superman

作者：Caroline Helwick  
出處：WebMD醫學新聞

　　May 20, 2010 (紐澳良) — 根據發表於美國胸腔協會2010年國際研討會中的第3b期隨機控制試驗，單株抗體omalizumab當作標準治療的輔助治療時，可顯著減少中度到嚴重過敏性氣喘患者的惡化，Omalizumab也可改善氣喘相關的生活品質。
　　
　　威斯康辛大學的William W. Busse醫師在最新發表中指出，在氣喘照護的第5和第6階段加入omalizumab可以減少風險且改善氣喘相關生活品質。
　　
　　在會中發表的其他研究中，omalizumab 在使用超過7年時仍有效，且與減少健康照護的使用有關。
　　
　　【第3b期研究確認效果】
　　這項第3b期研究包括了850名中度到重度氣喘病患，定義是過去一年內，雖有使用高劑量吸入型皮質類固醇(HDIC)和長效乙型致效劑治療，仍發生至少1次氣喘惡化。將近三分之二的病患也使用第三種控制藥物，包括長期口服皮質類固醇。
　　
　　使用穩定型HDIC和長效乙型致效劑(需要時加入其他控制劑)的病患，被隨機分派接受omalizumab或安慰劑治療48週，之後每月進行評估。每2- 4週以皮下方式給予Omalizumab 150 -375 mg；劑量與頻率則是根據開始時的血清總免疫球蛋白E和體重而定。
　　
　　主要結果是48週omalizumab治療期間的氣喘惡化比率，定義為需要全身性皮質類固醇至少3 天、或口服皮質類固醇劑量比開始時增加至少20-mg且至少3天。次要結果是氣喘症狀分數、急救藥品的使用噴數、氣喘相關生活品質。
　　
　　兩組的人口統計學資料相似，平均年紀約為45歲，平均氣喘期間為24年，平均一秒內用力呼氣量預測百分比為65%、過去一年的平均惡化次數為2次、過去一年約有10%曾因為氣喘住院。在12個月時，約三分之一只有接受HDIC和長效乙型致效劑，幾乎半數需要另一個控制劑(除了口服皮質類固醇之外)，17%需要至少4次口服皮質類固醇療程。
　　
　　48週結束時，約80%的安慰劑組和85%的omalizumab組依舊參與研究。
　　
　　【使用Omalizumab減少了25%的惡化】
　　48週時，omalizumab組顯示比安慰劑組減少了25%的惡化。Busse醫師報告指出，研究協定定義的惡化率分別是0.66%和0.88% (P= .0058)。
　　
　　Omalizumab組發生初次氣喘惡化的時間也顯著延後(P< .05)，除了需要口服皮質類固醇的病患之外，所有病患都有治療效果(P= .79)。
　　
　　接受omalizumab的病患其「氣喘生活品質問卷」分數也顯著改善，各方面都比開始時有顯著改變(P< .01)，平均整體改變在安慰劑組為1.0，omalizumab組為1.2 (P= .0047)。
　　
　　兩組的急救藥物需求都減少，但是接受omalizumab的病患更顯著(P= .0904)，omalizumab組的整體氣喘分數改變也顯著較大(P= .0379)。
　　
　　在探索性分析中，加入omalizumab與吐氣一氧化氮濃度顯著減少有關，Busse醫師報告指出，這是氣喘發炎的一個標記。
　　
　　安慰劑組有79.5%的副作用報告，omalizumab組為80.4%，嚴重副作用報告比率則分別是10%和9.3%，急性期反應或血小板過低的發生率沒有差異。
　　
　　無法使用吸入型皮質類固醇適當控制時，現行的中度到嚴重氣喘標準照護是加入一個長效型乙型致效劑和/或另一個控制劑。Busse醫師向媒體指出，該研究中，如果病患病情依舊難以控制時，讓他們接受長期口服皮質類固醇，作為最後選擇。
　　
　　他解釋，使用omalizumab (美國食品藥物管理局核准)限用於嚴重疾病，主要是因為費用考量。結果，它都是在最惡化、住院等風險最高的病患進行研究，他估計，至少有20%的氣喘病患落入此類別。
　　
　　他表示，這篇研究發現確認了國家心臟、肺臟與血液研究中心專家小組報告第3版(National Heart, Lung and Blood Institute Expert Panel Report 3，NHLBI EPR-3)的現行治療建議，在第5和第6階段氣喘照護仍有症狀的病患，可以從omalizumab輔助治療獲益。
　　
　　【長期效果─減少健康照護之使用】
　　在海報討論會議中，瑞士研究者報告指出，根據對接受該藥物達7年的7名嚴重皮質類固醇依賴型氣喘病患的研究，長期使用omalizumab是安全且有效的。Omalizumab減少了氣喘惡化，也減少了抗生素、噴霧劑治療、口服皮質類固醇的使用，效果在使用4年後最明顯。不過，根據來自瑞士Davos Dutch氣喘中心的研究者表示，一旦病患停用藥物，免疫調節的療效即消失。
　　
　　波蘭的研究者進行了一個隨機開放標籤研究，共有404名病患，發現因為惡化的住院率減少67% (P= .037)、急診就醫比率減少60%(P< .001)、住院天數縮短(P= .007)。
　　
　　全球氣喘創議組織主席、安大略漢彌爾頓McMaster大學的Paul O'Byrne醫師為Medscape Pulmonary Medicine對這些研究發表評論時表示，我們現在獲得omalizumab的長期效果與安全性資料，顯示它很有效且安全，但是，我們現在發現，免疫效果並非如我們所希望般永久改變，當你停藥，症狀又出現。
　　
　　他接著表示，因為開銷的關係，在多數國家中，使用omalizumab 相當清楚地限制於重症患者，也就是說，那些健康照護費用負擔較大者，在這類病患中，有清楚的治療利益，在多數極限情況下，成本效益研究顯示其使用有正當理由。
　　
　　Novartis藥廠支持這些臨床試驗，Busse醫師報告接受Novartis藥廠的資金支持與顧問費用，O'Byrne醫師宣告沒有相關財務關係。
　　
　　美國胸腔協會(ATS)2010年國際研討會：摘要A5405。發表於2010年5月19日。


