<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02991807</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-P00020332</org_study_id>
    <secondary_id>1U54NS092090</secondary_id>
    <nct_id>NCT02991807</nct_id>
  </id_info>
  <brief_title>RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome</brief_title>
  <official_title>A Randomized Double-Blind Controlled Trial of Everolimus in Individuals With PTEN Mutations (RAD001XUS257T)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Office of Rare Diseases (ORD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Center for Advancing Translational Sciences (NCATS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>PTEN Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Boston Children's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Phosphatase and TENsin homolog (PTEN) gene germline mutations are associated with a spectrum&#xD;
      of clinical manifestations characterized by neurocognitive deficits, intellectual disability,&#xD;
      autism symptomatology, skin lesions, macrocephaly, hamartomatous overgrowth of tissues, and&#xD;
      an increased risk of cancers. Investigators are conducting research to evaluate the potential&#xD;
      safety and efficacy of RAD001 (everolimus) in this patient population, and the potential&#xD;
      neurocognitive benefits from treatment with RAD001 or placebo for a six month period. The&#xD;
      investigators hope this trial will lead to a better understanding of PTEN and to new forms of&#xD;
      treatment that may benefit children and adults with PTEN in the future.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled&#xD;
      trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and&#xD;
      neurocognition as the primary endpoints.&#xD;
&#xD;
      Participant's or a legal guardian will need to sign an informed consent prior to enrollment&#xD;
      in the study. To determine eligibility participants will undergo a series of screening tests&#xD;
      and safety measures. If determined to be eligible for the blinded phase of the study,&#xD;
      participants will be randomly assigned to take either the study drug or a placebo (pill with&#xD;
      no medicine).&#xD;
&#xD;
      The blinded phase of the study involves about eight visits, five of which will occur at the&#xD;
      study site, and three of which will be conducted over the phone. These visits will take place&#xD;
      over a six month period. Study visits will vary in length. Baseline, three month and six&#xD;
      month visits may last up to 8 hours, if optional measures are done, while all other visits&#xD;
      will be less than 2 hours. The study visits include blood draws, general health exams, and&#xD;
      neuropsychological assessments. The study will also include optional eye-tracking, EEG and&#xD;
      auditory evoked potential (AEP) measures, and the collection of microbiome/mycobiome and&#xD;
      biomarker blood sample. There is no fee to participate in this study. The study drug will be&#xD;
      provided at no charge during the study.&#xD;
&#xD;
      After the 6 month treatment phase, individuals who were randomly assigned to take placebo&#xD;
      will be offered inclusion in a 6 month open label phase where the study drug will be provided&#xD;
      at no charge. The open label phase assessments will be similar to those done in the blinded&#xD;
      phase, but patients/families will only need to return to the study site three times during&#xD;
      this phase.&#xD;
&#xD;
      Participants will receive a developmental assessments report after completing the study.&#xD;
      After all study data has been analyzed, patients and families will also be informed of the&#xD;
      overall results. Treatment on this study may or may not improve an individual's learning&#xD;
      skills (neurocognition) or behavior. We hope that future patients and families will benefit&#xD;
      from what is learned by this study.&#xD;
&#xD;
      Specific Aims /Objectives Primary objective&#xD;
&#xD;
      -To evaluate the safety of everolimus compared with placebo in patients with PTEN mutations&#xD;
      focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4&#xD;
      laboratory toxicities.&#xD;
&#xD;
      Secondary objectives&#xD;
&#xD;
      -To evaluate the efficacy of everolimus on neurocognition and behavior in inividuals with&#xD;
      PTEN mutations compared to placebo as measured by standardized, direct and indirect&#xD;
      neurocognitive tools and behavioral measures.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 12, 2017</start_date>
  <completion_date type="Actual">December 22, 2021</completion_date>
