Doxycycline In Lymphangioleiomyomatosis (LAM) - Full Text View

Sponsor:	University of Nottingham
Information provided by:	University of Nottingham
ClinicalTrials.gov Identifier:	NCT00989742

Purpose

The purpose of the study is to test if the drug doxycycline is effective in slowing the progression of lung disease in LAM. Lymphangioleiomyomatosis (LAM) is a rare lung disease which affects young women. Women with LAM develop enlarged air spaces in the lungs called cysts, caused by an excess of matrix metalloproteinases (MMPs), protein-digesting enzymes. LAM is associated with kidney tumours, called angiomyolipomas, and causes recurrent lung collapse, breathlessness and death or need for lung transplant. There is no proven treatment. Doxycycline, a commonly used antibiotic can block MMP production and a small number of patients have shown some benefit from doxycycline. The investigators will perform a study to test if doxycycline can slow the fall in lung function in patients with LAM. Forty patients who consent to participate will take doxycycline or a placebo (dummy) tablet for two years in addition to their standard treatment.

Condition	Intervention	Phase
Lymphangioleiomyomatosis Tuberous Sclerosis	Drug: Doxycycline Drug: Placebo	Phase IV

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment
Official Title:	A Randomised, Double Blind, Placebo Controlled Trial of Doxycycline in Lymphangioleiomyomatosis.

Resource links provided by NLM:

Genetics Home Reference related topics: lymphangioleiomyomatosis tuberous sclerosis complex

MedlinePlus related topics: Tuberous Sclerosis

Drug Information available for: Doxycycline Doxycycline hyclate Doxycycline calcium

U.S. FDA Resources

Further study details as provided by University of Nottingham:

Primary Outcome Measures:

Mean rate of change of FEV1 over 24 months on doxycycline compared with placebo. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Rate change FVC over 24 months Change DLCO at 12 & 24 mths Change in shuttle walk distance at 12 & 24 mths Change in QOL at 12 & 24 mths Time to composite safety endpoint Number complications Number respiratory infections Adverse effects [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	40
Study Start Date:	July 2009
Estimated Study Completion Date:	December 2011
Estimated Primary Completion Date:	July 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Doxycycline	Drug: Doxycycline 50mg od
Placebo Comparator: Placebo	Drug: Placebo 50mg od

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Sporadic LAM diagnosed either by cystic lung disease on HRCT classical of LAM plus angiomyolipoma or chylous effusion or cystic lung disease on HRCT and tissue biopsy showing LAM or angiomyolipoma
TSC-LAM diagnosed by cystic lung disease on HRCT and tuberous sclerosis diagnosed by TSC consensus criteria(13).
Patients with either an FEV1 below 80% predicted or evidence of a 20% deterioration in FEV1.
Hormone and bronchodilator treatment for LAM* is allowed providing treatment has not changed in the three months prior to enrollment.
- progesterone, GnRh agonists and bronchodilators

Exclusion Criteria:

Inability to give informed consent.
Mental retardation.
Age less than 18 years.
Pneumothorax, chylous effusion, bleeding angiomyolipoma or change in hormone treatment within 3 months.
Previous organ transplantation.
Severe or uncontrolled epilepsy.
Use of any oral contraceptive pill.
Pregnancy or breast feeding. Pre-menopausal patients must be willing to use appropriate birth control measures to avoid pregnancy while enrolled in the study.
Major systemic diseases (malignancy, myocardial infarction or unstable angina, type1 diabetes, severe hypertension, liver cirrhosis).
Use of drugs known to interact with doxycycline, including anticoagulation with warfarin.
Anticoagulation with warfarin.
Hypersensitivity to tetracyclines.
Treatment with mTOR inhibitor within the previous 3 months (sirolimus, everolimus).
Use of doxycycline or other experimental drug within the previous three months.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00989742

Contacts

Contact: William YC Chang, BMBCh, MA (Oxon)	+33 115 8231069	william.chang@nottingham.ac.uk
Contact: simon johnson

Locations

United Kingdom
Nottingham University Hospitals	Recruiting
Nottingham, United Kingdom, NG7 2UH

Sponsors and Collaborators

University of Nottingham

Investigators

Principal Investigator:

Simon R Johnson, BSc(Hons) MBBS DM FRCP

University of Nottingham

More Information

Publications:

Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med. 1999 Aug;160(2):628-33.

