|
Question: What is the scientific evidence that the trial is based on?该项临床试验的科学依据是什么？
Response: A greatly simplified and condensed version is this; Dr. Henske found that LAM is caused by a loss of the protein, tuberin. Fruit fly biologists, Drs. Ito and Rubin, found that tuberin controls cell size and growth. Dr. Krymskaya found that tuberin plays very similar roles in LAM cells as it does in fly cells, and that an FDA approved drug called rapamycin can mimic the function of tuberin in LAM cells. Drs. Yeung and Kwiatkowski have found that rapamycin can shrink tumors in tuberous sclerosis animal models. Rapamycin is known to inhibit the proliferation of smooth muscle cells that contribute to recurrent blockage of coronary arteries after stent placement. Rapamycin for tuberous sclerosis and LAM is an elegant example of molecular therapy targeted at the precise cellular defect that causes disease.
尽量简单地说就是这样的；Henske博士发现：LAM是由于缺失了一种叫做马铃薯球蛋白(tuberin)的蛋白质而引起的。研究果蝇的生物学家Ito和Rubin博士发现马铃薯球蛋白控制着细胞的大小和生长。Krumskaya博士发现马铃薯球蛋白在LAM细胞中的作用和在果蝇细胞中的作用非常相似，并且FDA已经批准的一种叫做rapamycin的药物能够模拟马铃薯球蛋白在LAM细胞中的功能。Yeung和Kwiatkowski博士发现rapamycin能够使结节样硬化症的动物模型中的肿瘤缩小。另外，在放置冠状动脉支架以后，由于平滑肌细胞的增殖会使血管再次梗阻，现已知道rapamycin能够抑制这些平滑肌细胞的增殖。分子治疗就是要精确地瞄准导致疾病的细胞学缺陷，而Rapamycin用于治疗结节样硬化症和LAM这种治疗的极好例子。
Question: Who is conducting the trial, how long is it and where will it be performed?这项研究是由谁牵头的，将持续多久，在什么地方进行？
Response: The principal investigators of the trial are Drs. David Franz, a pediatric neurologist, John Bissler, a pediatric nephrologist, and Frank McCormack, adult pulmonary physician. The nurse clinicians are Jennifer Leonard, Gail Chuck and Cindy Tudor. The trial is two years long, one year of active treatment and frequent radiographic imaging and other testing, and one follow up year. The trial is based in the Tuberous Sclerosis Clinic at the Children's Hospital of the University of Cincinnati.
该项试验的主要研究人员是儿科神经病学家David Franz博士，儿科肾脏病学家John Bissler博士，以及成人肺脏病学家Frank McCormack。临床护士有Jennifer Leonard, Gail Chuck 和 Cindy Tudor。试验将持续两年，第一年是积极治疗，并有频繁的放射影像学和其他的一些检查；第二年是随诊。该试验在辛辛那提大学儿童医院的结节样硬化症门诊进行。
Question: Who is a candidate for the trial, and how many patients will be enrolled?哪些人可以参加试验，准备纳入多少病例呢？
Response: Any tuberous sclerosis or sporadic LAM patient (i.e., someone with LAM who does not have tuberous sclerosis) with an angiomyolipoma that is at least one centimeter in diameter is a candidate. Patients must be at least eighteen years of age, and capable of giving informed consent based on complete understanding of the risks involved. We are excluding patients who are on full time oxygen initially, because they may be less able to tolerate side effects. Patients must be willing to travel to Cincinnati at least six times in the first year and two times in the second year. We have funding from the LAM Foundation and the Tuberous Sclerosis Alliance to enroll thirty patients initially, and we have applied for additional funding from the National Cancer Institute and the Food and Drug Administration to expand the trial.
任何结节样硬化症或单发性的LAM病人（亦即患有LAM而没有结节样硬化症的人），只要是其血管肌脂瘤直径至少一厘米以上的都可参加试验。病人必须十八岁以上，并且能够在完全理解参与本试验的风险的前提下签署知情同意书。我们排除在开始时就需要不间断吸氧的患者，因为他们可能难以耐受药物的副作用。在第一年，患者必须能够到辛辛那提至少六次，第二年两次。我们有从LAM基金会和结节样硬化症联合会的资助，初步计划纳入30个患者；另外，为了扩大研究，我们正在申请国家癌症研究所和FDA的基金。
Question: How will patients be treated and when will it start?患者将怎样接受治疗，什么时候开始？
Response: Patients will be given daily oral rapamycin in pill form in very low doses for the first two months; doses that are not predicted to produce any complications. If there is no effect, the dose will be increased to moderate and full therapy levels over the next six months until an effect is seen. The drug will be stopped if there is no effect after one year on treatment. The trial started in mid May 2003.
