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Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis (SAIL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01687179
Recruitment Status : Completed
First Posted : September 18, 2012
Results First Posted : October 11, 2018
Last Update Posted : October 11, 2018
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Elizabeth Henske, Brigham and Women's Hospital

Brief Summary:

Specific Aim 1: To investigate whether, in Lymphangioleiomyomatosis (LAM) patients, the combination of sirolimus and hydroxychloroquine is safe and well tolerated

Specific Aim 2: To investigate whether, in LAM patients, 6 months of combination therapy with sirolimus and hydroxychloroquine results in improvement of indicators of disease, and whether the gains are sustained after stopping therapy.

Specific Aim 3: To investigate the potential role of a LAM-specific peripheral blood signature to predict rates of disease progression and determine responsiveness to combination therapy.

This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily. Up to 18 adult women with LAM will be enrolled.

Condition or disease Intervention/treatment Phase
Lymphangioleiomyomatosis Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg Phase 1

Detailed Description:
This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily for 6 months. The study is to be conducted at 2 sites. Up to 18 adult women with LAM will be enrolled, and each recruiting site will recruit between 8-12 subjects. The protocol will use the following eligibility criteria.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
Study Start Date : September 2012
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Arm Intervention/treatment
Experimental: "Sirolimus" and "Hydroxychloroquine"
Subjects will take Sirolimus at an initial dose of 2mg followed by dose adjustment to keep Sirolimus trough levels between 5-15ng/ml consistent with the effective dose in the MILES trial. In addition to Sirolimus subjects will receive Hydroxychloroquine at 200 mg daily for 6 months. Once safety is established at the lower dose ("Sirolimus" and "Hydroxychloroquine" 200 mg), subjects enrolled henceforth will receive Sirolimus and Hydroxychloroquine 400 mg (200 mg twice a day) for 6 months.
Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg
This will be a phase I dose escalation study of the combination of "Sirolimus" (2 mg adjusted to keep trough levels between 5-15 ng/ml) and "Hydroxychloroquine" 200 mg taken orally daily.
Other Name: sirolimus(rapamune), hydroxychloroquine (plaquenil)

Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg
Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.
Other Name: Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)

Primary Outcome Measures :
  1. Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients [ Time Frame: 48 weeks ]
    The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the "Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0".

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Female age 18 or older
  • Ability to give informed consent
  • Diagnosis of LAM as defined as typical cystic change on CT plus:

    • biopsy or cytology of any tissue demonstrating LAM
    • angiomyolipoma, chylothorax, lymphangioleiomyoma, or tuberous sclerosis
    • serum VEGFD greater or equal to 800pg/ml
  • Post-bronchodilator FEV1 equal or less than 80% of predicted or DLCO equal equal or less than 70% of predicted, or RV > 120% of predicted at baseline
  • Women of childbearing potential must agree to use 2 forms of barrier contraception during and for 8 weeks after the last dose of medication.

Exclusion Criteria:

  • History of intolerance of mTOR inhibitors
  • History of intolerance to hydroxychloroquine
  • History of severe psoriasis
  • History of porphyria cutanea tarda
  • Uncontrolled intercurrent illness
  • Pregnant, breast feeding, or plan to become pregnant in the next year
  • Inadequate contraception
  • Significant hematological or hepatic abnormalities
  • Use of an investigational drug within 30 days of study start
  • Inability to attend scheduled clinic visits
  • Inability to perform PFTs
  • Creatinine > 2.5mg/dL
  • Recent pneumothorax within 8 weeks of screening
  • History of malignancy in the last 2 years other than basal cell skin cancer
  • Use of estrogen containing medication within 30 days of screening
  • Abnormal G6PD levels at baseline
  • Preexisting maculopathy or retinopathy
  • Preexisting myopathy
  • Currently taking doxycycline, metformin, lupron, simvastatin
  • Unable to undergo CT or MRI
  • History of seizure within last year
  • Hepatitis B, C, HIV positive serology
  • Use of alternative medical therapies for LAM for at least 6 weeks prior to study participation
  • History of myocardial infarct, angina, or stroke related to atherosclerosis
  • History of cardiomyopathy
  • Previous lung transplant
  • Surgery (involving entry into a body cavity or requiring 3 or more stitches) within 2 months of initiation of study drug
  • Uncontrolled cholesterol > 350mg/dL, triglycerides > 400mg/dL

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01687179

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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02120
Sponsors and Collaborators
Brigham and Women's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Elizabeth P Henske, MD Brigham and Women's Hospital
Principal Investigator: Joel Moss, MD, PhD National Heart, Lung, and Blood Institute (NHLBI)
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Elizabeth Henske, Overall Principal Investigator, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01687179    
Other Study ID Numbers: SAIL-1100
1ZIAHL002541-21 ( U.S. NIH Grant/Contract )
First Posted: September 18, 2012    Key Record Dates
Results First Posted: October 11, 2018
Last Update Posted: October 11, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Elizabeth Henske, Brigham and Women's Hospital:
Additional relevant MeSH terms:
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Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Perivascular Epithelioid Cell Neoplasms
Neoplasms, Connective and Soft Tissue
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
MTOR Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents