A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study.
OBJECTIVE
To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients.


METHODS
Double-blind, randomized, placebo-controlled study.


METHODS
Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks.


METHODS
Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points.


RESULTS
On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo.


CONCLUSIONS
Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.
Weill Cornell Medical College, New York, NY 10021-7917, USA. ljaronne@med.cornell.edu
L J
LJ
Aronne
S
S
Tonstad
M
M
Moreno
I
I
Gantz
N
N
Erondu
S
S
Suryawanshi
C
C
Molony
S
S
Sieberts
J
J
Nayee
A G
AG
Meehan
D
D
Shapiro
S B
SB
Heymsfield
K D
KD
Kaufman
J M
JM
Amatruda
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides / Q000008:administration & dosage* / Q000009:adverse effects; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects* / Q000502:physiology; D004038:Diet, Reducing; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D018570:Risk Assessment; D016896:Treatment Outcome; D055815:Young Adult
D000577:Amides; D019440:Anti-Obesity Agents; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide