NEW ORLEANS (EGMN) – An investigational oral agent that combines naltrexone and bupropion produced clinically meaningful weight loss at 56 weeks, results from a multicenter phase III trial showed.

Bupropion is a norepinephrine-dopamine reuptake inhibitor that is approved for the treatment of depression and smoking cessation, while naltrexone is an opioid antagonist that is approved for alcohol and opioid dependence.

The investigational agent, known in the United States as Contrave (Orexigen Therapeutics Inc., La Jolla, California), combines the two drugs and targets hunger, fullness, and reward centers in the brain that control the balance of food intake and energy expenditure, Thomas A. Wadden, Ph.D., said at the annual scientific sessions of the American Diabetes Association.

Dr. Wadden, a psychologist who directs the Center for Weight and Eating Disorders at the University of Pennsylvania, Philadelphia, and his coinvestigators enrolled 793 patients with a body mass index between 27 kg/m² and 45 kg/m² at nine sites in the United States. They studied the safety and efficacy of naltrexone/bupropion in patients who received intensive behavioral modification in the form of 28 group sessions that provided diet and exercise counseling.

Of the 793 patients, 591 were randomized to the study drug, which consisted of 32 mg of naltrexone and 360 mg bupropion per day, while 202 were randomized to placebo. The coprimary end points were percentage change in body weight and the proportion of patients who achieved a 5% loss of weight.

The mean age of patients was 46 years, 90% were female, 70% were white, and their mean BMI was 37 kg/m².

Overall, 460 patients (58%) completed the study. At 56 weeks, a modified intent-to-treat analysis showed that patients in the medication treatment group lost 9.3% of their body weight, compared with a loss of 5.1% in the placebo patients, a difference that was statistically significant.

In addition, significantly more patients in the medication treatment group than in the placebo group achieved a weight loss of 5% or more (66% vs. 42%, respectively). A similar pattern was seen for those who achieved a weight loss of 10% or more (42% vs. 20%) and for those achieved a weight loss of 15% or more (29% vs. 11%).

The overall discontinuation rate due to adverse events was 26% in the medication treatment group, compared with 13% in the placebo group. The most frequent adverse events were nausea (34% in the medication treatment group vs. 11% in the placebo group), headache (24% vs. 18%), and constipation (24% vs. 14%).

“Nausea had a fairly rapid onset in participants, was generally mild or moderate, and tended to resolve in the first 4 weeks, and in most patients by 12 weeks,” noted Dr. Wadden, who is also professor of psychology in psychiatry at the University of Pennsylvania. “But there were some isolated cases that went further out.”

The most frequent psychiatric adverse events reported were insomnia (9% in the medication treatment group vs. 6% in the placebo group), anxiety (5% vs. 4%), sleep disorder (2% vs. 3%), and depressed mood (2% vs. 4%).

Two serious cases of cholecystitis occurred in the medication treatment group and were believed to be triggered by rapid and significant loss of body weight.

Dr. Wadden disclosed that he is adviser to Orexigen Therapeutics Inc., which funded the study, as well as to Merck & Co., Novo Nordisk Inc., and Vivus Inc.

 

 

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新奥尔良(EGMN)——一项多中心的III期临床试验结果显示，口服一种以纳曲酮和安非他酮为主要成分的试验药物56周后，可产生具有临床意义的减肥效果。

安非他酮是去甲肾上腺素-多巴胺再摄取抑制剂，可用以戒烟和治疗抑郁症。纳曲酮则是阿片受体拮抗剂，可治疗酒精和阿片成瘾症。

该试验药在美国称之为Contrave(Orexigen Therapeutics公司，La Jolla市，加利福尼亚州)。在美国糖尿病学会科学年会上，Thomas A. Wadden博士指出，该药2种成分作用在大脑饥饿、饱胀感以及奖赏中枢，这些中枢控制着食物摄取和能量消耗之间的平衡。

Wadden博士是来自费城的宾夕法尼亚大学体重和饮食障碍研究中心的心理学家。他和其合作者将793名来自全美9个地点，体重指数在27~45 kg/m²之间的患者纳入研究，以研究应用纳曲酮/安非他酮的安全性和有效性。所有患者均接受了强化的行为矫正治疗，即以28个小组会议的形式为患者提供饮食和锻炼指导。

研究者将793名患者中591名随机分至药物治疗组，每人每日服用药量为纳曲酮32 mg和安他非酮360 mg。另外202名患者则随机分至安慰剂组。研究的共同主要研究终点分别为患者体重变化的百分数和体重减轻5%的患者数量比率。

患者平均年龄46岁，90%为女性，70%为白种人，其平均体重指数为37 kg/m²。

总共有460名(58%)患者完成研究。56周后，通过修正的意向处理分析，结果显示药物治疗组患者体重减少了9.3%，而安慰剂组患者减少了5.1%，两组间差异有统计学意义。

另外，体重减轻≥5%的患者比率在药物治疗组较安慰剂组显著增高(分别为66%和42%)。两组体重减轻≥10%的患者比率(分别为42%和20%)和≥15%者(分别为29%和11%)的情况均如此。

因不良反应所至研究终止率在药物治疗组为26%，而在安慰剂组则为13%。最常见的不良反应包括恶心(发生率在药物治疗组和安慰剂组分别为34%和11%)、头痛(分别为24%和18%)以及便秘(分别为24%和14%)。

来自宾夕法尼亚大学精神病学系心理学教授Wadden博士指出：“参试者相当早期就出现恶心，基本上是轻度或中度水平，在试验头4周就趋于缓解，大多数患者在14周内解决。但有个别患者恶心会持续发生。”

研究显示，最常见的精神病学方面不良反应包括失眠(发生率在药物治疗组和安慰剂组分别为9%和6%)、焦虑(分别为5%和4%)、睡眠障碍(分别为2%和3%)以及抑郁情绪(分别为2%和4%)。

在药物治疗组中有两例患者出现严重的胆囊炎，这可能由于患者体重减轻过于快速和显著而引起的。

Wadden博士声明，他是为本研究提供资金支持的Orexigen Therapeutics公司的顾问。他还是默克公司、诺和诺德公司以及Vivus公司的顾问。