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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
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Elizabeth Henske, Brigham and Women's Hospital

Tracking Information
First Submitted Date  ICMJE August 2, 2012
First Posted Date  ICMJE September 18, 2012
Results First Submitted Date  ICMJE March 30, 2017
Results First Posted Date  ICMJE October 11, 2018
Last Update Posted Date October 11, 2018
Study Start Date  ICMJE September 2012
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2018)
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".
Original Primary Outcome Measures  ICMJE
 (submitted: September 13, 2012)
safety of everolimus and hydroxychloroquine [ Time Frame: 4 years ]
We will conduct a two-center phase I trial of sirolimus (mTOR inhibitor) in combination with hydroxychloroquine (autophagy inhibitor 200-400mg) administered daily for 24 weeks. Eligible subjects will receive 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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation design. All adverse events will be captured.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis
Official Title  ICMJE Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus
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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Lymphangioleiomyomatosis
Intervention  ICMJE
  • 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)
Study Arms  ICMJE 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.
Interventions:
  • Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg
  • Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 11, 2016)
14
Original Estimated Enrollment  ICMJE
 (submitted: September 13, 2012)
18
Actual Study Completion Date  ICMJE August 2015
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01687179
Other Study ID Numbers  ICMJE SAIL-1100
1ZIAHL002541-21 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Elizabeth Henske, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Elizabeth P Henske, MD Brigham and Women's Hospital
Principal Investigator: Joel Moss, MD, PhD National Heart, Lung, and Blood Institute (NHLBI)
PRS Account Brigham and Women's Hospital
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP