Dr. McCormack Q&A MILES Trial

What is the scientific evidence that the trial is based on?

Rapamycin is known to inhibit the proliferation of smooth muscle cells that contribute to recurrent blockage of coronary arteries after stent placement. This drug for tuberous sclerosis and LAM is an elegant example of molecular therapy targeted at the precise cellular defect that causes disease. A greatly simplified and condensed version of how we arrived at where we are today 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, rapamycin, can mimic the function of tuberin in LAM cells.
Drs. Yeung and Kwiatkowski then found that rapamycin can shrink tumors in tuberous sclerosis animal models.
Researchers at the University of Cincinnati conducted a pilot trial to determine the effects of rapamycin in women with tuberous sclerosis or sporadic LAM patient (i.e., someone with LAM but not tuberous sclerosis).

What is the MILES Trial?

The MILES Trial will be conducted through the Rare Lung Diseases Consortium - a network of Universities funded by the National Heart, Lung and Blood Institute (NHLBI) to perform cooperative trials. The Trial is a randomized, double-blind, placebo-controlled trial -- a tried and true design which eliminates biases. We will measure pulmonary function and six-minute walk distance, as well as quality of life and dyspnea (shortness of breath) via a questionnaire. Patients who receive rapamycin will take the intermediate dose used in the previous Cincinnati trial, less than what is generally used in kidney transplant patients. 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.

At what locations are clinical sites planned?

Initially Cincinnati; NIH; Charleston; Tyler; Gainesville; Cleveland; Portland; Denver; Osaka/Niigata, Japan; Boston; and Los Angeles; Toronto, Canada.

What is the overall timeline for the MILES Trial, once it gets started?

We are hoping to enroll at least 60 patients each in the placebo and treatment groups, anticipating it will take a year to fully enroll. Six visits are required in the first year, and two in the second year. The trial will be two years long, but we will take "peeks" at the data at six and twelve months. If lung function 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 (6 and 12 months) and a more subtle effect late (two-year point).

What are the risks and/or side effects of the drug?

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. Rapamycin can reduce the level of the platelets in the blood, which are essential for clotting. Wound healing can be delayed in patients taking 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.

Who is a candidate for the MILES trial?

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.

With studies already showing that rapamycin benefits these patients, why a placebo?

Despite previous pilot studies, the MILES trial is out 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. No matter how encouraging it sounds, no result from the first 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 the 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.

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