The International Rapamycin Treatment Trial (August 2004)

The Cincinnati Rapamycin Trial is testing the effect of the drug sirolimus, also known by the commercial name rapamycin, on the size of kidney tumors called angiomyolipomas in patients with LAM or tuberous sclerosis. Since last May we have enrolled 22 patients, and we think that we have enough candidates to close the trial this summer when we reach our target of 30 patients. Every patient in the trial receives rapamycin in escalating amounts from low, to intermediate, to full dose as kidney tumor size is monitored by MRI over the course of four months. The drug is then continued for a total period of one year, at which point rapamycin is withdrawn and the kidney tumor size is monitored off of therapy. In addition to MRI of the kidney, we are following secondary endpoints of quality of life (measured by questionnaire), lung function, CT scans of the chest, and brain MRIs and skin lesions in patients with tuberous sclerosis.

The Cincinnati Rapamycin Trial is a pilot study to get an idea of whether the drug is safe and has promise. There are three reasons that the study does not have the statistical power to prove that the drug works for lung disease, 1) the numbers are too small, 2) the study was not designed to minimize biases that lead to erroneous conclusions (more later), 3) the primary endpoint was kidney tumor size and not lung structure or function. It is too early to interpret the results of the Cincinnati trial, but we are sufficiently encouraged by our preliminary observations to be hurriedly writing the next trial, which will be based solely on lung function.

The Multicenter LAM Trial will be conducted through the Rare Lung Diseases Consortium – a network of Universities funded by the NIH to perform cooperative trials. The Trial will be placebo controlled, meaning some patients will get a ‘sugar pill’; randomized, meaning that the process of assigning patients to placebo or rapamycin therapy is based on chance, such as the flipping of a coin; and double blind, meaning that neither the patient or the doctor will know who is getting what. This is a tried and true design which eliminates biases. We are hoping to enroll at least 100 patients each in the placebo and treatment groups, beginning before the end of the year in some centers. Patients who receive rapamycin will take the intermediate dose used in the Cincinnati, less than what is generally used in kidney transplant patients. We will measure pulmonary function tests, six-minute walk distance, and quality of life and dyspnea (shortness of breath) scores by questionnaire. To qualify, patients must be able to give informed consent, have abnormal lung function (FEV1<70%) and be free from pleural effusion (fluid in the chest cavity) of a size that is sufficient to influence lung function. There are no CT scans or MRIs included at this point, and kidney tumor size will not be followed. The trial will be two years long, but we will take “peeks’ at the data at six and twelve months. If lung function (FEV1 or FVC) is significantly better in the rapamycin group at either of these points, all patients will be crossed over from the placebo group to receive the drug and the trial will continue to monitor safety and efficacy to the two year point. The intent of this design is to be able to detect a robust effect of the drug early (six and twelve months) and a more subtle effect late (two-year point). The side effects that we will be monitoring include susceptibility to infection, mouth ulcers, elevated cholesterol and an unusual form of pneumonia-like lung inflammation that is not due to infection. We have written the protocol, submitted it to the RLD Data Center, and acquired about half of the $1 million dollars we will need to do the trial.

Many LAM patients have asked why we need a placebo group. The answer is that we will have only one opportunity to answer the question of whether rapamycin is an effective therapy for LAM. If we don’t do this correctly, a lot of people may be harmed.

Perhaps the best way to illustrate this point is to review how we as investigators and physicians have failed patients in finding therapies for another scarring lung disease, idiopathic pulmonary fibrosis (IPF). In IPF, the lung becomes progressively stiffer and more shrunken over time as scar replaces the tiny air sacs that take up oxygen. The disease is relentlessly progressive, and usually fatal, often within two years of presenting with shortness of breath. Treatment with high doses of prednisone and chemotherapy agents were accepted as the standard of care for decades without any proof; a proper trial was never performed. Over time, it became clear to almost all physicians who manage IPF patients that this toxic therapy, which was often complicated by serious infections, osteoporosis, cataracts, hip and spine fractures, is usually ineffective. A lot of patients were hurt. A few years ago, an investigator in Europe reported very encouraging results with a new drug from a small pilot, much like the rapamycin trial we are performing in Cincinnati. Patients with IPF who had received the drug interferon gamma had improved lung function. There we testimonials from patients and physicians about the miraculous benefits of the drug, including reports that the need for oxygen vanished and patients were again able to exercise, etc. Although the drug was FDA approved for another indication, and many physicians began prescribing it for IPF ‘off label’ at tremendous cost to patients and insurance companies, the FDA would not approve it for IPF without a proper clinical state trial. The Multicenter IPF study was completed this year, and it showed no effect of the drug on lung function. Again, people were hurt.

One more illustration; this time for the power of positive trial results. My nephew, Jason, was diagnosed with advanced Hodgkin’s lymphoma at age eleven. He will graduate from the University of Michigan next year. He is alive today, thanks to the courage and intelligence of families before him that made the difficult decision to enroll their children in properly designed clinical trials.

No matter how encouraging it sounds, no result from the Cincinnati Rapamycin Trial can prove that the drug is effective for LAM. The outcome measures that we are using are effort-dependent tests that can be affected by state of mind and motivation. The only way to be sure that we are not fooling ourselves is to eliminate as many biases as possible; especially by blinding patient and physician to treatment status. I so admire the bravery and faith of LAM patients who have pledged their support to do this together and to do it right.

LAM is the model for effective patient advocacy. Patients have moved the disease from obscurity to a targeted molecular therapy in under five years. Now it’s time to close. My confidence in the LAM community to set the standard for the conduct of clinical trials is complete. Let’s get started.