在最初两个月，患者将每天口服很低剂量的rapamycin片剂，这时候的剂量预计是不会有任何并发症的。如果没有疗效，在随后的六个月里，药物剂量会增加到中等水平以及足量治疗水平，直至见到疗效。如果治疗一年没有效果将停药。该试验于2003年五月中旬开始。
Question: What are you measuring?您要观测哪些指标？
Response: The primary outcome that we are measuring is reduction in the size of renal angiomyolipomas (AMLs). This outcome was chosen because the size of AMLs can be determined accurately using special techniques, and shrinkage can be unequivocally documented. Renal MRIs are done at the beginning, and at two months, four months, six months and one year. One of our hypotheses is that responses in AMLs may predict responses in LAM, since the cells that make up AMLs share many characteristics with LAM cells. We will also assess lung function by pulmonary function testing and lung structure by high resolution CT scans in those trial patients who have LAM, but proving that rapamycin is helpful in LAM will likely require many patients and multiple centers. Changes in tuberous sclerosis manifestations in the skin and the brain are additional secondary outcome measures.
我们要观测的最主要指标是肾脏的血管肌脂瘤（AML）的缩小程度。选用这一指标是因为AML的大小能够通过特殊检查手段精确地测量，因此其缩小程度能被清楚地记录下来。为此，在试验开始时、两个月、四个月、六个月以及一年时分别进行肾脏的核磁显像（MRI）。我们的一个假设是AML的反应程度或许能预计LAM的反应情况，因为构成AML的细胞有很多特性跟LAM细胞是一样的。
另外我们还会对参与试验的LAM患者进行肺功能测定和高分辨CT扫描，以分别评价肺脏的功能和结构。但是为了证明rapamycin对LAM有效可能需要很多患者的参与以及多个医疗机构的协作。结节样硬化症的皮肤和脑部的表现的变化也是另一个次要观测指标。
Question: What are the risks?有什么风险？
Response: Rapamycin interferes with the function of infection fighting cells called lymphocytes. Patients on rapamycin in moderate or full doses are therefore at risk for infections with common organisms and organisms that would not threaten a patient with a completely normal immune system. Rapamycin also increases blood cholesterol and triglyceride levels, but this side effect can usually be managed with diet or drug therapy (e.g., Lipitor). Rapamycin can reduce the level of the platelets in the blood, which are essential for clotting. Wound healing can be delayed in patients on rapamycin, and the drug should not be given immediately following major surgery. Finally, rapamcyin can rarely induce a pneumonia-like syndrome (about 50 reported cases in the literature), which can be a particularly serious development in a patient with advanced LAM. All rapamycin side effects go away when the drug is stopped, and our strategy is to maintain a high level of vigilance for complications during the trial so that potential problems are identified early.
Rapamycin会影响抵抗感染的细胞——淋巴细胞。因此，接受中等剂量或足量rapamycin的患者会容易感染普通病菌以及一些在平时对免疫功能正常的患者没有威胁的病原体。Rapamycin还会使血中的胆固醇�****腿ド撸庖桓弊饔猛ǔ？赏ü车髡蛞┪锢纯刂啤�Rapamycin会降低血小板水平，血小板是止血过程必不可少的。服用rapamycin会延缓伤口的愈合，此药不可用于刚刚接受大手术的患者。最后，rapamycin的一个罕见副作用是会导致一种肺炎样的综合征（文献报道的总共有大约50例），特别对晚期LAM的患者来说这将导致病情的严重恶化。停用rapamycin之后，所有的副作用都会消失；我们的策略是在试验过程中对药物副作用保持高度的警惕性，及早发现潜在的问题。
Question: When will we know something?我们什么时候能知道一些结果？
Response: We are hoping to have an idea of whether the drug has promise within a year.
我们希望在一年以内对此药是否有前途有个眉目。
Question: What’s next?然后呢？
Response: The first phase of the trial with rapamycin is designed to determine if the drug has an effect on tuberous sclerosis tumors. If the trial is positive, larger trials will be required to determine the utility of rapamycin or similar drugs in preventing or reversing tuberous sclerosis lesions in several different organ systems, and to define the optimal dose, duration, timing of the drug. Several grants have already been submitted for the second phase, even before the results of the first trial are available.
对rapamycin的第一期临床试验是设计用来判断此药对结节样硬化症的瘤子是否有效。如果试验结果是阳性（有效），那就要进行规模更大的试验以判断rapamycin或者类似的药物对于多个不同器官的结节样硬化病灶是否有预防或逆转的作用，并且确定药物的合适剂量、疗程以及服药时间。尽管第一期临床试验的结果还没有出来，我们已经申请了多份二期试验的基金。
Question: Who should I contact if I have questions about the trial?如果我对该试验有问题要问该找谁联系？
Response: Feel free to contact Frank McCormack at frank.mccormack@uc.edu; or, John Bissler at john.bissler@chmcc.org, or David Franz at david.franz@chmcc.org.
欢迎和我们联系： Frank McCormack，电子邮箱 frank.mccormack@uc.edu，电话513-558-4831； John Bissler，电子邮箱 john.bissler@chmcc.org；David Franz，电子邮箱david.franz@chmcc.org
（翻译：北京协和医院呼吸科主治医师 留永健博士） |
打印本页
关闭窗口