Benefits Shown for Omalizumab in Uncontrolled Asthma

By Caroline Helwick
Medscape Medical News

May 20, 2010 (New Orleans, Louisiana) — As add-on therapy to standard treatment, the monoclonal antibody omalizumab significantly reduced exacerbations in patients with moderate to severe allergic asthma. Omalizumab also improved asthma-related quality of life, according to a phase?3b randomized controlled trial presented here at the American Thoracic Society 2010 International Conference.

"The addition of omalizumab to patients at steps?5 and 6 of asthma care reduced risks and improved asthma-related quality of life," reported William W. Busse, MD, from the University of Wisconsin, Madison, in a late-breaking presentation.

In other studies reported at the meeting, omalizumab was effective over 7 years of use, and was associated with a reduction in healthcare use.

Efficacy Validated in Phase?3b Study

The phase?3b study consisted of 850 patients with moderate to severe asthma, defined as the occurrence of at least 1 asthma exacerbation in the previous year, despite treatment with high-dose inhaled corticosteroids (HDIC) and a long-acting beta-agonist. Nearly two thirds of patients also used a third controller medication, including chronic oral corticosteroids.

Patients on stable HDIC and a long-acting beta-agonist (and additional controllers if necessary) were randomized to receive omalizumab for 48 weeks or placebo, and were then assessed monthly. Omalizumab 150 to 375?mg was given subcutaneously every 2 to 4 weeks; dosage and frequency were determined by baseline serum total immunoglobulin?E and body weight.

The primary outcome was rate of asthma exacerbations during the 48 weeks of omalizumab treatment requiring systemic corticosteroids for at least 3 days or at least a 20-mg increase in oral corticosteroids over baseline for at least 3 days. Secondary outcomes were asthma symptom scores, number of puffs of rescue medication, and asthma-related quality of life.

The groups were similar with regard to demographics. Mean age was approximately 45 years, mean duration of asthma was 24 years, mean percent predicted forced expiratory volume in 1 second was 65%, the mean number of exacerbations in the previous year was 2, and about 10% had been hospitalized for asthma in the previous year. About one third were receiving only HDIC and a long-acting beta-agonist, nearly half needed another controller (excluding oral corticosteroids), and 17% required at least 4 oral corticosteroid courses in 12 months.

