suicidality. There were no events of
suicidal attempt, completed suicide,
self-injurious ideation, or overdose.
*Any adverse event with a frequency of
5% or more in either naltrexone plus
bupropion group; any psychiatric event
occurring in 1% of participants or more
in any treatment group. One participant
can report several events. †p<0・05
compared with placebo. ‡Values are
based on the safety analysis
population at week 56, with the last
observation carried forward (LOCF) for
participants who prematurely
discontinued or with observed values
at week 56 (placebo, n=281;
naltrexone 16 mg plus bupropion,
n=276; naltrexone 32 mg plus
bupropion, n=292).
Table 4: Adverse events and safety endpoints*
Adverse event data are number of
participants (%); safety analysis
population. Baseline values are mean
(SD), change values are least squares
mean (SE) for change from baseline to
week 56. No participants in any of the
groups had an adverse event related to
suicidality. There were no events of
suicidal attempt, completed suicide,
self-injurious ideation, or overdose.
*Any adverse event with a frequency of
5% or more in either naltrexone plus
bupropion group; any psychiatric event
occurring in 1% of participants or more
in any treatment group. One participant
can report several events. †p<0・05
compared with placebo. ‡Values are
based on the safety analysis
population at week 56, with the last
observation carried forward (LOCF) for
participants who prematurely
discontinued or with observed values
at week 56 (placebo, n=281;
naltrexone 16 mg plus bupropion,
n=276; naltrexone 32 mg plus
bupropion, n=292).
Results
1742 participants were enrolled and randomised to double-blind treatment
(naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion,
n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment
(n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary
analysis (n=471; n=471; n=511). Mean change in bodyweight was –1・3% (SE 0・3)
in the placebo group, –6∙1% (0・3) in the naltrexone 32 mg plus bupropion group
(p<0∙0001 vs placebo) and –5・0% (0・3) in the naltrexone 16 mg plus bupropion
group (p<0∙0001 vs placebo). 84 (16%) participants assigned to placebo had a
decrease in bodyweight of 5% or more compared with 226 (48%) assigned to
naltrexone 32 mg plus bupropion (p<0∙0001 vs placebo) and 186 (39%) assigned to
naltrexone 16 mg plus bupropion (p<0∙0001 vs placebo). The most frequent
adverse event in participants assigned to combination treatment was nausea
(naltrexone 32 mg plus bupropion, 171 participants [29∙8%]; naltrexone 16 mg
plus bupropion, 155 [27∙2%]; placebo, 30 [5∙3%]). Headache, constipation,
dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus
bupropion groups than in the placebo group. A transient increase of around 1・5
mm Hg in mean systolic and diastolic blood pressure was followed by a reduction
of around 1 mm Hg below baseline in the naltrexone plus bupropion groups.
Combination treatment was not associated with increased depression or
suicidality events compared with placebo.
Conclusion
A sustained-release combination of
naltrexone plus bupropion could be a
useful therapeutic option for treatment
of obesity.
Funding Orexigen Therapeutics.
This study is registered with ClinicalTrials.gov, number NCT00532779.
Message
肥満薬経口薬の合剤も米国では開発されている。
Contrave is an experimental treatment for obesity in phase III clinical trials.
Currently being developed by Orexigen in a sustained-release formulation, it
is a combination of two approved drugs, bupropion and naltrexone. Both
drugs have individually shown some evidence of effectiveness in weight loss,
and the combination is expected to have a synergistic effect. In clinical trials,
patients taking Contrave combined with diet and exercise lost more weight
than patients taking a placebo and following the same diet and exercise
program. On March 31st 2010, Orexigen submitted a New Drug Application
(NDA) to the U.S. Food and Drug Administration (FDA) for Contrave.