Trial of Sirolimus for Cognitive Impairment in Sturge-Weber Syndrome

Sponsor
Anne Comi, MD (Other)
Overall Status
Completed
CT.gov ID
NCT03047980
Collaborator
Children's Hospital Medical Center, Cincinnati (Other), Pfizer (Industry), National Institutes of Health (NIH) (NIH), Faneca 66 Foundation (Other), National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
10
2
1
45.8
5
0.1

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
10 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Trial of Sirolimus for Cognitive Impairment in Sturge-Weber Syndrome
Study Start Date :
Jan 1, 2017
Actual Primary Completion Date :
Jun 4, 2019
Actual Study Completion Date :
Oct 27, 2020

Arms and Interventions

Arm Intervention/Treatment
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.

Drug: Sirolimus
Low dose oral sirolimus
Other Names:
  • Rapamycin
  • Rapamune
  • Outcome Measures

    Primary Outcome Measures

    1. 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 Outcome Measures

    1. 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).

    2. 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.

    3. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    3 Years to 31 Years
    Sexes Eligible for Study:
    All
    Accepts 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

    1. Ability to participate in direct neuropsychological and developmental testing.

    2. English as primary language.

    3. Stable anti-epileptic drugs (no changes in medications except dose for >3 months).

    4. 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

    1. 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.

    2. 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.)

    3. Adequate liver function as shown by:

    • Serum bilirubin ≤ 1.5x ULN

    • ALT and AST ≤ 2.5x ULN

    1. Written informed consent according to local guidelines. Local guidelines for subject assent will also be followed.

    2. 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.).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Kennedy Krieger Institute Baltimore Maryland United States 21205
    2 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229

    Sponsors and Collaborators

    • Anne Comi, MD
    • Children's Hospital Medical Center, Cincinnati
    • Pfizer
    • National Institutes of Health (NIH)
    • Faneca 66 Foundation
    • National Institute of Neurological Disorders and Stroke (NINDS)

    Investigators

    • Principal Investigator: Anne M Comi, M.D., Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    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.
    ClinicalTrials.gov Identifier:
    NCT03047980
    Other Study ID Numbers:
    • IRB00079722
    • 2U54NS065705
    • BVMC6209
    First Posted:
    Feb 9, 2017
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Sep 1, 2021
    Keywords provided by 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.
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail All enrolled participants will receive oral sirolimus.
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Period Title: Overall Study
    STARTED 10
    COMPLETED 9
    NOT COMPLETED 1

    Baseline Characteristics

    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Overall Participants 10
    Age (Count of Participants)
    <=18 years
    9
    90%
    Between 18 and 65 years
    1
    10%
    >=65 years
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    12.58
    (5.17)
    Sex: Female, Male (Count of Participants)
    Female
    5
    50%
    Male
    5
    50%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    10
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    10%
    White
    9
    90%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    10
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Cognitive Function as Assessed by the National Institute of Health (NIH) Toolbox Cognitive Battery
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Measure Participants 9
    National Institute of Health Toolbox Vocabulary Baseline
    44.2
    (12.5)
    National Institute of Health Toolbox Vocabulary Follow-up
    42.3
    (12.3)
    National Institute of Health Toolbox Attention Baseline
    34.1
    (10.5)
    National Institute of Health Toolbox Attention Follow-up
    35.2
    (14.1)
    National Institute of Health Toolbox Working Memory Baseline
    26.3
    (9.8)
    National Institute of Health Toolbox Working Memory Follow-up
    28.1
    (3.9)
    National Institute of Health Toolbox Executive Function Baseline
    33.1
    (10.2)
    National Institute of Health Toolbox Executive Function Follow-up
    35.7
    (15.4)
    National Institute of Health Processing Speed Baseline
    27.0
    (14.5)
    National Institute of Health Processing Speed Follow-up
    36.4
    (17.6)
    National Institute of Health Toolbox Sequential Memory Baseline
    39.3
    (12.3)
    National Institute of Health Toolbox Sequential Memory Follow-up
    40.9
    (8.6)
    National Institute of Health Toolbox Recognition Baseline
    37.7
    (12.8)
    National Institute of Health Toolbox Recognition Follow-up
    36.0
    (10.4)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Baseline
    43.5
    (8.3)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety Follow-up
    35.4
    (20.5)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Baseline
    45.9
    (7.9)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Follow-up
    35.7
    (20.4)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Baseline
    53.8
    (5.1)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Follow-up
    36.7
    (15.3)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference
    49.2
    (11.1)
    Patient-Reported Outcomes Measurement Information System Pain (PROMIS) Interference Follow-up
    36.1
    (18.8)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Baseline
    46.9
    (10.9)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Interference Follow-up
    41.9
    (15.7)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Peer Relations Baseline
    49.8
    (10.9)
    Patient-Reported Outcomes Measurement Information System (PROMIS) Peer Relations Follow-up
    44.1
    (17.5)
    Grip Strength Dominant Baseline
    39.0
    (14.4)
    Grip Strength Dominant Follow-up
    42.0
    (5.1)
    Grip Strength Non-Dominant Baseline
    26.1
    (28.2)
    Grip Strength Non-Dominant Follow-up
    20.6
    (28.9)
    Dexterity Dominant Baseline
    30.6
    (16.8)
    Dexterity Dominant Follow-up
    31.6
    (14.3)
    Dexterity Non-Dominant Baseline
    31.6
    (14.3)
    Dexterity Non-Dominant Follow-up
    30.1
    (19.9)
    2. Secondary Outcome
    Title Difference in Mean Power Asymmetry of the Occipital Alpha Frequency Band
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Measure Participants 10
    Patients with Stroke-Like Episodes Baseline
    0.686
    (0.03)
    Patients with Stroke-Like Episodes Follow-up
    0.426
    (0.19)
    Patients without Stroke-like episodes Baseline
    0.167
    (0.23)
    Patients without stroke-line episodes follow-up
    0.247
    (0.13)
    3. Secondary Outcome
    Title Change in Sturge-Weber Syndrome Clinical Neuroscore
    Description 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Measure Participants 10
    Composite Score Baseline
    4.5
    Composite Score Follow-up
    4.5
    Seizure Score Baseline
    1
    Seizure Score Follow-Up
    1
    Hemiparesis Score Baseline
    1
    Hemiparesis Score Follow-up
    1
    Visual Field Cut Score Baseline
    0.5
    Visual Field Cut Score Follow-up
    0
    Cognitive Function Score Baseline
    2.5
    Cognitive Function Score Follow-Up
    2.5
    4. Secondary Outcome
    Title Number of Participants With a Change in Sturge-Weber Syndrome Birthmark Score
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    Measure Participants 10
    Improved Port-Wine Score
    4
    40%
    No Change Port-Wine Score
    2
    20%
    Worsened Port-Wine Score
    2
    20%
    No Port-Wine Birthmark
    2
    20%