At the end of 48 weeks, approximately 80% of the placebo group and approximately 85% of the omalizumab group remained in the study.

Exacerbations Reduced by 25% With Omalizumab

At 48 weeks, the omalizumab group demonstrated a 25% reduction in exacerbations, compared with placebo. The protocol-defined exacerbation rates were 0.66% and 0.88%, respectively (P?= .0058), Dr. Busse reported.

Time to first asthma exacerbation was also significantly delayed with omalizumab (P?< .05). Treatment benefit was seen in all patients except those requiring oral corticosteroids (P?= .79).

Patients receiving omalizumab also experienced a statistically significant improvement in Asthma Quality of Life Questionnaire scores, with significantly greater changes observed over baseline at all time points (P?< .01). Mean change overall was 1.0 for placebo and 1.2 for omalizumab (P?= .0047), he reported.

A reduction in the need for rescue medication was observed in both groups, but was significantly greater in patients receiving omalizumab (P?= .0904). Change in total asthma symptoms score was also significantly greater with omalizumab (P?= .0379).

In an exploratory analysis, the addition of omalizumab was associated with significant reductions in the fractional concentration of exhaled nitric oxide, a marker of inflammation in asthma, Dr. Busse added.

Adverse events occurred in 79.5% of the placebo group and 80.4% of the omalizumab group, with serious adverse events reported in 10% and 9.3%, respectively. There was no difference in the occurrence of acute-phase reactions or thrombocytopenia.

The current standard of care for moderate to severe asthma that is inadequately controlled by inhaled corticosteroids is the addition of a long-acting beta-agonist and/or another controller medication. In this study, when patients remained refractory, they were allowed to receive chronic oral corticosteroids "as a last resort," Dr. Busse told the media.

Use of omalizumab (and US Food and Drug Administration approval) has been restricted to severe disease, primarily because of cost concerns, he explained. "As a consequence, it has been studied in patients with the most exacerbations, hospitalizations, and so forth — the group at greatest risk." He estimated that at least 20% of asthma patients fall into this category.

The findings "validate the current treatment recommendations" of the National Heart, Lung and Blood Institute Expert Panel Report?3 (NHLBI EPR-3), he said, which are that patients at steps?5 and 6 of asthma care who remain symptomatic might benefit from omalizumab add-on therapy.

Long-Term Benefit, Reduction in Healthcare Use

At a poster discussion session, Swiss investigators reported that long-term use of omalizumab was safe and effective, according to a study of 7 severe corticosteroid-dependent asthmatics who received the drug for 7 years. Omalizumab reduced asthma exacerbations and the use of antibiotics, aerosol therapy, and oral corticosteroids, with the effects most evident after 4 years of use. Once patients discontinued the drug, however, the beneficial immunomodulatory effects disappeared, according to investigators from the Dutch Asthma Centre in Davos, Switzerland.

Investigators from Poland conducted a randomized open-label study of 404 patients and found a 67% reduction in the rate of hospitalizations for exacerbations (P?= .037), a 60% reduction in visits to the emergency department (P?< .001), and shorter hospitalizations (P?= .007).

Paul O'Byrne, MD, from McMaster University in Hamilton, Ontario, who is chair of the Global Initiative for Asthma, commented on these findings for Medscape Pulmonary Medicine. "We are now getting long-term efficacy and safety data for omalizumab, which is showing it to be very effective and safe," he said, "but we learned today that the immune effects are not permanently altered, as we had hoped they would be. When you stop the drug, they come back."

"Because of its expense, in most countries, [the use of] omalizumab has been very clearly limited to the severe end of the spectrum, that is, patients whose disease carries a large healthcare cost," he continued. "In this population, there is evidence of clear benefit and, at the most extreme end, the cost-benefit studies show justification for its use."

The clinical trials were supported by Novartis. Dr. Busse reports receiving grant support and consulting fees from Novartis. Dr. O'Byrne has disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2010 International Conference: Abstract?A5405. Presented May?19, 2010.