Efficacy and Safety of Sirolimus in LAM
Condition: Lymphangioleiomyomatosis
MeSH terms: Lymphangioleiomyomatosis
Intervention: Sirolimus; Placebo
Intervention description: A sirolimus dose of 2 tablets (1 mg/tablet) per day for 1 year.; A placebo dose of 2 tablets per day for 1 year.
Intervention MeSH terms: Sirolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Unlabeled sirolimus tablets were provided by Pfizer. Identical appearing placebo tablets were obtained from a commercial source. Sirolimus levels were reported only to the medical monitor. To maintain the blind, when dose adjustments were made in the sirolimus group, a sham adjustment was also made in the placebo group
Enrollment: 89.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lymphangiomyomatosis; mTOR

Summary:

      Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that is caused by genetic
      mutations. It results in the uncontrolled growth of an unusual type of smooth muscle cell in
      the lung. These cells invade lung tissue, including the airways, blood vessels, and lymph
      vessels, and restrict the flow of air, blood, and lymph, respectively. Respiratory failure,
      lung collapse (pneumothorax), and pleural effusions (chylothorax) are hallmarks of the
      disease. This study will evaluate the safety and effectiveness of sirolimus, an inhibitor of
      the mTOR pathway, in stabilizing or improving lung function in people with LAM.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age 18 or older

          -  Signed and dated informed consent

          -  Diagnosis of LAM based on compatible chest CT scan and a) biopsy or cytology
             consistent with LAM, or b) presence of tuberous sclerosis, angiomyolipoma or chylous
             pleural effusion; or c) a VEGF-D level of at least 800 pg/ml

          -  Forced expiratory volume in one second (FEV1) of 70% or less of predicted value after
             administration of a bronchodilator

        Exclusion Criteria:

          -  Known allergy to sirolimus

          -  History of heart attack, angina, or stroke due to clogging, narrowing, and hardening
             of the arteries and blood vessels

          -  Significant hematologic or hepatic abnormality (transaminase levels greater than three
             times the upper limit of normal, HCT less than 30%, platelets less than 80,000/cubic
             mm, adjusted absolute neutrophil count less than 1,000/cubic mm, total white blood
             cell count less than 3,000/cubic mm)

          -  Intercurrent infection at the time treatment with sirolimus begins

          -  Any surgery involving entry into a body cavity or requiring three or more sutures
             within 8 weeks of initiation of study drug

          -  Use of an investigational drug within the 30 days prior to random assignment

          -  Uncontrolled hyperlipidemia

          -  Previous lung transplant or currently on lung transplant list

          -  Unable to attend scheduled study visits

          -  Unable to perform pulmonary function tests

          -  Creatinine levels greater than 2.5 mg/dl

          -  Chylous ascites severe enough to affect diaphragmatic function

          -  Pleural effusion severe enough to affect pulmonary function, as determined by the
             study physician

          -  History of acute pneumothorax within the 2 months prior to study entry

          -  History of malignancy within the 2 years prior to study entry (except for squamous or
             basal cell skin cancer)

          -  Use of estrogen containing medication within the thirty days prior to randomization

          -  Unable or unwilling to use adequate contraception

          -  Pregnant, breastfeeding, or plans to become pregnant within the next 2 years