Sildenafil for the Treatment of Lymphatic Malformations

NCT02335242 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 23400R01FD004372
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 3

Brief Summary

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

Conditions

Lymphatic Malformations; Lymphatic Diseases

Keywords

Sildenafil; Magnetic Resonance Imaging; Dermatology; Pediatrics

Outcome Measures

Primary Outcomes (1)

• Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination.

  Participants will be followed for the duration of the study, an expected average of 20 weeks.

  Baseline, week 20

Secondary Outcomes (1)

• Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score

  Baseline, week 20

Study Arms (2)

Placebo tablets (resembling Revatio)

PLACEBO COMPARATOR

Placebo Drug: Placebo tablets (resembling Revatio)

Other: Placebo tablets (resembling Revatio)

Sildenafil 20 mg tablets (Revatio)

EXPERIMENTAL

Active Drug: Sildenafil tablets (Revatio)

Drug: Sildenafil 20 mg tablets

Interventions

Sildenafil 20 mg tablets DRUG

Sildenafil 20 mg tablets (Revatio)

Placebo tablets (resembling Revatio) OTHER

Placebo tablets (resembling Revatio)

Eligibility Criteria

• Age: 6 Months - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Stanford University: lead
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator

Study Sites (3)

Stanford University

Stanford, California, 94305, United States

Location

University of Colorado, Denver

Aurora, Colorado, 80045-2571, United States

Location

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Related Publications (20)

• 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.

  PMID: 10908271 BACKGROUND

• 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.

  PMID: 22128226 BACKGROUND

• 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.

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• Blei F. Congenital lymphatic malformations. Ann N Y Acad Sci. 2008;1131:185-94. doi: 10.1196/annals.1413.016.

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• 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.

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• 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.

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• 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.

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• 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.

  PMID: 19840341 BACKGROUND

• 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.

  PMID: 21576558 BACKGROUND

• 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.

  PMID: 10475547 BACKGROUND

• 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.

  PMID: 21095473 BACKGROUND

• 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.

  PMID: 15849783 BACKGROUND

• 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.

  PMID: 15823634 BACKGROUND

• 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.

  PMID: 18550886 BACKGROUND

• Pfizer. (2007).

  BACKGROUND

• 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.

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• 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.

  PMID: 19706583 BACKGROUND

• 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.

  PMID: 11956051 BACKGROUND

• 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.

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• 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.

  PMID: 1268059 BACKGROUND

MeSH Terms

Conditions

Lymphatic Abnormalities; Lymphatic Diseases

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Only 1 of 4 planned sites participated in this trial; the study did not meet its planned enrollment and the results are underpowered.

Results Point of Contact

• Title: Jean Teng, MD, PhD
• Organization: Stanford University

jteng3@stanford.edu

(650) 724-9627

Study Officials

• Joyce Teng, MD, PhD

  Stanford School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2015
• First Posted: January 9, 2015
• Study Start: May 23, 2015
• Primary Completion: March 30, 2021
• Study Completion: March 30, 2021
• Last Updated: November 17, 2022
• Results First Posted: November 17, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)