  <primary_completion_date type="Actual">February 18, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>Through study completion, an average of 6 months</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Working Memory at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Working memory will be evaluated using the Stanford Binet 5 or Mullen Scales of Early Learning at 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Processing Speed at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Fine Motor Skills at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Attention at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Attention will be measured by Conners' Continuous Performance Test - 3 - Discriminability index (d') and Omissions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Impulsivity at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Impulsivity will be measured by Conners' Continuous Performance Test-3- Commissions and Bias (B').</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Global Cognitive Ability at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Motor Functioning at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Communication Ability at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>Communication ability will be measured by using standard scores of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>PTEN Gene Mutation</condition>
  <condition>PTEN Hamartoma Tumor Syndrome</condition>
  <arm_group>
    <arm_group_label>RAD001</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RAD001</intervention_name>
    <description>RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.&#xD;
Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.</description>
    <arm_group_label>RAD001</arm_group_label>
    <other_name>Everolimus</other_name>
    <other_name>Afinitor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.&#xD;
Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Double-Blind Inclusion Criteria&#xD;
&#xD;
          1. Male and female outpatients between 5 and 45 years of age (inclusive);&#xD;
&#xD;
          2. Pathogenic PTEN mutation confirmed by clinical genetic testing;&#xD;
&#xD;
          3. Participant must be able to complete one of the following three standardized&#xD;
             assessments: Conners' Continuous Performance Tasks (CPT-3-mean reaction time),&#xD;
             Stanford Binet (SB-5; working memory), or the Purdue Pegboard Test;&#xD;
&#xD;
          4. Performance below the age-adjusted population mean on at least one of the above&#xD;
             standardized measure: attention (CPT-3, mean reaction time), working memory (SB5), or&#xD;
             fine motor skills (Purdue Pegboard Test; either dominant hand, non-dominant hand, or&#xD;
             both hands);&#xD;
&#xD;
          5. Adequate bone marrow function as shown by:&#xD;
&#xD;
               1. platelets ≥ 80,000/mm3&#xD;
&#xD;
               2. absolute neutrophil count ≥ 1,000/mm3&#xD;
&#xD;
               3. hemoglobin ≥ 9 g/dL&#xD;
&#xD;
          6. Adequate liver function as shown by:&#xD;
&#xD;
               1. Total serum bilirubin &lt; 1.5 x ULN&#xD;
&#xD;
               2. AST and ALT levels &lt; 2.5 x ULN&#xD;
&#xD;
               3. INR ≤ 2&#xD;
&#xD;
          7. Adequate renal function: serum creatinine &lt; 1.5 x ULN,&#xD;
&#xD;
          8. Signed informed consent obtained prior to any screening procedures;&#xD;
&#xD;
          9. Individuals on psychotropic and anti-epileptic medications should maintain a stable&#xD;
             dose for at least 2 months prior to the screening visit;&#xD;
&#xD;
         10. Negative serum pregnancy test for females at screening and no plans to become pregnant&#xD;
             or conceive a child while participating in the study. The effects of mTOR inhibitors&#xD;
             on the developing fetus at the doses used in this study are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             prior to study entry and for the duration of the study. Estrogen-containing oral&#xD;
             contraceptives are not recommended in women enrolled in this study. Abstinence or two&#xD;
             effective non-estrogen or barrier methods of contraception (such as condoms +&#xD;
             spermicidal foam) must be used;&#xD;
&#xD;
         11. No anticipated changes in the frequency and intensity of existing interventions such&#xD;
             as behavioral and developmental treatments, in home services, and speech therapy;&#xD;
&#xD;
         12. No planned changes in school placement;&#xD;
&#xD;
         13. For individuals under 18 or who are otherwise incapable, there must be an available&#xD;
             caregiver who can reliably bring subject to clinic visits and provide trustworthy data&#xD;
&#xD;
         14. Able to communicate fluently in English&#xD;
&#xD;
        Double-Blind Exclusion Criteria&#xD;
&#xD;
          1. Patients currently receiving anticancer therapies or who have received anticancer&#xD;
             therapies within 4 weeks of the start of Everolimus (including chemotherapy, radiation&#xD;
             therapy, antibody based therapy, etc.);&#xD;
&#xD;
          2. Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g.&#xD;
             sirolimus, temsirolimus);&#xD;
&#xD;
          3. Known impairment of gastrointestinal (GI) function or GI disease that may&#xD;
             significantly alter the absorption of oral Everolimus;&#xD;
&#xD;
          4. Uncontrolled diabetes mellitus as defined by HbA1c &gt;8% despite adequate therapy.&#xD;
             Patients with a known history of impaired fasting glucose or diabetes mellitus (DM)&#xD;
             may be included, however blood glucose and antidiabetic treatment must be monitored&#xD;
             closely throughout the trial and adjusted as necessary;&#xD;
&#xD;
          5. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol &gt; 300 mg/dL OR&#xD;
             &gt;7.75 mmol/L AND fasting triglycerides &gt; 2.5 x ULN.&#xD;
&#xD;
          6. Patients who have any severe and/or uncontrolled medical or psychiatric conditions&#xD;
             (see section 4.6 for additional details)&#xD;
&#xD;
          7. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or&#xD;
             inhaled corticosteroids are allowed;&#xD;
&#xD;
          8. Known history of or seropositivity for Hepatitis B, Hepatitis C, or HIV;&#xD;
&#xD;
          9. Patients who have received live attenuated vaccines within 1 week of start of&#xD;
             Everolimus and during the study. Patient should also avoid close contact with others&#xD;
             who have received live attenuated vaccines. Examples of live attenuated vaccines&#xD;
             include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,&#xD;
             varicella and TY21a typhoid vaccines;&#xD;
&#xD;
         10. Patients who have a history of another primary malignancy, with the exceptions of:&#xD;
&#xD;
               1. non-melanoma skin cancer,&#xD;
&#xD;
               2. and carcinoma in situ of the cervix, uteri, or breast from which the patient has&#xD;
                  been disease free for ≥3 years;&#xD;
&#xD;
         11. Planned changes to concomitant medications;&#xD;
&#xD;
         12. Prior or concomitant therapy with known or possible anti-mTOR activity, including&#xD;
             rapamycin (sirolimus);&#xD;
&#xD;
         13. Concomitant therapy with strong inhibitor (e.g., cyclosporine and ketoconazole) or&#xD;
             inducer of CYP3A;&#xD;
&#xD;
         14. Active infection at time of enrollment;&#xD;
&#xD;
         15. Patients with a history of non-compliance to medical regimens or who are considered&#xD;
             potentially unreliable or will not be able to complete the entire study;&#xD;
&#xD;
         16. Patients who are currently part of or have participated in any clinical investigation&#xD;
             with an investigational drug within 1 month prior to dosing;&#xD;
&#xD;
         17. Pregnant or nursing (lactating) women;&#xD;
&#xD;
         18. Women of child-bearing potential (WOCBP), defined as all women physiologically capable&#xD;
             of becoming pregnant, must use highly effective methods of contraception during the&#xD;
             study and 8 weeks after. Highly effective contraception methods include:&#xD;
&#xD;
             a. A combination of any two of the following: i. Use of oral, injected or implanted&#xD;
             hormonal non-estrogen containing methods of contraception or; ii. Placement of an&#xD;
             intrauterine device (IUD) or intrauterine system (IUS); iii. Barrier methods of&#xD;
             contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with&#xD;
             spermicidal foam/gel/film/cream/ vaginal suppository; b. Total abstinence or; c.&#xD;
             Male/female sterilization. Women are considered post-menopausal and not of&#xD;
             child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea&#xD;
             with an appropriate clinical profile (e.g. age appropriate, history of vasomotor&#xD;
             symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy)&#xD;
             or tubal ligation at least six weeks prior to randomization. In the case of&#xD;
             oophorectomy alone, only when the reproductive status of the woman has been confirmed&#xD;
             by follow up hormone level assessment is she considered not of child-bearing&#xD;
