Trial of Sirolimus for Cognitive Impairment in Sturge-Weber Syndrome


The purpose of this research study is to gain a preliminary understanding of the safety of sirolimus in Sturge-Weber syndrome (SWS) and determine best outcomes to be used to assess the utility of sirolimus for the treatment of cognitive impairments related to Sturge-Weber syndrome.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 4, 2019

Detailed Description

Sirolimus will be administered as an adjunct to all current medications. The impact of sirolimus upon cognitive functioning in Sturge-Weber syndrome is the primary outcome measure. This outcome will be assessed using a panel of testing selected based upon extensive experience in testing cognitive function in adults and children with SWS at the Kennedy Krieger Sturge-Weber Center. Changes in a quantitative EEG before and after the trial, Sturge-Weber syndrome clinical neuroscore, port-wine birthmark score, and the impact of sirolimus upon seizures will be assessed.


  • Drug: Sirolimus
    • Low dose oral sirolimus

Arms, Groups and Cohorts

  • Experimental: Sirolimus
    • All subjects will receive the sirolimus oral solution to be taken at home twice daily and will be treated on an outpatient basis. The drug will be taken for six months.

Clinical Trial Outcome Measures

Primary Measures

  • Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery
    • Time Frame: Baseline and at 6 months on the study drug
    • Change over six months in cognitive functioning in Sturge-Weber syndrome is the primary outcome measure. This outcome will be assessed using the NIH Toolbox Cognitive Battery, a panel of testing which includes the following measures: the Flanker Inhibitory Control and Attention Test (executive function and attention) the Dimensional Change Card Sort Test (executive function) Picture Sequence Memory Test (episodic memory) Oral Reasoning Recognition Test and Picture Vocabulary Test (language skills) Pattern Comparison Processing Speed Test (processing speed) List Sorting Working Memory Test (working memory) 9-hole Peg Test (dexterity) Grip Strength Test (grip strength) and Patient-Reported Outcomes Measurement Information System (PROMIS) (self-report emotional functioning). These scores are rescaled to T scores (mean = 50, standard deviation (SD) = 10), referenced against the US population. Higher scores indicate better outcome. T scores only were analyzed.

Secondary Measures

  • Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band
    • Time Frame: Baseline and at 6months on the study drug
    • Change in mean laterality score (by qEEG power analysis) was done comparing hemispheres and occipital lobes in the following frequency bands; delta, theta, alpha, beta, as previously described. As post-hoc analysis, baseline and follow-up qEEG of patients with and without stroke-like episodes were compared. Greater asymmetry with decreased power on the affected side is worse. We calculated a mean Laterality Score (LSb) for each band, averaged over 30 epochs and included channel pairs. Laterality Scores less than zero indicate lower power on the side ipsilateral to the port wine birthmark. In subjects who had a bilateral port wine birthmark, the side of maximal involvement was used (or the side of known involvement by MRI findings, where present).
  • Change in Sturge-Weber Syndrome Clinical Neuroscore
    • Time Frame: Baseline and at 6 months on the study drug
    • Change in clinical neuroscore over the course of the study were measured. The neuroscore is comprised of frequency of seizures (0-4) , extent of hemiparesis (0-4), assessment of visual field cut (0-2) , and degree of cognitive functioning (0-5) with a minimum total score of 0 and a maximum total score of 15. Higher scores mean worsening of symptoms.
  • Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score
    • Time Frame: Visits at 2 weeks (baseline) and 28 weeks (study end)
    • Frontal and profile photograph will be taken under standardized conditions with scoring of the port-wine birthmark for percent of face covered, thickness of birthmark, and darkness of birthmark color.

Participating in This Clinical Trial

Inclusion Criteria

1. Male or female patients ages 3 to 31 years of age, inclusive. 2. Cognitive impairment as defined by the following: SWS cognitive neuroscore of ≥ 1 3. Ability to participate in direct neuropsychological and developmental testing. 4. English as primary language. 5. Stable anti-epileptic drugs (no changes in medications except dose for >3 months). 6. Adequate renal function. GFR must be greater than 50 ml/min/m2 as determined by the Schwartz Formula for children and MDRD for adults: 7. If female and of child bearing potential, documentation of a negative pregnancy test prior to enrollment determined by a urine test is required. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on the study drug. Abstinence will be considered an adequate contraceptive measure. 8. INR ≤1.5 (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks.) 9. Adequate liver function as shown by:

  • Serum bilirubin ≤ 1.5x ULN – ALT and AST ≤ 2.5x ULN 10. Written informed consent according to local guidelines. Local guidelines for subject assent will also be followed. 11. Stable dose of medications affecting the cytochrome P 450 3A4 (CYP3A4) and p glycoprotein (P gp) systems for at least 3 months prior to consent. Exclusion Criteria:

1. Allergy to sirolimus or other rapamycin analogues. 2. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder, drug abuse or current seizures related to an acute medical illness. 3. Inability to keep follow-up appointments, maintain close contact with Principal Investigators, and/or complete all necessary studies to maintain safety. 4. Patients in need of immediate major surgical intervention. 5. Concurrent severe and/or uncontrolled medical disease, which could compromise participation in the pilot study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration, impaired or restrictive pulmonary function, pneumonitis or pulmonary infiltrates). 6. Chronic treatment with systemic steroids or another immunosuppressive agent. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Inhaled steroids are allowed. 7. Known history of HIV seropositivity or known immunodeficiency. Testing is not required unless a condition is suspected. 8. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A gastric tube or nasogastric tube is allowed. 9. Patients with an active, bleeding diathesis. 10. Patients with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL AND fasting triglycerides > 2.5 x ULN. 11. Patients who have had a major surgery or significant traumatic injury within four weeks of study entry. Patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the pilot study. 12. Patients with a prior history of organ transplant. 13. Patients who have received live attenuated vaccines within one week of start of sirolimus and during the pilot study. 14. Patients who have a history of malignancy. 15. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within one month prior to enrollment. 16. Patients being treated with felbamate, unless treatment has been continuous for ≥ one year. 17. Patients currently receiving anticancer therapies or who have received anticancer therapies within four weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.).

Gender Eligibility: All

Minimum Age: 3 Years

Maximum Age: 31 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Anne Comi, MD
  • Collaborator
    • Children’s Hospital Medical Center, Cincinnati
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Anne Comi, MD, Principal Investigator, Director Sturge-Weber Center, Kennedy Krieger Institute, Professor Johns Hopkins University School of Medicine – Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
  • Overall Official(s)
    • Anne M Comi, M.D., Principal Investigator, Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

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