A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)
A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)
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DOI：
10.3310/hta19780
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发表时间：
2015-10-01
影响因子：
3.6
通讯作者：
Reeves, Barnaby C.
中科院分区：
文献类型：
--
作者：
Chakravarthy, Usha;Harding, Simon P.;Reeves, Barnaby C.
工作背景：贝伐单抗（Avastin（R），Roche）用于癌症治疗，是雷珠单抗（Lucentis（R），Novartis）用于治疗新生血管性年龄相关性黄斑变性（nAMD）的“母体”分子。文献中有关于贝伐珠单抗治疗nAMD的有效性的报告，但没有试验。贝伐单抗每剂量的成本约为雷珠单抗的5-10%。目的：比较雷珠单抗和贝伐单抗两种治疗方案治疗nAMD的临床疗效和成本效果。设计图：多中心、析因随机对照试验，从英国NHS的角度进行试验内成本效用和成本最小化分析。参与者、卫生专业人员和研究人员对药物分配不知情，但对方案不知情。计算机生成的随机分配到雷珠单抗或贝伐单抗的组合，以及连续或不连续的方案，按中心分层，封闭和隐藏。在糖尿病视网膜病变早期治疗研究中测量的最佳矫正远视力（BCVA）≥ 25个字母的研究眼活动性nAMD患者≥ 50岁（ETDRS）图表。排除标准为nAMD既往治疗、长期存在的疾病、病变直径> 6000 μ m、中心凹处的浓血和任何其他混淆性眼部疾病。每名参与者的一只眼睛进行了研究，另一只眼睛根据常规护理进行治疗，如果需要的话。干预措施：雷珠单抗和贝伐单抗是商业采购。剂量为雷珠单抗0.5 mg或贝伐单抗1.25 mg。重新包装的贝伐珠单抗质量有保证。所有受试者均在访视0、1和2时接受治疗。此后，随机分配至连续治疗方案的受试者每月接受一次治疗。随机分配至不连续方案的受试者在访视2后不得再次接受治疗，除非符合预先规定的活动性疾病标准。如果需要再治疗，则在3个月内每月注射一次。主要结果测量：主要结果是BCVA。非劣效性界值为3.5个字母。次要结局为对比敏感度、近视力、阅读指数、新生血管病变形态、一般和疾病特异性患者报告结局，包括黄斑疾病特异性生活质量、无治疗失败生存率、资源使用、质量调整生命年（Qs）和新发地图状萎缩（GA）（试验期间增加结局）。结果报告的研究眼，除了患者报告outcomes.Results：2008年3月27日和2010年10月15日之间，610名参与者进行分配和治疗（314雷珠单抗，296贝伐单抗;在3个月，305连续，300不连续）。2年后，贝伐珠单抗既不劣于也不劣于雷珠单抗[-1.37个字母，95%置信区间（CI）-3.75至+1.01个字母]，间断治疗既不劣于也不劣于连续治疗（-1.63个字母，95% CI -4.01至+0.75个字母）。不同药物组的中央凹病变厚度相似[几何平均值比（GMR）0.96，95% CI 0.90 - 1.03; p = 0.24]，但连续治疗组低9%（GMR 0.91，95% CI 0.85 - 0.97; p = 0.004）。试验期间发生新GA的几率与药物相似[比值比（OR）0.87，95% CI 0.61至1.25; p = 0.46]，但连续治疗显著更高（OR 1.47，95% CI 1.03至2.11; p = 0.033）。不同药物的安全性结局无差异，但连续治疗的死亡率较低（OR 0.47，95% CI 0.22 - 1.03; p = 0.05）。与连续贝伐单抗相比，连续雷珠单抗每QALY的成本为350万磅;与不连续贝伐单抗相比，连续贝伐单抗每QALY的成本为30，220磅。这些结果在敏感性分析中是稳健的。结论：雷珠单抗和贝伐单抗具有相似的疗效。停止治疗并在需要时重新开始治疗会导致疗效稍差。间断治疗的安全性更差，尽管连续治疗更常发生新的GA。雷珠单抗并不具有成本效益，尽管与20，000磅/QALY阈值的间断贝伐珠单抗相比，仍然不确定连续贝伐珠单抗是否具有成本效益。未来的研究应关注两种药物的眼部安全性，进一步优化治疗方案和停止治疗的标准。
Background: Bevacizumab (Avastin (R), Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis (R), Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.Objective: To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD. Design: Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.Setting: Twenty-three ophthalmology departments in NHS hospitals.Participants: Patients >= 50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) >= 25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter > 6000 mu m, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.Interventions: Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5 mg or bevacizumab 1.25 mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.Main outcome measures: The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.Results: Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [ geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p = 0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p = 0.004). Odds of developing new GA during the trial were similar by drug [ odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p = 0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p = 0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p = 0.05). Continuous ranibizumab cost 3.5M pound per QALY compared with continuous bevacizumab; continuous bevacizumab cost 30,220 pound per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.Conclusions: Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at 20,000 pound per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment.