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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

Study Type Interventional
Study Design Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphangioleiomyomatosis
Interventions Drug: "Sirolimus" and "Hydroxychloroquine" 200 mg
Drug: "Sirolimus" and "Hydroxychloroquine" 400 mg
Enrollment 14
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sirolimus and Hydroxychloroquine 200 mg Sirolimus and HydroxyChloroquine 400 mg
Hide Arm/Group 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 taken orally daily. 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.
Period Title: Overall Study
Started 3 10
Completed 2 6
Not Completed 1 4
Arm/Group Title Sirolimus and Hydroxychloroquine
Hide Arm/Group Description

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 or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation.

sirolimus and hydroxychloroquine: 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.

Overall Number of Baseline Participants 14
Hide Baseline Analysis Population Description
1 subject failed to qualify for the study at the screening visit. Since the subject had signed consent, we considered the participant to be enrolled on the study.
Age, Continuous   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 13 participants
49
(40 to 65)
[1]
Measure Analysis Population Description: 1 subject screen failed.
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
Female 13
Male 0
[1]
Measure Analysis Population Description: 1 subject screen failed.
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
American Indian or Alaska Native
0
   0.0%
Asian
1
   7.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
12
  92.3%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Region of Enrollment   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 13 participants
13
 100.0%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Post-Menopause   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
6
  46.2%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Pneumothorax   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
9
  69.2%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Angiomyolipoma   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
2
  15.4%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Tuberous Sclerois (TSC)- Lymphangioleiomyomatosis (LAM)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
0
   0.0%
Lung Biopsy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
8
  61.5%
[1]
Measure Analysis Population Description: 1 subject screen failed.
Chylothorax   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
1
   7.7%
[1]
Measure Analysis Population Description: 1 subject screen failed
6 minute walk distance (6MWD) (m)   [1] 
Mean (Standard Deviation)
Unit of measure:  m
Number Analyzed 13 participants
442  (103)
[1]
Measure Analysis Population Description: 1 subject screen failed.
St. George's Respiratory Questionnaire (SGRQ)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 13 participants
43.8  (19.2)
[1]
Measure Description: The Saint George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.
[2]
Measure Analysis Population Description: 1 subject screen failed.
Log VEGF-D (Veascular Endothelial Growth factor)   [1] 
Mean (Standard Deviation)
Unit of measure:  Log(pg/ml)
Number Analyzed 13 participants
3.11  (0.33)
[1]
Measure Analysis Population Description: 1 subject screen failed.
FEV1   [1] 
Mean (Standard Deviation)
Unit of measure:  Litres
Number Analyzed 13 participants
1.6  (0.7)
[1]
Measure Analysis Population Description: 1 Subject Screen failed.
FEV1 (%)  
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 14 participants
59  (21)
FVC (L)   [1] 
Mean (Standard Deviation)
Unit of measure:  Litres
Number Analyzed 13 participants
2.8  (0.7)
[1]
Measure Analysis Population Description: 1 subject screen failed.
FVC (%)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 13 participants
81  (16)
[1]
Measure Analysis Population Description: 1 Subject Screen failed.
DLCO (ml/min/mmhg)   [1] 
Mean (Standard Deviation)
Unit of measure:  Ml/min/mmhg
Number Analyzed 13 participants
9.8  (3.1)
[1]
Measure Analysis Population Description: 1 Subject screen failed.
DLCO (%)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent predicted
Number Analyzed 13 participants
43  (15)
[1]
Measure Analysis Population Description: 1 Subject screen failed.
1.Primary Outcome
Title Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
Hide Description 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".
Time Frame 48 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Sirolimus and Hydroxychloroquine 200 mg Sirolimus and Hydroxychloroquine 400 mg
Hide Arm/Group 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 taken orally daily. Safety of the drug combination was assessed by the occurrence of adverse events in these 3 patients.
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. Safety of this dose was assessed by the occurrence of adverse events in these 10 patients.
Overall Number of Participants Analyzed 3 10
Measure Type: Number
Unit of Measure: Percentage of adverse events
Cardiac Disorders 2.27 1.11
Eye Disorders 0 1.11
GI Disorders 18.18 22.22
General Disorders, Administration site condistions 18.18 6.67
Immune System disorders 0 0.56
Infections and infestations 15.91 8.33
Injury, poisoning, procedural complications 0 0.56
Investigations 6.82 20
Metabolism and nutrition disorders 0 3.33
Musculoskeletal, connective tissue disorders 0 4.44
Nervous system disorders 4.55 5.00
Psychiatric disorders 0 0.56
Renal and urinary disorders 0 7.78
Reproductive system and breast disorder 6.82 1.11
Respiratory, thoracic, mediastinal disorders 2.27 9.44
Skin and Subcutaneous disorders 25.0 6.11
Vascular disorders 0 1.67
Time Frame 48 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Sirolimus and Hydroxychloroquine 200 mg Sirolimus and Hydroxychloroquine 400 mg
Hide Arm/Group 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 taken orally daily. 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.
All-Cause Mortality
Sirolimus and Hydroxychloroquine 200 mg Sirolimus and Hydroxychloroquine 400 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)      0/10 (0.00%)    
Hide Serious Adverse Events
Sirolimus and Hydroxychloroquine 200 mg Sirolimus and Hydroxychloroquine 400 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/3 (0.00%)      1/10 (10.00%)    
Nervous system disorders     
radiculitis * 1  0/3 (0.00%)  0 1/10 (10.00%)  1
1
Term from vocabulary, CTCAE (4.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Sirolimus and Hydroxychloroquine 200 mg Sirolimus and Hydroxychloroquine 400 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      9/10 (90.00%)    
Gastrointestinal disorders     
Diarrhea * 1  2/3 (66.67%)  6/10 (60.00%) 
Oral Mucositis * 1  2/3 (66.67%)  6/10 (60.00%) 
Investigations     
Abnormal Investigations * 1  1/3 (33.33%)  6/10 (60.00%) 
Skin and subcutaneous tissue disorders     
Rash/ Acne * 1  3/3 (100.00%)  5/10 (50.00%) 
1
Term from vocabulary, CTCAE (4.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Elizabeth P. Henske, MD
Organization: Brigham and Women's Hospital
Phone: 857-307-0782
EMail: ehenske@bwh.harvard.edu
Layout table for additonal information
Responsible Party: Elizabeth Henske, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01687179    
Other Study ID Numbers: SAIL-1100
1ZIAHL002541-21 ( U.S. NIH Grant/Contract )
First Submitted: August 2, 2012
First Posted: September 18, 2012
Results First Submitted: March 30, 2017
Results First Posted: October 11, 2018
Last Update Posted: October 11, 2018