RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome
- Conditions
- PTEN Hamartoma Tumor SyndromePTEN Gene Mutation
- Interventions
- Drug: Placebo
- Registration Number
- NCT02991807
- Lead Sponsor
- Boston Children's Hospital
- Brief Summary
Phosphatase and TENsin homolog (PTEN) gene germline mutations are associated with a spectrum of clinical manifestations characterized by neurocognitive deficits, intellectual disability, autism symptomatology, skin lesions, macrocephaly, hamartomatous overgrowth of tissues, and an increased risk of cancers. Investigators are conducting research to evaluate the potential safety and efficacy of RAD001 (everolimus) in this patient population, and the potential neurocognitive benefits from treatment with RAD001 or placebo for a six month period. The investigators hope this trial will lead to a better understanding of PTEN and to new forms of treatment that may benefit children and adults with PTEN in the future.
- Detailed Description
This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and neurocognition as the primary endpoints.
Participant's or a legal guardian will need to sign an informed consent prior to enrollment in the study. To determine eligibility participants will undergo a series of screening tests and safety measures. If determined to be eligible for the blinded phase of the study, participants will be randomly assigned to take either the study drug or a placebo (pill with no medicine).
The blinded phase of the study involves about eight visits, five of which will occur at the study site, and three of which will be conducted over the phone. These visits will take place over a six month period. Study visits will vary in length. Baseline, three month and six month visits may last up to 8 hours, if optional measures are done, while all other visits will be less than 2 hours. The study visits include blood draws, general health exams, and neuropsychological assessments. The study will also include optional eye-tracking, EEG and auditory evoked potential (AEP) measures, and the collection of microbiome/mycobiome and biomarker blood sample. There is no fee to participate in this study. The study drug will be provided at no charge during the study.
After the 6 month treatment phase, individuals who were randomly assigned to take placebo will be offered inclusion in a 6 month open label phase where the study drug will be provided at no charge. The open label phase assessments will be similar to those done in the blinded phase, but patients/families will only need to return to the study site three times during this phase.
Participants will receive a developmental assessments report after completing the study. After all study data has been analyzed, patients and families will also be informed of the overall results. Treatment on this study may or may not improve an individual's learning skills (neurocognition) or behavior. We hope that future patients and families will benefit from what is learned by this study.
Specific Aims /Objectives Primary objective
-To evaluate the safety of everolimus compared with placebo in patients with PTEN mutations focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.
Secondary objectives
-To evaluate the efficacy of everolimus on neurocognition and behavior in inividuals with PTEN mutations compared to placebo as measured by standardized, direct and indirect neurocognitive tools and behavioral measures.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 46
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RAD001 RAD001 RAD001 is formulated as tablets of 5.0 mg or 2.5mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. Placebo Placebo Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.
- Primary Outcome Measures
Name Time Method Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability], Dropout Through study completion, an average of 6 months The primary endpoint will be safety as measured by study drop-out rate due to side effects, comparing everolimus vs. placebo. We will also determine the frequency of adverse events by type and severity.
This section displays participant dropout rate and for what reason.Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability], Adverse Events (AEs) Overview (% of Participants) Through study completion, an average of 6 months The primary endpoint will be safety as measured by study drop-out rate due to side effects, comparing everolimus vs. placebo. We will also determine the frequency of adverse events by type and severity.
this section displays the number of participants who experienced an AE and the description of such AEs, pertaining to:
1. Seriousness
2. Grade,
3. Relation to treatment
4. Recovery from AE
5. Category
- Secondary Outcome Measures
Name Time Method Change at 6 Months in Composite Score 6 months Composite score was based on the following:
Stanford-Binet Intelligence Scales, 5th Ed (SB-5) non-verbal and verbal working memory standard score; for the SB-5, the minimum score is 40 and the maximum score is 160, where the higher score represents a better outcome.
Conners' Continuous Performance Test, 3rd Ed (CPT-3) hit reaction time standard score (reverse coded; standard score generated from T-score); for the CPT-3, the min score is 0 and the max score is 90, where the lower the T-score, the better the outcome.
Purdue Pegboard Test (PPT) both hands standard score (generated from T-score); for the PPT, the min score is 20 and the max score is 190, where the higher the T-score, the better the outcome.
For the composite score, the higher the score, the better the outcome. The composite score is on the SS metric (M=100, SD=15, min=20, max=180).Change in Processing Speed at 6 Months, Conner's Continuous Performance Test (CPT)-3 6 months Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3. This outcome evaluates the change from baseline to 6 months.
Change in Fine Motor Skills at 6 Months, Purdue Pegboard 6 months Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands. This outcome evaluates the change from baseline to 6 months.
Change in Global Cognitive Ability at 6 Months, Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) or Mullen Scales of Early Learning 6 months Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ). This outcome evaluates the change from baseline to 6 months.
Change in Motor Functioning at 6 Months, Purdue Pegboard and Developmental Coordination Disorder Questionnaire (DCDQ) 6 months Motor functioning will be measured by the Purdue Pegboard (Pegs): Dominant and non-dominant hand combined standard scores and Developmental Coordination Disorder Questionnaire (DCDQ): Total score. This outcome evaluates the change from baseline to 6 months.
Change in Memory, Executive Functioning, Autism Symptoms, Adaptive Behaviors, and Other Behaviors at 6 Months 6 months 1. Change in memory measured by Wide Range Assessment of Memory and Learning (WRAML-2) verbal learning core subtest, delayed recall, and recognition scaled scores over 6 months.
2. Change in executive functioning measured by Behavior Rating Inventory of Executive Function (BRIEF-2) global executive composite standard score over 6 months.
3. Change in autism symptoms measured by Social Responsiveness Scale (SRS-2) total standard score and Repetitive Behaviors Scale (RBS-R) total subscale score over 6 months.
4. Change in adaptive behaviors measured by Vineland Adaptive Behavior Scales (VABS-III) adaptive behavior composite standard score over 6 months.
5. Change in other behaviors measured by Child Behavior Checklist (CBCL) total problems standard score and Short Sensory Profile (SSP) total score over 6 months.
Trial Locations
- Locations (3)
Stanford University
🇺🇸Palo Alto, California, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States