Johnson SR. Lymphangioleiomyomatosis. Eur Respir J. 2006 May;27(5):1056-65. Review.

Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6085-90.

Sato T, Seyama K, Fujii H, Maruyama H, Setoguchi Y, Iwakami S, Fukuchi Y, Hino O. Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. J Hum Genet. 2002;47(1):20-8.

Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003 Jul;200(4):448-64. Review.

Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, Ferrans VJ. Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med. 2000 Feb;124(2):267-75.

Bendeck MP, Conte M, Zhang M, Nili N, Strauss BH, Farwell SM. Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury. Am J Pathol. 2002 Mar;160(3):1089-95.

Onoda T, Ono T, Dhar DK, Yamanoi A, Fujii T, Nagasue N. Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells. J Lab Clin Med. 2004 Apr;143(4):207-16.

Duivenvoorden WC, Popovi? SV, Lhoták S, Seidlitz E, Hirte HW, Tozer RG, Singh G. Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer. Cancer Res. 2002 Mar 15;62(6):1588-91.

Prall AK, Longo GM, Mayhan WG, Waltke EA, Fleckten B, Thompson RW, Baxter BT. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg. 2002 May;35(5):923-9.

Moses MA, Harper J, Folkman J. Doxycycline treatment for lymphangioleiomyomatosis with urinary monitoring for MMPs. N Engl J Med. 2006 Jun 15;354(24):2621-2. No abstract available.

Tattersfield AE, Glassberg MK. Lymphangioleiomyomatosis: a national registry for a rare disease. Am J Respir Crit Care Med. 2006 Jan 1;173(1):2-4. No abstract available.

Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998 Dec;13(12):624-8. Review.

Lazor R, Valeyre D, Lacronique J, Wallaert B, Urban T, Cordier JF; Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires. Low initial KCO predicts rapid FEV1 decline in pulmonary lymphangioleiomyomatosis. Respir Med. 2004 Jun;98(6):536-41.

Taveira-DaSilva AM, Stylianou MP, Hedin CJ, Hathaway O, Moss J. Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone. Chest. 2004 Dec;126(6):1867-74.

Johnson S, Knox A. Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation. Am J Physiol. 1999 Dec;277(6 Pt 1):L1109-17.

Henderson N, Markwick LJ, Elshaw SR, Freyer AM, Knox AJ, Johnson SR. Collagen I and thrombin activate MMP-2 by MMP-14-dependent and -independent pathways: implications for airway smooth muscle migration. Am J Physiol Lung Cell Mol Physiol. 2007 Apr;292(4):L1030-8. Epub 2006 Dec 22.

Elshaw SR, Henderson N, Knox AJ, Watson SA, Buttle DJ, Johnson SR. Matrix metalloproteinase expression and activity in human airway smooth muscle cells. Br J Pharmacol. 2004 Aug;142(8):1318-24. Epub 2004 Jul 20.

Crooks DM, Pacheco-Rodriguez G, DeCastro RM, McCoy JP Jr, Wang JA, Kumaki F, Darling T, Moss J. Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17462-7. Epub 2004 Dec 6.

Responsible Party:	Dr Simon Johnson, Reader in Respiratory Medicine, University of Nottingham
ClinicalTrials.gov Identifier:	NCT00989742 History of Changes
Other Study ID Numbers:	07061
Study First Received:	October 2, 2009
Last Updated:	June 2, 2010
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University of Nottingham:

lymphangioleiomatosis
LAM
tuberous sclerosis

doxycycline
matrix metalloproteinases
MMP

Additional relevant MeSH terms:

Sclerosis
Tuberous Sclerosis
Lymphangioleiomyomatosis
Pathologic Processes
Hamartoma
Neoplasms
Malformations of Cortical Development
Nervous System Malformations
Nervous System Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Congenital Abnormalities
Genetic Diseases, Inborn
Lymphangiomyoma

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
Doxycycline
Doxycycline hyclate
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimalarials

ClinicalTrials.gov processed this record on February 09, 2012