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随机试验的结果显示，相较于安慰剂，对于肌萎缩性脊髓侧索硬化症(amyotrophic lateral sclerosis，ALS)病患来说，第1型类胰岛素成长因子(IGF-1)对于延缓疾病恶化没有疗效。
之前两个第三期IGF-1用于ALS试验的结果互异，一个在北美进行的试验显示有好处，另一个欧洲试验则未确认之前的发现。
主要研究者、梅约诊所的Eric J. Sorenson医师结论表示，我们的研究结果大致上像之前的欧洲研究，对于存活或者功能都没有好处。令人失望的是，我们无法确认北美研究所提的好处。
目前的研究结果登载于11月25日的神经学期刊中。
【突破僵局的研究】
作者写道，在运动神经元培养中，IGF-1显示对于促进胚胎运动神经元存活与减少它们对于谷氨酸盐引起的神经毒性有效。在动物模式中，IGF-1 延迟运动神经元细胞死亡。
他们写道，之前此药剂用于ALS病患的两个第三期试验结果不一致。第一个是北美的ALS IGF-1 Study Group，发表于1997年(Neurology. 1997;49:1621-1630)，发现有治疗好处；不过，一年后发表的欧洲ALS/IGF-1 Study Group并未确认此一好处(Neurology 1998;51:583-586).
Sorenson医师在访问中向Medscape Neurology & Neurosurgery表示，至于北美试验的研究发现强度，Cephalon公司采取一个不同于美国食品药物管理局(FDA)核准的新的IGF-1给药方式，但是FDA并未接受且要求更多资料。
他表示，因为一些合法原因，它被放在次要类别，但是它的确是有关ALS的基本努力，需要另一个研究看它是否得到明确答案；我们的研究变成突破僵局的研究，有点介于之前的两个第三期研究之间。
总共招募来自美国20个医学中心的330名ALS病患，随机分派接受0.05 mg/kg 的合成IGF-1、每天皮下给药两次，或者给予安慰剂，为期两年。Sorenson医师表示，所用的剂量和之前试验中的高剂量组一样，我们试着尽可能重现它们，但是用更简单的方法厘清药物有无效果；新研究的治疗时间也更长：为期两年而非原本的九个月。
本试验的初级终点测量为病患徒手肌力检查(MMT)分数的改变，次级终点包括无气切存活与改版ALS功能量表分数的改变；进行治疗意向分析。
整体在两年时的平均MMT分数改变为每个月0.41单位，两组之间没有差异(治疗组为每月0.44单位，安慰剂组为每月0.39单位；P= .529)。
次级终点也没有差异。他们指出，使用其他分析与继续治疗都未能改变结果；作者写道，全部都是负面结果，和安慰剂没有差别。
他们指出，大部份病患之治疗是安全且耐受良好的；最常见的严重不良反应是与疾病并不太有关的血栓性栓塞症(thromboembolism)，不过试验终点时并无显著差异。作者指出，一如预期也发生过低血糖，是因为IGF-1类似胰岛素的性质。
他们写道，有趣的是，我们也发现四个视网膜动脉阻塞案例，之前ALS临床试验中没有报告过的不良反应。
【新给药方式的希望？】
Sorenson医师表示，虽然这很令人失望，至少它很清楚且就这个药物策略提出一个明确答案，不过，他指出，仍有许多证据指出，IGF-1这个方向对ALS患者会有帮助，只是我们目前还没找到答案。
他表示，新的IGF-1给药方式现在正在研究中，包括使用病毒调节剂或者干细胞。
本研究由国家健康研究中心与ALS学会支持。研究药物与安慰剂由Cephalon公司提供。作者宣称没有相关资金上的往来。
No Benefit of Treatment With IGF-1 in ALS
By Susan Jeffrey
Medscape Medical News
Results of a randomized trial have shown no benefit of treatment with insulin-like growth-factor type?1 (IGF-1) in slowing progression of disease, compared with placebo, among patients with amyotrophic lateral sclerosis (ALS).
Two previous phase?3 trials of IGF-1 in ALS showed inconsistent results: 1 trial, carried out in North America, did find a benefit, whereas the other, a European trial, did not confirm the earlier findings.
"The results of our study most resemble those of the previous European study, with no benefit in either survival or functional scales," the researchers, led by Eric J. Sorenson, MD, from the Mayo Clinic, Rochester, Minnesota, conclude. "It is disappointing that we were unable to confirm the benefit that was noted in the previous North American study."
The current results are published in the November 25 issue of Neurology.
Tie-Breaker Study
In motor neuron cultures, IGF-1 has been shown to be effective in enhancing the survival of embryonic motor neurons and reducing their susceptibility to glutamate-induced neurotoxicity, the authors write. In animal models, IGF-1 delayed motor neuron cell death.
The 2 previous phase?3 trials of this agent in patients with ALS were inconsistent, they write. The first, by the North America ALS IGF-1 Study Group, published in 1997 (Neurology. 1997;49:1621-1630), found a benefit with treatment; however, this benefit was not confirmed by the European ALS/IGF-1 Study Group, who published a year later (Neurology 1998;51:583-586).
On the strength of the North American trial findings, Cephalon took a new drug application for IGF-1 to the US Food and Drug Administration (FDA), but the FDA was not convinced and asked for more data, Dr. Sorenson told Medscape Neurology & Neurosurgery in an interview.
"The company kind of put it on the back burner for a number of very legitimate reasons, but it was really a grass-roots effort from the ALS community to get another study done to see if they could get a definitive answer for this," he said. "Our study really became the tie-breaker study, if you will, between the first 2 phase?3 trials."
A total of 330 patients with ALS were enrolled from 20 medical centers in the United States and were randomized to receive 0.05?mg/kg body weight of recombinant IGF-1, given subcutaneously twice daily, or placebo, for 2 years.
The dose used was the same as in the high-dose groups in the previous trials, Dr. Sorenson said. "We tried to replicate them as much as possible, but with simpler outcome measures to clarify what the drug may be doing." They also had longer treatment time: 2 years instead of 9 months.
The primary outcome measure of this trial was the change in patients' manual muscle testing (MMT) score. Secondary end points included tracheostomy-free survival and the rate of change in the revised ALS Functional Rating Scale. Analysis was by intention-to-treat.
The overall mean rate of change over the 2 years in the MMT score was 0.41 units per month, and was not different between groups (0.44 units per month in the treatment group and 0.39 units per month in the placebo group; P?= .529).
There were also no differences in secondary end points. The results were not altered when on-treatment and other analyses were used, they note. "All confirmed the negative result, with any difference favoring placebo," the authors write.
Treatment appeared to be safe and well tolerated in the "vast majority" of patients, they note. The most common serious adverse event that was not clearly disease-related was thromboembolic events, although the difference was not statistically significant at the end of the trial. There were also episodes of hypoglycemia, as expected because of the insulin-like properties of IGF-1, the authors add.
"Interestingly we also encountered 4 cases of retinal artery occlusion, an adverse event not previously reported in ALS clinical trials," they write.
Hope for Novel Delivery Methods?
"While this is very disappointing, at least it was definitive and gives, I think, a pretty definitive answer, at least for this strategy for this drug," Dr. Sorenson said. However, he added, "there is still a great deal of evidence that the IGF-1 pathway can be beneficial to people who have ALS, but just not the way we administered it."
Novel methods of delivering IGF-1 in a more selected fashion are now underway, including the use of viral mediators or stem cells, he said.
The study was supported by the National Institutes of Health and the ALS Association. Study drug and placebo were provided by Cephalon Inc. The authors have disclosed no relevant financial relationships.
Neurology. 2008;71:1770-1775.