Sildenafil for the Treatment of Lymphatic Malformations
Condition: Lymphatic Malformations; Lymphatic Diseases
MeSH terms: Lymphangioma; Lymphatic Diseases; Lymphatic Abnormalities; Congenital Abnormalities
Intervention: Sildenafil 20 mg tablets; Placebo tablets (resembling Revatio)
Intervention MeSH terms: Sildenafil Citrate
Phase: Phase 2
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 6 Months
Maximum age: 10 Years
Healthy volunteers: No
Keywords: Sildenafil; Magnetic Resonance Imaging; Dermatology; Pediatrics

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
    

Eligibility criteria:

        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.