LOS ANGELES (EGMN) – The experimental drug telcagepant for acute migraine therapy appears to be tolerated by patients with stable coronary artery diseaseand consistently effective in various subgroups of patients, several analyses of randomized, double-blind, placebo- or active-controlled studies show.

The results, presented in fiveposters at the annual meeting of the American Headache Society, suggest that acute treatment with the drug is safe in migraineurs with stable cardiovascular disease and effective in patients with or without aura, with migraines that are or are not associated with menstruation, or who have a history of opioid treatment.

A separate study found that telcagepant appeared to be unappealing to recreational polydrug users and thus to have no abuse potential. In another analysis, the addition of ibuprofen or acetaminophen to telcagepant therapy produced a statistically insignificant improvement in efficacy.

The studies were led by employees of Merck, which is developing telcagepant and which funded the studies.

Previous studies have shown that telcagepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, is effective in acute treatment of migraine (Neurology 2009;73:970-7; Lancet 2008;372:2115-23; Neurology 2008;70:1304-12).

Merck also had been developing the drug for migraine prophylaxis, but stopped those trials when some patients taking twice-daily doses for 3 months developed elevated liver enzyme levels, a company spokeswoman said in an e-mail interview after the meeting. Following discussions with the U.S. Food and Drug Administration at the end of 2009, Merck is conducting an additional safety study this year before regulators consider the drug further –a 6-month study of 4,500 females with menstrually associated migraine who will take 140 mg of telcagepant or placebo once daily for 7 consecutive days on a monthly basis.

In a double-blind, crossover study, patients with migraines and stable coronary artery disease (CAD) were randomized to one of two treatment groups. Patients in the first group treated up to 12 moderate to severe migraines with telcagepant in a 280-mg tablet plus a 300-mg capsule during a 6-week period, then treated 12 more migraines in the next 6-week period with acetaminophen 1,000 mg. Patients in the second group got placebo for the first moderate to severe migraine attack, then acetaminophen for up to 11 more migraines in the first 6-week period; in the second 6 weeks, up to 12 migraines were treated with the telcagepant regimen.

Final data were available to analyze safety in 184 patients and efficacy in 105 patients.

Adverse events were reported within 48 hours of treatment by 17 of 98 patients on telcagepant (17%) and 9 of 86 patients on acetaminophen (10%), reported Dr. Tony Ho, senior director of clinical research at Merck Research Laboratories, North Wales, Pennsylvania, and his associates. Drug-related adverse events were reported by eight patients (8%) on telcagepant and four (5%) on acetaminophen. No patients stopped treatment because of adverse events.

Three serious vascular events –two reports of chest pain after telcagepant and one report of renal artery stenosis after acetaminophen –were sent for adjudication by a blinded independent expert committee. The committee declared all to be non-thromboembolic events, and each occurred longer than 48 hours after migraine treatment. No patients had transaminase elevations three times the upper limit of normal or higher.

The study did not find significant differences in efficacy, perhaps because of the small number of patients, the investigators suggested. No pain was reported in 13 (25%) of 52 patients 2 hours after taking telcagepant, compared with 10 (19%) of 53 patients on placebo.

When asked about those findings, Dr. Leslie Kelman, medical director of the Headache Center of Atlanta, said in an interview that it appears that the investigators showed in one of the studies that “there isn’t any significant risk from using telcagepant in patients” with CAD. “That’s a huge plus,” said Dr. Kelman, pointing out that clinicians do not prescribe triptans for patients who have had CAD because of the risks. “This could be an alternative for patients who can’t use triptans.”

A pooled analysis of single-attack data from three randomized, double-blind, placebo-controlled studies involving a total of 3,829 patients compared the efficacy of 140 mg or 150 mg of telcagepant, 280 mg or 300 mg of the drug, or placebo.

For migraine with aura, 21% of 230 patients on the lower doses of telcagepant and 28% of 222 patients on the higher doses were pain-free 2 hours after treatment, compared with 10% of 233 patients on placebo. For migraine without aura, 21% of 1,020 patients on lower-dose telcagepant, 24% of 1,019 patients on higher doses, and 10% of 996 patients on placebo were pain-free after 2 hours. Rates were higher for pain relief at 2 hours but similar between aura and no-aura subgroups.

For menstrually associated migraines, 52% of 216 patients on lower doses and 56% of 209 on higher doses were pain-free after 2 hours, compared with 29% of 221 patients on placebo. For non-menstrual migraines, 54% of 571 patients on lower doses, 60% of 557 on higher doses, and 33% of 557 on placebo were pain-free at 2 hours, Dr. Ho and his associates reported.

Among patients who reported that previous migraine treatment with a triptan was of “no use,” 62% of 343 patients on the lower doses of telcagepant and 56% of 339 on the higher doses were pain-free after 2 hours, compared with 39% of 346 patients on placebo.

Among patients who reported that previous treatment with a non-steroidal anti-inflammatory drug was of “no use,” 53% of 443 patients on lower-dose telcagepant, 57% of 418 on higher doses, and 26% of 484 patients on placebo were free of pain after 2 hours.

The investigators in this study “analyzed the sort of things we want to know,” said Dr. Kelman, who was not involved in the telcagepant studies but has been a speaker of Merck – the developer of telcagepant. “What sort of results do you get using telcagepant? But even more so, what are the results if you break down the data by certain groups – patients with aura, without aura, patients who have menstrual migraine versus those who don’t have menstrual migraine, or patients who have used a triptan before?

“The conclusion was that basically, no matter which group you look at, the results are very similar.”

A post-hoc analysis of data from a randomized, double-blind placebo-controlled trial suggests that patients with or without a prior response to opioid treatment for migraines might respond similarly to telcagepant. Among 111 patients who reported at least a 75% response to prior opioid therapy, 64% of those who took telcagepant 140 mg for a migraine attack and 69% on 280 mg were pain-free after 2 hours, compared with 54% on placebo.

Among 243 patients who reported less than a 75% response to prior opioid therapy, telcagepant brought pain relief at 2 hours in 54% of patients who received 140 mg and in 55% of patients on 280 mg, compared with 26% of patients on placebo. Among 1,163 patients with no history of opioid use for migraine, freedom from pain at 2 hours was reported by 60% on 140 mg telcagepant, 56% on 280 mg telcagepant, and 32% on placebo, Dr. Ho and his associates reported.

The findings require confirmation in prospective studies with larger numbers of patients, they suggested.

Thirty-six healthy recreational polydrug users were randomized in a double-blind, six-period crossover study to evaluate their liking for single doses of placebo or telcagepant 280 mg, 560 mg, 1,120 mg, or 1.5 mg or 3 mg of alprazolam as a positive control known to have abuse potential. Patient ratings on a Drug Liking visual analogue scale showed no significant differences between telcagepant and placebo, while alprazolam was ranked significantly higher than telcagepant or placebo, reported Rebecca Blanchard, Ph.D., also of Merck Research Laboratories, and her associates.

Combining telcagepant with ibuprofen or acetaminophen did not significantly change efficacy in a pilot randomized, double-blind, placebo-controlled study, reported Dr. David J. Hewitt of Merck Research Laboratories and his associates.

Pain freedom at 2 hours was reported by 35% of 145 patients who took telcagepant 280 mg plus ibuprofen 400 mg, 38% of 133 patients who took the same telcagepant dose plus acetaminophen 1,000 mg, 31% who got telcagepant alone, and 11% who received placebo.

Previous studies have suggested that adding naproxen or acetaminophen to sumatriptan or rizatriptan, respectively, significantly improved efficacy compared with triptan monotherapy, they noted.

