- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02335242
Sildenafil for the Treatment of Lymphatic Malformations
Phase 2 Study of Sildenafil for the Treatment of Lymphatic Malformations
A Phase 2 study to evaluate safety and efficacy of sildenafil taken orally to improve or resolve lymphatic malformations in children. Subjects may receive either placebo or treatment in an oral dosage with an open label extension for subjects who received placebo. The study treatment assignment will be randomized in a double blind fashion. MRI examination will evaluate change in lesion volume due to treatment. Other safety and efficacy measures will be taken through the 32-week study duration.
Funding Source - FDA OOPD
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
Stanford, California, United States, 94305
- Stanford University
-
-
Colorado
-
Aurora, Colorado, United States, 80045-2571
- University of Colorado, Denver
-
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Illinois
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Chicago, Illinois, United States, 60611
- Ann & Robert H. Lurie Children's Hospital of Chicago
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Subjects must:
- Be legally authorized representative of subjects willing and able to give consent. Assent obtained for subjects 7 - 10 years old.
- Be between the ages of 6 months - 10 years of age at the time of entry into the study.
- Be at the minimum weight of 8 kg at the time of enrollment.
- Be required to have the clinical diagnosis of lymphatic malformation that appears to be over 3 cm in greatest diameter in order to be evaluated for entry. A review of a previous MRI examination may help confirm the entry criteria on subjects selected to come to Stanford for the MRI screening.
- Have the lymphatic malformation cause enough disability for the subject that requires them to consider systemic therapy.
- For female subjects: must not be pregnant or breast-feeding.
- Have a parent or legally authorized representative willing and able to ensure subject is present for all required study visits.
- Have a required MRI examination to confirm that the lymphatic malformation is present and is greater than 3 cm in diameter in order for the subjects to receive medication, which happens during the initial screening evaluation portion of the trial.
- Have no contraindications for the use of sildenafil.
- Have a normal eye examination.
- Have normal liver and kidney function.
- Have no contraindication to MRI examinations such as metal implants, etc.
- Not be a smoker.
Exclusion Criteria:
A Subject with any of the following criteria is not eligible for inclusion in this study:
- Medically unstable health status that may interfere with his/her ability to complete the study.
- Has one or more of the following medical conditions:
Hepatic impairment, severe renal impairment, lymphedema conditions such as Milroy disease, Meige lymphedema, Hennekam syndrome, Njolstad syndrome, Aagenaes syndrome, and Fabry disease, hypotension or at risk for hypotension, seizures or history of seizures, any significant cardiovascular risk factors and any condition which requires participants to use nitric oxide donors or nitrates in any form, underlying anatomic or vascular risk factor for developing non-arteritic anterior ischemic optic neuropathy (NAION) including low ocular cup to disc ratio, diabetes, hypertension, coronary artery disease, or hyperlipidemia Participants with Down syndrome, Turner syndrome and Noonan syndrome will be considered on a case-by-case basis.
Has received at least one of the following medications contraindicated in association with sildenafil within 15 days of inclusion:
- Organic nitrates in any form, either regularly or intermittently -- Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates.
- Ritonavir and other Potent CYP3A Inhibitors --- Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended.
- Alpha-blockers --- co-administering alpha-blockers with REVATIO because of additive blood pressure-lowering effects
- Amlodipine
- Cimetidine
- Requires concomitant use of potent cytochrome P450 3A4 inhibitors (such as ketoconazole, itraconazole, erythromycin, saquinavir), or concomitant use of ritonavir. Also excluded are concomitant use of organic nitrates, alpha-blockers, amlodipine, or cimetidine.
- Cannot confirm that the lesion is a lymphatic malformation or the lymphatic malformation is less than 3 cm in its greatest diameter during the MRI screening.
- Has had extensive prior surgery or sclerotherapy to treat LM such that scarring may interfere with evaluation and treatment effect of sildenafil.
- Have had recurrent infection and significant scarring of the lesion secondary to infection to such an extent that the that scarring may interfere with evaluation and treatment effect of sildenafil
- Known to have an allergy to sildenafil.
- Has ulcerated or currently infected LMs.
- Has diagnosis of the soft tissue tumor as LM not clinically certain.
- Participating in another clinical study which may interfere.
- Has a history of priapism or is diagnosed with sickle cell anemia or any other disorder which may predispose to priapism.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Supportive Care
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo tablets (resembling Revatio)
Placebo Drug: Placebo tablets (resembling Revatio)
|
|
Experimental: Sildenafil 20 mg tablets (Revatio)
Active Drug: Sildenafil tablets (Revatio)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination.
Time Frame: Baseline, week 20
|
Participants will be followed for the duration of the study, an expected average of 20 weeks.
|
Baseline, week 20
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score
Time Frame: Baseline, week 20
|
Subject's evaluation of the overall change in lymphatic malformation. Participants will be followed from baseline to 20 weeks. Patients rated change as no improvement, minimal improvement (1-25% change), fair improvement (25-50% change), good improvement (50-75% change), and excellent improvement (75-100% change). |
Baseline, week 20
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Joyce Teng, MD, PhD, Stanford School of Medicine
Publications and helpful links
General Publications
- Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):2649-51. doi: 10.1056/NEJMc0708819. No abstract available.
- Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, Lipsker D, Dupuis E, Ezzedine K, Vergnes P, Taieb A, Leaute-Labreze C. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009 Sep;124(3):e423-31. doi: 10.1542/peds.2008-3458. Epub 2009 Aug 10.
- Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: promise, peril, pathogenesis. Pediatr Dermatol. 2009 Sep-Oct;26(5):642-4. doi: 10.1111/j.1525-1470.2009.00977.x. No abstract available.
- Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart. 2000 Aug;84(2):E4. doi: 10.1136/heart.84.2.e4.
- Barst RJ, Ivy DD, Gaitan G, Szatmari A, Rudzinski A, Garcia AE, Sastry BK, Pulido T, Layton GR, Serdarevic-Pehar M, Wessel DL. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012 Jan 17;125(2):324-34. doi: 10.1161/CIRCULATIONAHA.110.016667. Epub 2011 Nov 29.
- Berk DR, Berk EJ, Bruckner AL. A novel method for calculating the volume of hemangiomas. Pediatr Dermatol. 2011 Jul-Aug;28(4):478-82. doi: 10.1111/j.1525-1470.2011.01498.x.
- Blei F. Congenital lymphatic malformations. Ann N Y Acad Sci. 2008;1131:185-94. doi: 10.1196/annals.1413.016.
- Churchill P, Otal D, Pemberton J, Ali A, Flageole H, Walton JM. Sclerotherapy for lymphatic malformations in children: a scoping review. J Pediatr Surg. 2011 May;46(5):912-22. doi: 10.1016/j.jpedsurg.2011.02.027.
- de Graaf M, Breur JMPJ, Raphael MF, Vos M, Breugem CC, Pasmans SGMA. Adverse effects of propranolol when used in the treatment of hemangiomas: a case series of 28 infants. J Am Acad Dermatol. 2011 Aug;65(2):320-327. doi: 10.1016/j.jaad.2010.06.048. Epub 2011 May 20.
- Fisher R, Partington A, Dykes E. Cystic hygroma: comparison between prenatal and postnatal diagnosis. J Pediatr Surg. 1996 Apr;31(4):473-6. doi: 10.1016/s0022-3468(96)90477-7.
- Fuchsmann C, Quintal MC, Giguere C, Ayari-Khalfallah S, Guibaud L, Powell J, McCone C, Froehlich P. Propranolol as first-line treatment of head and neck hemangiomas. Arch Otolaryngol Head Neck Surg. 2011 May;137(5):471-8. doi: 10.1001/archoto.2011.55.
- Gallagher PG, Mahoney MJ, Gosche JR. Cystic hygroma in the fetus and newborn. Semin Perinatol. 1999 Aug;23(4):341-56. doi: 10.1016/s0146-0005(99)80042-1.
- Greene AK, Perlyn CA, Alomari AI. Management of lymphatic malformations. Clin Plast Surg. 2011 Jan;38(1):75-82. doi: 10.1016/j.cps.2010.08.006.
- Howarth ES, Draper ES, Budd JL, Konje JC, Clarke M, Kurinczuk JJ. Population-based study of the outcome following the prenatal diagnosis of cystic hygroma. Prenat Diagn. 2005 Apr;25(4):286-91. doi: 10.1002/pd.1100.
- Karatza AA, Bush A, Magee AG. Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005 Apr 20;100(2):267-73. doi: 10.1016/j.ijcard.2004.09.002.
- Pfizer. (2007).
- Redondo P, Aguado L, Martinez-Cuesta A. Diagnosis and management of extensive vascular malformations of the lower limb: part I. Clinical diagnosis. J Am Acad Dermatol. 2011 Nov;65(5):893-906; quiz 907-8. doi: 10.1016/j.jaad.2010.12.047.
- Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2002 Apr 15;165(8):1098-102. doi: 10.1164/ajrccm.165.8.2107097.
- Wang P, Wu P, Egan RW, Billah MM. Identification and characterization of a new human type 9 cGMP-specific phosphodiesterase splice variant (PDE9A5). Differential tissue distribution and subcellular localization of PDE9A variants. Gene. 2003 Sep 18;314:15-27. doi: 10.1016/s0378-1119(03)00733-9.
- Whimster IW. The pathology of lymphangioma circumscriptum. Br J Dermatol. 1976 May;94(5):473-86. doi: 10.1111/j.1365-2133.1976.tb05134.x.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Lymphatic Vessel Tumors
- Congenital Abnormalities
- Lymphatic Diseases
- Lymphangioma
- Lymphatic Abnormalities
- Molecular Mechanisms of Pharmacological Action
- Vasodilator Agents
- Urological Agents
- Enzyme Inhibitors
- Phosphodiesterase Inhibitors
- Phosphodiesterase 5 Inhibitors
- Sildenafil Citrate
Other Study ID Numbers
- 23400
- R01FD004372 (U.S. FDA Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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