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

• 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: Brigham and Women's Hospital
• 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

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Sirolimus and Hydroxychloroquine 200 mg	Sirolimus and HydroxyChloroquine 400 mg
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

Baseline Characteristics

Arm/Group Title		Sirolimus and Hydroxychloroquine
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
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.

Outcome Measures

1. Primary Outcome

Title	Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus and Hydroxychloroquine 200 mg	Sirolimus and Hydroxychloroquine 400 mg
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

Adverse Events

Time Frame	48 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Sirolimus and Hydroxychloroquine 200 mg		Sirolimus and Hydroxychloroquine 400 mg
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%)
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
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Elizabeth P. Henske, MD
• Organization: Brigham and Women's Hospital
• Phone: 857-307-0782
• EMail: ehenske@bwh.harvard.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tang Y, El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Rosas IO, Moss J, Priolo C, Henske EP. Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex 2-Deficient Cells. Chest. 2019 Dec;156(6):1137-1148. doi: 10.1016/j.chest.2019.05.038. Epub 2019 Jul 9.

Lamattina AM, Taveira-Dasilva A, Goldberg HJ, Bagwe S, Cui Y, Rosas IO, Moss J, Henske EP, El-Chemaly S. Circulating Biomarkers From the Phase 1 Trial of Sirolimus and Autophagy Inhibition for Patients With Lymphangioleiomyomatosis. Chest. 2018 Nov;154(5):1070-1082. doi: 10.1016/j.chest.2018.08.1029. Epub 2018 Aug 23.

El-Chemaly S, Taveira-Dasilva A, Goldberg HJ, Peters E, Haughey M, Bienfang D, Jones AM, Julien-Williams P, Cui Y, Villalba JA, Bagwe S, Maurer R, Rosas IO, Moss J, Henske EP. Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis: Results of a Phase I Clinical Trial. Chest. 2017 Jun;151(6):1302-1310. doi: 10.1016/j.chest.2017.01.033. Epub 2017 Feb 10.

• 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