 

 

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

洛杉矶(EGMN)——对随机、双盲、安慰剂或阳性对照研究进行的数项分析显示，用于治疗急性偏头痛的试验药telcagepant看似可被稳定性冠状动脉疾病患者所耐受，且对各种亚组患者均有效。

 

美国头痛学会年会上的5篇壁报论文中均公布了该结果，表明合并稳定性心血管病变的偏头痛患者使用此药进行急性治疗安全，而且无论患者偏头痛是否有先兆，是否与月经有关，以及是否有阿片类药物治疗史，该药均有效。

 

另有一项研究发现，telcagepant看似不受娱乐性多种药滥用者的欢迎，因此无滥用潜能。在另外一项分析中，telcagepant治疗辅以布洛芬或对乙酰氨基酚治疗后在疗效方面获得有统计学意义的显著改善。

 

这些研究由默克公司员工领导完成，该公司正在研发telcagepant，对上述研究给予了资助。

 

先前的研究已表明，口服的降钙素基因相关肽(CGRP)受体拮抗剂telcagepant治疗急性偏头痛很有效(Neurology 2009;73:970-7; Lancet 2008;372:2115-23; Neurology 2008;70:1304-12)。

 

默克之前也一直在开发该药作为偏头痛预防性用药的适应证，但在某些患者服用该药(每天2次)3个月后发生肝酶水平升高时停止了这些试验，公司的一位女发言人在会后的电子邮件采访中说。继与美国食品药品管理局(FDA)在2009年底商谈后，默克公司今年在监管部门对该药进一步考虑前又开展了一项安全性研究，目前仍在进行之中。该试验以4,500位月经相关性偏头痛女性为受试者，分为140 mg telcagepant治疗组和安慰剂处置组，每天服用1次，连续服用7天为1个疗程，每月1个疗程。

 

在一项双盲、交叉研究中，合并稳定性冠状动脉病变(CAD)的患者被随机分配至其中1个治疗组中。第一组患者中，有12例中、重度偏头痛患者在6周治疗期内服用telcagepant：一片280 mg的片剂加1粒300 mg的胶囊，随后在下一个6周的治疗期内使用1,000 mg对乙酰氨基酚又治疗了12例偏头痛。在第二组中，首例中、重度偏头痛发作的患者接受安慰剂处置，随后在第一个6周治疗期内使用对乙酰氨基酚又治疗了11例偏头痛；在第二个6周治疗期内，对12例偏头痛采用telcagepant治疗方案进行治疗。

 

最后的安全性数据分析中共有184例患者，疗效分析中有105例患者。

 

宾夕法尼亚州北威尔士默克研究实验室临床研究高级主管Tony Ho博士及其同事报告称，在治疗48 h内，98例telcagepant治疗组中有17例(17%)、86例对乙酰氨基酚治疗组患者中有9例(10%)报告了不良事件。Telcagepant治疗组中有8例(8%)、对乙酰氨基酚治疗组中有4例(5%)报告了药物相关的不良事件。无患者因不良事件而停药。

 

有3例严重的血管事件被送至独立专家委员会接受盲法裁定，其中包括2例服用telcagepant后发生胸痛的报告，1例服用对乙酰氨基酚后发生肾动脉狭窄的报告。该委员会声明上述所有报告均为非血栓栓塞性事件，每例均发生于治疗偏头痛后48 h以上。所有患者均未出现转氨酶水平的升高超出正常上限2倍或2倍以上。

 

该研究未发现在疗效上有显著差异，可能是因为受试者例数较少，研究者表示。52例患者在服用telcagepant后2 h有13例无疼痛报告(25%)，而53例安慰剂对照组患者中有10例(19%)。

 

亚特兰大头痛中心医学主管Leslie Kelman博士在一次访问中被问及这些研究结果时说，研究者在其中一项研究中指出，合并CAD的偏头痛患者“使用telcagepant无任何明显的风险”。Kelman博士说：“这是一个巨大的收获”，同时指出临床医生考虑到风险，不为CAD患者开具曲坦类药。“此药可能是不能使用曲坦类药物者的一个治疗选择。”

 

对3项随机、双盲、安慰剂对照研究中单次发作的数据进行汇总分析(包括3,829例患者)，比较140 mg或150 mg、280 mg或300 mg telcagepant或安慰剂的疗效。

 

对于有先兆的偏头痛，230例服用较低剂量telcagepant的患者中有21%、222例服用较高剂量患者中有28%在治疗后2 h疼痛消失，而233例安慰剂对照组患者中有10%获得此效果。对于无先兆的偏头痛，1,020例服用较低剂量telcagepant的患者中有21%、1,019例服用较高剂量患者中有24%在治疗后2 h疼痛消失，而996例安慰剂对照组患者中有10%获得此效果。有先兆与无先兆偏头痛亚组2 h时疼痛缓解率均较高，无组间差异。

