作者：Allison Gandey
出處：WebMD醫學新聞
December 6, 2009（麻州波士頓）－來自兩項隨機分派、雙盲、安慰劑控制研究結果顯示，使用brivaracetam有兩個不同的結論。一項研究顯示，這個實驗性藥物，結構與levetiracetam相似，可以誘發局部發作癲癇。然而，由同一團隊進行的另一項研究顯示，主要療效終點並未達到統計上顯著差異。這些研究結果都發表在美國癲癇醫學會第63屆科學座談會議上。
主要作者小岩城阿肯色癲癇計畫的Victor Biton醫師向Medscape神經學表示，這些研究結果讓研究者們摸不著頭緒，我個人則是感到震驚。他說，一開始研究結果是這麼地有潛力，且這是我共事過最好的藥物。我想這個藥物將順利通過這些評估。
Brivaracetam是一種突觸囊泡蛋白2A接合子，屬於racetam衍生物，具有抗癲癇藥物性質。UCB Pharma是levetiracetam（Keppra）的製造廠商，他們研發這個藥物。
研究者們進行了兩項前瞻性、多中心研究，一項在北美、澳洲、與拉丁美洲進行，另一項則在歐洲與亞洲進行。
每個研究收納將近400位罹患對治療反應不佳局部發作型癲癇患者。研究者們隨機分派大約100位病患到每項研究的分支。在美國進行研究的病患接受安慰劑或每天兩次的brivaracetam 20、50或100 mg。病患在這兩項研究中都接受治療達12週。
受試者們年齡介於16~70歲。在接受篩選前，3個月內至少發生2次局部發作性癲癇。在前瞻性8週的試驗前階段，受試者們發作超過8次以上，且同時併用1或是2種抗癲癇藥物。研究者們限制20%病患使用levetiracetam。
Biton醫師與其團隊報告在美國進行的研究主要試驗終點都達到統計上顯著差異。他們觀察到，相較於安慰劑，接受50 mg劑量組的病患，每週發生局部癲癇的頻率顯著下降。然而，他們也看到5 mg劑量組癲癇頻率上升。
在歐洲進行的研究中，研究者們報告癲癇下降率並未達統計上顯著差異。
表一、在美國進行的研究：相較於安慰劑，局部發作癲癇率下降。
Brivaracetam 劑量， mg | 下降百分比 % | P 值 |
5 | -0.9 | .885 |
20 | 4.1 | .492 |
50 | 12.8 | .025 |
表二、在歐洲與亞洲進行的研究：相較於安慰劑，局部發作癲癇率下降。
Brivaracetam 劑量， mg | 下降百分比 % | P 值 |
20 | 6.8 | .239 |
50 | 6.5 | .261 |
100 | 11.7 | .037 （沒有適當地控制多樣性；並未呈現其他數字） |
造成這樣不同結果的原因仍然不明，但是Biton醫師表示這可能有許多原因。有時候研究中不同的結果，並沒有合乎邏輯的解釋。有時候你重複進行同樣的研究，卻會得到不同的結果。
在這個例子中，Biton醫師懷疑這項研究的不同劑量可能扮演角色。在歐洲進行研究的安慰劑組中，我們也有很強的表現，那是我們沒有預期到的。
在訪談中，北卡羅萊納州羅利UCB Pharma臨床計畫主任Zhihong Lu醫師表示，該公司正與美國食品藥物管理局及歐洲醫藥署討論下一步。她現在無法進一步談論細節。
Biton醫師說另一項研究是可能的。
這兩項研究中，次級研究終點結果比較一致。相較於安慰劑組，較高劑量brivaracetam達50%反應比例顯著較高。在美國進行的試驗中，50mg劑量組的效果最好（32.7%；P=0.008）。在歐洲進行的研究中，100 mg劑量組有最好的表現（36%；P=0.023）。
在發表這些結果會議的壁報座談中，聽眾對研究者們提出了許多問題。他們大部分的問題都是為什麼有這樣的差異？Biton醫師表示，他希望在未來的研究中回答這個問題。
這項研究由UCB Pharma公司資助。該公司參與這項研究的設計、數據執行、收集、管理、準備以及檢視壁報。
Conflicting Results for Brivaracetam in Partial-Onset Seizures
By Allison Gandey
Medscape Medical News
December 6, 2009 (Boston, Massachusetts) — Results from 2 randomized, double-blind, placebo-controlled trials of brivaracetam have come to 2 very different conclusions. One trial suggests that the experimental drug, structurally similar to levetiracetam, can reduce partial-onset seizures. However, another trial conducted by the same research team did not achieve statistical significance on the primary efficacy endpoint. The results were presented here at the American Epilepsy Society 63rd Annual Scientific Conference.
The findings have left investigators scratching their heads. "I was personally shocked," lead researcher Victor Biton, MD, from the Arkansas Epilepsy Program in Little Rock, told Medscape Neurology. "Initial study results were so promising, and this was the best drug I was working with," he said. "I thought it would sail through these evaluations."
Brivaracetam is a synaptic vesicle protein 2A ligand. It is a racetam derivative with anticonvulsant properties. UCB Pharma, the maker of levetiracetam (Keppra), is developing the drug.
Investigators conducted 2 prospective, multicenter trials. One study took place in North America, Australia, and Latin America, the second in Europe and Asia.
Each trial included about 400 people with refractory partial-onset seizures. Investigators randomized roughly 100 participants to each arm of the study. Patients in the Americas study received placebo or twice-daily brivaracetam, 5, 20, or 50 mg. Patients in the Europe and Asia study received placebo or brivaracetam, 20, 50, or 100 mg. Patients were treated for 12 weeks in both studies.
Participants were 16 to 70 years of age. They had 2 or more partial-onset seizures in the 3 months before screening. Participants had 8 or more seizures during the 8-week prospective baseline and were taking 1 or 2 concomitant antiepileptic drugs. Investigators limited levetiracetam use to 20% of randomized patients.
I was personally shocked.
Dr. Biton and his team report the Americas trial achieved statistical significance on the primary endpoint. They observed a reduction in partial-onset seizure frequency per week over placebo in the 50-mg dose. However, they also saw an increase in seizures in the 5-mg dose.
In the European trial, investigators report that the reduction in seizures was not statistically significant.
Table 1. Americas Trial: Reduction Over Placebo in Partial-Onset Seizures
| Brivaracetam Dose, mg | Reduction, % | P Value |
| 5 | ?0.9 | .885 |
| 20 | 4.1 | .492 |
| 50 | 12.8 | .025 |
Table 2. Europe and Asia Trial: Reduction Over Placebo in Partial-Onset Seizures
| Brivaracetam Dose, mg | Reduction, % | P Value |
| 20 | 6.8 | .239 |
| 50 | 6.5 | .261 |
| 100 | 11.7 | .037 (without appropriate controls for multiplicity;
other number not presented) |
Reasons for the divergent findings are not clear, but Dr. Biton says it could be any number of things. "Sometimes there is no logical explanation for conflicting results in studies," he said. "Sometimes you repeat the same study and get very different results."
In this case, Dr. Biton suspects that the different doses in the study might have played a role. "We also had a very strong showing in our placebo group in the European study, and that is something we would not have predicted."
Asked by
Medscape Neurology to comment on the trials, Patricio Espinosa, MD, from the International Center on Neurosciences in Mandeville, Louisiana, said the results suggest that brivaracetam will fall short of its predecessor. "Levetiracetam is a great drug. It is effective, has few interactions, and a reasonable safety profile," he said.
Investigators report that 15% of patients taking brivaracetam experienced somnolence, another 14% had dizziness, close to 9% had fatigue, and more than 6% had influenza. Four deaths occurred during the trials — 2 patients were taking brivaracetam. One died from acute respiratory failure, and the other died of brain hypoxia.
"These deaths are worrisome," Dr. Espinosa said.
During an interview, Zhihong Lu, MD, clinical program director at UCB Pharma in Raleigh, North Carolina, said the company is talking with the US Food and Drug Administration and the European Medicines Agency about the next steps. She was not able to discuss the details.
Dr. Biton says another study is likely.
Results from the secondary endpoint were more consistent between the 2 trials. There was a statistically significant 50% responder rate versus placebo for the higher doses of brivaracetam. In the Americas trial, the 50-mg dose worked best (32.7%,
P = .008). In the European trial, the 100-mg dose had the strongest showing (36%,
P = .023).
At the poster session at the meeting, where these results were presented, attendees had many questions for investigators. The basis for most of their questions — why the discrepancy?
Dr. Biton says he hopes to answer that in time with further study.
This study was funded by UCB Pharma. The company was involved in the design and conduct of the study, collection, management, and analysis of the data, and preparation and review of the poster.
American Epilepsy Society (AES) 63rd Annual Scientific Conference: Poster 1.216. Presented December 5, 2009.
