Sturge-Weber Syndrome
Conditions
Keywords
SWS, Cognitive impairment, sirolimus
Brief summary
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.
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.
Interventions
DRUGSirolimus
Low dose oral sirolimus
Sponsors
Children's Hospital Medical Center, Cincinnati
Pfizer
National Institutes of Health (NIH)
Faneca 66 Foundation
National Institute of Neurological Disorders and Stroke (NINDS)
Anne Comi, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 31 Years
Healthy volunteers
No
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: http://www.nkdep.nih.gov/professionals/gfr\_calculators/index.htm 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.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | 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
| Measure | Time frame | Description |
|---|---|---|
| Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band | 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 | 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 | 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. |
Countries
United States
Participant flow
Pre-assignment details
All enrolled participants will receive oral sirolimus.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Sirolimus: Low dose oral sirolimus | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 9 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 12.58 years STANDARD_DEVIATION 5.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 9 / 10 |
| serious Total, serious adverse events | 2 / 10 |
Outcome results
Primary
Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery
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.
Time frame: Baseline and at 6 months on the study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Vocabulary Baseline | 44.2 T score | Standard Deviation 12.5 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Vocabulary Follow-up | 42.3 T score | Standard Deviation 12.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Attention Baseline | 34.1 T score | Standard Deviation 10.5 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Attention Follow-up | 35.2 T score | Standard Deviation 14.1 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Working Memory Baseline | 26.3 T score | Standard Deviation 9.8 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Working Memory Follow-up | 28.1 T score | Standard Deviation 3.9 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Executive Function Baseline | 33.1 T score | Standard Deviation 10.2 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Executive Function Follow-up | 35.7 T score | Standard Deviation 15.4 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Processing Speed Baseline | 27.0 T score | Standard Deviation 14.5 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Processing Speed Follow-up | 36.4 T score | Standard Deviation 17.6 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Sequential Memory Baseline | 39.3 T score | Standard Deviation 12.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Sequential Memory Follow-up | 40.9 T score | Standard Deviation 8.6 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Recognition Baseline | 37.7 T score | Standard Deviation 12.8 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | National Institute of Health Toolbox Recognition Follow-up | 36.0 T score | Standard Deviation 10.4 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Baseline | 43.5 T score | Standard Deviation 8.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Follow-up | 35.4 T score | Standard Deviation 20.5 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Baseline | 45.9 T score | Standard Deviation 7.9 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Follow-up | 35.7 T score | Standard Deviation 20.4 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Baseline | 53.8 T score | Standard Deviation 5.1 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Follow-up | 36.7 T score | Standard Deviation 15.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference | 49.2 T score | Standard Deviation 11.1 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System Pain (PROMIS) Interference Follow-up | 36.1 T score | Standard Deviation 18.8 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Baseline | 46.9 T score | Standard Deviation 10.9 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Interference Follow-up | 41.9 T score | Standard Deviation 15.7 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Peer Relations Baseline | 49.8 T score | Standard Deviation 10.9 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Patient-Reported Outcomes Measurement Information System (PROMIS) Peer Relations Follow-up | 44.1 T score | Standard Deviation 17.5 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Grip Strength Dominant Baseline | 39.0 T score | Standard Deviation 14.4 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Grip Strength Dominant Follow-up | 42.0 T score | Standard Deviation 5.1 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Grip Strength Non-Dominant Baseline | 26.1 T score | Standard Deviation 28.2 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Grip Strength Non-Dominant Follow-up | 20.6 T score | Standard Deviation 28.9 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Dexterity Dominant Baseline | 30.6 T score | Standard Deviation 16.8 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Dexterity Dominant Follow-up | 31.6 T score | Standard Deviation 14.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Dexterity Non-Dominant Baseline | 31.6 T score | Standard Deviation 14.3 |
| Sirolimus | Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery | Dexterity Non-Dominant Follow-up | 30.1 T score | Standard Deviation 19.9 |
Secondary
Change in Sturge-Weber Syndrome Clinical Neuroscore
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.
Time frame: Baseline and at 6 months on the study drug
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Composite Score Baseline | 4.5 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Composite Score Follow-up | 4.5 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Seizure Score Baseline | 1 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Seizure Score Follow-Up | 1 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Hemiparesis Score Baseline | 1 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Hemiparesis Score Follow-up | 1 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Visual Field Cut Score Baseline | 0.5 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Visual Field Cut Score Follow-up | 0 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Cognitive Function Score Baseline | 2.5 score on a scale |
| Sirolimus | Change in Sturge-Weber Syndrome Clinical Neuroscore | Cognitive Function Score Follow-Up | 2.5 score on a scale |
Secondary
Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band
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).
Time frame: Baseline and at 6months on the study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sirolimus | Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band | Patients with Stroke-Like Episodes Baseline | 0.686 score on a scale | Standard Deviation 0.03 |
| Sirolimus | Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band | Patients with Stroke-Like Episodes Follow-up | 0.426 score on a scale | Standard Deviation 0.19 |
| Sirolimus | Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band | Patients without Stroke-like episodes Baseline | 0.167 score on a scale | Standard Deviation 0.23 |
| Sirolimus | Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band | Patients without stroke-line episodes follow-up | 0.247 score on a scale | Standard Deviation 0.13 |
Secondary
Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score
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.
Time frame: Visits at 2 weeks (baseline) and 28 weeks (study end)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score | Improved Port-Wine Score | 4 Participants |
| Sirolimus | Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score | No Change Port-Wine Score | 2 Participants |
| Sirolimus | Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score | Worsened Port-Wine Score | 2 Participants |
| Sirolimus | Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score | No Port-Wine Birthmark | 2 Participants |