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

September 13, 2018 updated by: Elizabeth Henske, Brigham and Women's Hospital

Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

14

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02120
        • Brigham and Women's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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".
48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Brigham and Women's Hospital

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • 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 and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

August 1, 2015

Study Completion (Actual)

August 1, 2015

Study Registration Dates

First Submitted

August 2, 2012

First Submitted That Met QC Criteria

September 13, 2012

First Posted (Estimate)

September 18, 2012

Study Record Updates

Last Update Posted (Actual)

October 11, 2018

Last Update Submitted That Met QC Criteria

September 13, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SAIL-1100
  • 1ZIAHL002541-21 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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