    Adverse Events

    Time Frame 6 months
    Adverse Event Reporting Description The Rare Diseases Clinical Research Network defines an adverse event as "...an unfavorable and unintended sign, symptom or disease associated with a participants' participation in a Rare Disease Clinical Research Network Study." The three types of adverse events are serious adverse events, unexpected adverse events and expected adverse events. This classification is using Common Terminology Criteria for Adverse Events developed and maintained by CTEP at National Cancer Institute.
    Arm/Group Title Sirolimus
    Arm/Group Description 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
    All Cause Mortality
    Sirolimus
    Affected / at Risk (%) # Events
    Total 0/10 (0%)
    Serious Adverse Events
    Sirolimus
    Affected / at Risk (%) # Events
    Total 2/10 (20%)
    Blood and lymphatic system disorders
    Anemia 1/10 (10%) 1
    Nervous system disorders
    Headache 1/10 (10%) 1
    Headache 1/10 (10%) 1
    Other (Not Including Serious) Adverse Events
    Sirolimus
    Affected / at Risk (%) # Events
    Total 9/10 (90%)
    Gastrointestinal disorders
    Abdominal Pain 1/10 (10%) 1
    Nausea 1/10 (10%) 1
    Infections and infestations
    Upper Respiratory Infection 1/10 (10%) 1
    Investigations
    Increased Alanine Aminotransferase 1/10 (10%) 1
    Increased aspartate aminotransferase 2/10 (20%) 3
    Cholesterol High 1/10 (10%) 4
    Decreased HDL Cholesterol 2/10 (20%) 9
    Metabolism and nutrition disorders
    Hypertriglyceridemia 4/10 (40%) 9
    Nervous system disorders
    Headache 2/10 (20%) 4
    Seizure 1/10 (10%) 2
    Somnolence 1/10 (10%) 1
    Product Issues
    Personality Change 2/10 (20%) 2
    Psychiatric disorders
    Behavioral Issues/ Aggression 1/10 (10%) 1
    Renal and urinary disorders
    Abnormal Urine Labs 1/10 (10%) 2
    Skin and subcutaneous tissue disorders
    Skin Ulceration in Mouth 3/10 (30%) 7

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Research Assistant
    Organization Kennedy Krieger Institute
    Phone 443-923-9569 ext 3-9569
    Email vedmurthyp@kennedykrieger.org
    Responsible Party:
    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.
    ClinicalTrials.gov Identifier:
    NCT03047980
    Other Study ID Numbers:
    • IRB00079722
    • 2U54NS065705
    • BVMC6209
    First Posted:
    Feb 9, 2017
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Sep 1, 2021