Doxycycline In Lymphangioleiomyomatosis (LAM)

NCT00989742 | Completed Phase 4

• 1 other identifier: 07061
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Lymphangioleiomyomatosis; Tuberous Sclerosis

Keywords

lymphangioleiomatosis; LAM; tuberous sclerosis; doxycycline; matrix metalloproteinases; MMP

Outcome Measures

Primary Outcomes (1)

• Mean rate of change of FEV1 over 24 months on doxycycline compared with placebo.

  2 years

Secondary Outcomes (1)

• 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

  2 years

Study Arms (2)

Doxycycline

ACTIVE COMPARATOR

Drug: Doxycycline

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Doxycycline DRUG

50mg od

Doxycycline

Placebo DRUG

50mg od

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Nottingham: lead

Study Sites (1)

Nottingham University Hospitals

Nottingham, Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (19)

• 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. doi: 10.1164/ajrccm.160.2.9901027.

  PMID: 10430739 BACKGROUND

• Johnson SR. Lymphangioleiomyomatosis. Eur Respir J. 2006 May;27(5):1056-65. doi: 10.1183/09031936.06.00113303.

  PMID: 16707400 BACKGROUND

• 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. doi: 10.1073/pnas.97.11.6085.

  PMID: 10823953 BACKGROUND

• 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. doi: 10.1007/s10038-002-8651-8.

  PMID: 11829138 BACKGROUND

• Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003 Jul;200(4):448-64. doi: 10.1002/path.1400.

  PMID: 12845612 BACKGROUND

• 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. doi: 10.5858/2000-124-0267-RFAOMM.

  PMID: 10656737 BACKGROUND

• 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. doi: 10.1016/S0002-9440(10)64929-2.

  PMID: 11891205 BACKGROUND

• 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. doi: 10.1016/j.lab.2003.12.012.

  PMID: 15085079 BACKGROUND

• Duivenvoorden WC, Popovic SV, Lhotak 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.

  PMID: 11912125 BACKGROUND

• 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. doi: 10.1067/mva.2002.123757.

  PMID: 12021708 BACKGROUND

• 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. doi: 10.1056/NEJMc053410. No abstract available.

  PMID: 16775248 BACKGROUND

• 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. doi: 10.1164/rccm.2509010. No abstract available.

  PMID: 16368790 BACKGROUND

• Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol. 1998 Dec;13(12):624-8. doi: 10.1177/088307389801301206.

  PMID: 9881533 BACKGROUND

• 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. doi: 10.1016/j.rmed.2003.11.013.

  PMID: 15191039 BACKGROUND

• 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. doi: 10.1378/chest.126.6.1867.

  PMID: 15596686 BACKGROUND

• 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):L1109-17. doi: 10.1152/ajplung.1999.277.6.L1109.

  PMID: 10600880 BACKGROUND

• 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. doi: 10.1152/ajplung.00317.2006. Epub 2006 Dec 22.

  PMID: 17189319 BACKGROUND

• 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. doi: 10.1038/sj.bjp.0705883. Epub 2004 Jul 20.

  PMID: 15265805 BACKGROUND

• 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. doi: 10.1073/pnas.0407971101. Epub 2004 Dec 6.

  PMID: 15583138 BACKGROUND

MeSH Terms

Conditions

Lymphangioleiomyomatosis; Tuberous Sclerosis

Interventions

Doxycycline

Condition Hierarchy (Ancestors)

Lymphangiomyoma; Neoplasm, Lymphatic Tissue; Neoplasms by Histologic Type; Neoplasms; Perivascular Epithelioid Cell Neoplasms; Neoplasms, Connective and Soft Tissue; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hamartoma; 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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Simon R Johnson, DM FRCP

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2009
• First Posted: October 5, 2009
• Study Start: July 1, 2009
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: December 2, 2015

Record last verified: 2015-12

Locations

GB (1)