 

Ho博士及其同事报告指出，对于月经相关性偏头痛，216例服用较低剂量的患者中有21%、209例服用较高剂量患者中有56%在治疗后2 h疼痛消失，而221例安慰剂对照组患者中有29%获得此效果。对于非月经性偏头痛，571例服用较低剂量的患者中有54%、557例服用较高剂量患者中有60%在治疗后2 h疼痛消失，而557例安慰剂对照组患者中有33%获得此效果。

 

在报告先前接受曲坦类药物治疗偏头痛“无效”的患者中，343例服用较低剂量telcagepant的患者中有62%、339例服用较高剂量患者中有56%在治疗后2 h疼痛消失，而346例安慰剂对照组患者中有39%获得此效果。

 

在报告先前接受非甾体类抗炎药治疗“无效”的患者中，443例服用较低剂量telcagepant的患者中有53%、418例服用较高剂量患者中有57%在治疗后2 h疼痛消失，而484例安慰剂对照组患者中有26%获得此效果。

 

Kelman博士说，本研究的研究者“分类分析了我们想知道的情况”，他本人未参与telcagepant研究，但一直担任telcagepant的研发商——默克公司的发言人。“使用telcagepant你会得到哪些类型的结果？不仅如此，如果你把数据再做细分——有前兆与无先兆患者，有月经性偏头痛与无月经性偏头痛患者，或有曲坦类药物服用史的患者——你会得到什么结果？”

 

“结论为，基本上，无论你观察何组，结果均非常相近。”

 

对随机、双盲、安慰剂对照试验的事后分析结果显示，既往应用阿片类药物治疗偏头痛有效或无效的患者应用telcagepant治疗可能有相近的疗效。在111例报告对既往阿片类药物治疗至少达到75%疗效的患者中，服用140 mg telcagepant治疗偏头痛发作的患者中有64%、280 mg治疗组中有69%在2 h后疼痛消失，相比之下，安慰剂对照组有54%。

 

在243例报告既往阿片类药物治疗疗效不足75%的患者中，140 mg telcagepant治疗组有54%、280 mg治疗组中有55%的患者在2 h时疼痛获得缓解。Ho博士及其同事报告称，在1,163例既往未应用阿片类药物治疗偏头痛的患者中，140 mg telcagepant治疗组有60%、280 mg治疗组中有56%、安慰剂对照组有32%在2 h时疼痛消失。

 

上述研究结果需要通过纳入较大宗病例的前瞻性研究加以验证，他们指出。

 

在一项双盲、6个周期的交叉性研究中，36位健康的娱乐性多种药物滥用者被随机分组，旨在评估对单剂安慰剂或telcagepant 280 mg、560 mg、1,120 mg或阿普唑仑(已知具有滥用潜能的药物，作为阳性对照)1.5 mg、3 mg的偏爱。Blanchard博士及其同事报告说，应用药物偏爱视觉类似物量表对患者进行分级显示，telcagepant与安慰剂之间无显著差异，而阿普唑仑的偏爱级别显著高于telcagepant和安慰剂，默克研究实验室Rebecca。

 

默克研究实验室的David J. Hewitt博士及其同事报告称，一项前导性、随机、双盲、安慰剂对照研究表明，telcagepant联合布洛芬或对乙酰氨基酚并未显著提高疗效。

 

145例服用telcagepant 280 mg配伍布洛芬 400 mg治疗的患者中，有35%报告在用药后2 h时疼痛消失，而133例服用相同剂量的telcagepant配伍对乙酰氨基酚1,000 mg的患者中有38%、单纯telcagepant治疗者中有31%、接受安慰剂处置者中有11%获此疗效。

 

先前研究已表明，相对于曲坦类药单药治疗，舒马曲坦或利扎曲坦分别辅以萘普生或对乙酰氨基酚可显著提高疗效，他们指出。

 

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