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Sildenafil for the Treatment of Lymphatic Malformations

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ClinicalTrials.gov Identifier: NCT02335242
Recruitment Status : Recruiting
First Posted : January 9, 2015
Last Update Posted : June 9, 2020
Sponsor:
Collaborator:
Ann & Robert H Lurie Children's Hospital of Chicago
Information provided by (Responsible Party):
Joyce Teng, Stanford University

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


Condition or disease Intervention/treatment Phase
Lymphatic Malformations Lymphatic Diseases Drug: Sildenafil 20 mg tablets Other: Placebo tablets (resembling Revatio) Phase 2

Detailed Description:
Lymphatic malformations (LMs) are localized areas of abnormal development of the lymphatic system that commonly occur in the head and neck of children. LMs are considered a rare or orphan disease which causes complications including pain, ulceration, secondary infection, infiltration of other organs, and death. Current therapies involve surgical excision or methods of chemical or physical destruction of portions of lesions. No therapies are uniformly effective and all have the risk of significant adverse events. We recently witnessed almost complete resolution of a LM lesion in a child who was treated with sildenafil oral therapy for pulmonary arterial hypertension. We have subsequently evaluated additional subjects who improved with sildenafil. The goal of this clinical research trial is to document the benefit or absence of benefit of sildenafil therapy for LMs and identify which type of patient will benefit from sildenafil. This study is a double-blind placebo-controlled trial which involves precise documentation of volume changes associated with therapy or placebo by using MRI segmentation techniques. We will also observe and document the clinical response to sildenafil or placebo using clinical evaluation scores and surveys. The results of the study should identify characteristics of LM lesions which may suggest a beneficial response to sildenafil therapy. Sildenafil has very low risk of side effects in the dosage used in this trial. Documentation of an effective response of LMs to sildenafil will accelerate the interest in, and the ability to understand, the mechanisms of LM formation and treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: Phase 2 Study of Sildenafil for the Treatment of Lymphatic Malformations
Actual Study Start Date : May 23, 2015
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo tablets (resembling Revatio)
Placebo Drug: Placebo tablets (resembling Revatio)
Other: Placebo tablets (resembling Revatio)
Experimental: Sildenafil 20 mg tablets (Revatio)
Active Drug: Sildenafil tablets (Revatio)
Drug: Sildenafil 20 mg tablets



Primary Outcome Measures :
  1. Change in lesion volume of the test medication as evaluated by MRI examination. [ Time Frame: 20 weeks ]
    Participants will be followed for the duration of the study, an expected average of 20 weeks.


Secondary Outcome Measures :
  1. Change in lesion volume estimated using a soft tape measure to measure the length, width, and hemispheric measurement of each of the lymphatic malformations. [ Time Frame: 20 weeks ]
    Participants will be followed for the duration of the study, an expected average of 20 weeks.

  2. Subject's evaluation of the change in lesion clinical characteristics. [ Time Frame: 20 weeks ]
    Participants will be followed from baseline to 20 weeks.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 10 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02335242


Contacts
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Contact: Joyce Teng, MD, PhD (650) 724-9627 jteng3@stanford.edu
Contact: Elidia C Tafoya, MPH (650) 724-1982 econtrer@stanford.edu

Locations
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United States, California
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Elidia C Tafoya, MPH    650-724-1982    econtrer@stanford.edu   
Contact: Joyce Teng, MD, PhD    (650) 723-6493    jteng3@stanford.edu   
Principal Investigator: Joyce Teng, MD, PhD         
Sub-Investigator: Anthony Mancini, MD         
Sub-Investigator: Anna Bruckner, MD         
United States, Colorado
University of Colorado, Denver Recruiting
Aurora, Colorado, United States, 80045-2571
Contact: Anna Bruckner, MD    720-777-0955    ANNA.BRUCKNER@UCDENVER.EDU   
Principal Investigator: Anna Bruckner, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Thy Huynh, MD    312-227-6486    MAsztalos@luriechildrens.org   
Contact: Thy Huynh, MD    312.227.6486    thy.huynh@northwestern.edu   
Principal Investigator: Anthony Mancini, MD         
Sponsors and Collaborators
Stanford University
Ann & Robert H Lurie Children's Hospital of Chicago
Investigators
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Principal Investigator: Joyce Teng Stanford School of Medicine
Publications of Results:
Pfizer. (2007).

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Responsible Party: Joyce Teng, Professor of Dermatology and Pediatrics, Stanford University
ClinicalTrials.gov Identifier: NCT02335242    
Other Study ID Numbers: 23400
R01FD004372 ( U.S. FDA Grant/Contract )
First Posted: January 9, 2015    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The IPD will only be shared de-identified to our study staff and human subjects approved subsites. These results will eventually be published, but will be completed around 2022.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Joyce Teng, Stanford University:
Sildenafil
Magnetic Resonance Imaging
Dermatology
Pediatrics
Additional relevant MeSH terms:
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Lymphangioma
Lymphatic Diseases
Lymphatic Abnormalities
Congenital Abnormalities
Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Neoplasms
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents