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Doxycycline In Lymphangioleiomyomatosis (LAM)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00989742
First Posted: October 5, 2009
Last Update Posted: December 2, 2015
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.
Information provided by (Responsible Party):
University of Nottingham
  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 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomised, Double Blind, Placebo Controlled Trial of Doxycycline in Lymphangioleiomyomatosis.

Resource links provided by NLM:


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 ]

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 ]

Enrollment: 24
Study Start Date: July 2009
Study Completion Date: January 2013
Primary Completion Date: January 2013 (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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes 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
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00989742


Locations
United Kingdom
Nottingham University Hospitals
Nottingham, United Kingdom, NG7 2UH
Sponsors and Collaborators
University of Nottingham
Investigators
Principal Investigator: Simon R Johnson, 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, Popović 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.
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.
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: University of Nottingham
ClinicalTrials.gov Identifier: NCT00989742     History of Changes
Other Study ID Numbers: 07061
First Submitted: October 2, 2009
First Posted: October 5, 2009
Last Update Posted: December 2, 2015
Last Verified: December 2015

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
Neoplasms, Multiple Primary
Neoplastic Syndromes, Hereditary
Malformations of Cortical Development, Group I
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
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials


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