Lymphatic Diseases, Lymphatic Malformations
Conditions
Keywords
Sildenafil, Magnetic Resonance Imaging, Dermatology, Pediatrics
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
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.
Interventions
DRUGSildenafil 20 mg tablets
OTHERPlacebo tablets (resembling Revatio)
Sponsors
Ann & Robert H Lurie Children's Hospital of Chicago
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 10 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination. | Baseline, week 20 | Participants will be followed for the duration of the study, an expected average of 20 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | 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). |
Countries
United States
Participant flow
Pre-assignment details
78 individuals were assessed for eligibility; 22 were enrolled, and 19 were randomized to a study arm.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Placebo Then Open-Label Sildenafil Placebo (resembling Revatio) for 20 weeks. Participants randomized to placebo had the option to enter a 20-week open-label phase to receive active sildenafil (Revatio) for 20 weeks three times daily (weight-based: 10 mg TID for participants weighing 8-20 kg; 20 mg TID for participants weighing \>20 kg), followed by a 12 week follow-up period. | 8 |
| Double-Blind Sildenafil Sildenafil (Revatio) for 20 weeks three times daily (weight-based: 10 mg TID for participants weighing 8-20 kg; 20 mg TID for participants weighing \>20 kg), followed by a 12-week follow-up period. | 11 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period (12 Weeks) | Discontinued intervention | 1 | 1 |
| Follow-up Period (12 Weeks) | Lost to Follow-up | 1 | 0 |
| Randomized Phase (20 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Double-Blind Placebo Then Open-Label Sildenafil | Total | Double-Blind Sildenafil |
|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 19 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Lesion volume | 49 mm^3 | 87 mm^3 | 144 mm^3 |
| Race/Ethnicity, Customized African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Indian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown/Not reported | 1 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 8 Participants | 19 Participants | 11 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 8 / 8 | 5 / 6 | 10 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 10 |
Outcome results
Primary
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.
Time frame: Baseline, week 20
Population: Participants who completed each treatment period are included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind Placebo | Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination. | 5.89 percentage of volume | Standard Deviation 13.5 |
| Open-Label Sildenafil | Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination. | -8.54 percentage of volume | Standard Deviation 12.1 |
| Double-blind Sildenafil | Change in Lesion Volume of the Test Medication as Evaluated by MRI Examination. | -0.642 percentage of volume | Standard Deviation 18.3 |
Secondary
Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score
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).
Time frame: Baseline, week 20
Population: Participants with data at both baseline and week 20 are included in the analysis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-Blind Placebo | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Minimal improvement | 2 Participants |
| Double-Blind Placebo | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Good improvement | 2 Participants |
| Double-Blind Placebo | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Fair improvement | 0 Participants |
| Double-Blind Placebo | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Excellent improvement | 0 Participants |
| Double-Blind Placebo | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | No improvement | 1 Participants |
| Open-Label Sildenafil | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Excellent improvement | 0 Participants |
| Open-Label Sildenafil | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | No improvement | 2 Participants |
| Open-Label Sildenafil | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Minimal improvement | 4 Participants |
| Open-Label Sildenafil | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Fair improvement | 1 Participants |
| Open-Label Sildenafil | Change in Subject's Assessment of Change in Lymphatic Malformation Overall Score | Good improvement | 1 Participants |