             potential.&#xD;
&#xD;
         19. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate&#xD;
             contraception, during the study and for 8 weeks after the end of treatment&#xD;
&#xD;
         20. Major surgery, radiation therapy, or stereotactic radio-surgery within previous 4&#xD;
             weeks at time of screening&#xD;
&#xD;
         21. Neurosurgery within prior 6 months at time of screening.&#xD;
&#xD;
        Open-Label Inclusion Criteria&#xD;
&#xD;
          1. Patients who completed Double-Blind phase of the study and were assigned to the&#xD;
             placebo treatment arm;&#xD;
&#xD;
          2. Verbal consent (and assent, as appropriate) obtained prior to any open-label phase&#xD;
             study procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mustafa Sahin, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.rarediseasesnetwork.org/cms/dsc</url>
    <description>Developmental Synaptopathies Consortium</description>
  </link>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 14, 2016</study_first_posted>
  <last_update_submitted>February 7, 2022</last_update_submitted>
  <last_update_submitted_qc>February 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston Children's Hospital</investigator_affiliation>
    <investigator_full_name>Mustafa Sahin</investigator_full_name>
    <investigator_title>Director, Translational Neuroscience Center/ Professor of Neurology, Harvard Medical School</investigator_title>
  </responsible_party>
  <keyword>PTEN</keyword>
  <keyword>PTEN Gene Mutation</keyword>
  <keyword>PTEN Hamartoma Tumor Syndrome</keyword>
  <keyword>Autism</keyword>
  <keyword>Intellectual Disability</keyword>
  <keyword>Neurocognition</keyword>
  <keyword>Afinitor</keyword>
  <keyword>Everolimus</keyword>
  <keyword>RAD001</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hamartoma</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Hamartoma Syndrome, Multiple</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be shared with the National Database of Autism Research (NDAR)</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>May 6, 2022</submitted>
    <returned>June 2, 2022</returned>
    <submitted>August 18, 2022</submitted>
    <returned>September 12, 2022</returned>
    <submitted>December 1, 2022</submitted>
    <returned>December 21, 2022</returned>
    <submitted>January 10, 2023</submitted>
    <returned>February 3, 2023</returned>
    <submitted>May 11, 2023</submitted>
    <returned>May 11, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02991807
org study id: IRB-P00020332
secondary id: 1U54NS092090
nct id: NCT02991807
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
time frame: Through study completion, an average of 6 months
description: 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.
measure: Change in Working Memory at 6 Months
time frame: 6 months
description: Working memory will be evaluated using the Stanford Binet 5 or Mullen Scales of Early Learning at 6 months
measure: Change in Processing Speed at 6 Months
time frame: 6 months
description: Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3.
measure: Change in Fine Motor Skills at 6 Months
time frame: 6 months
description: Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands
measure: Change in Attention at 6 Months
time frame: 6 months
description: Attention will be measured by Conners' Continuous Performance Test - 3 - Discriminability index (d') and Omissions
measure: Change in Impulsivity at 6 Months
time frame: 6 months
description: Impulsivity will be measured by Conners' Continuous Performance Test-3- Commissions and Bias (B').
measure: Change in Global Cognitive Ability at 6 Months
time frame: 6 months
description: Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ)
measure: Change in Motor Functioning at 6 Months
time frame: 6 months
description: 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.
measure: Change in Communication Ability at 6 Months
time frame: 6 months
description: Communication ability will be measured by using standard scores of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2)
arm group label: RAD001
arm group type: Experimental
description: 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.
arm group label: Placebo
arm group type: Placebo Comparator
description: Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.
intervention type: Drug
intervention name: RAD001
description: RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.
Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.
arm group label: RAD001
other name: Everolimus
other name: Afinitor
intervention type: Drug
intervention name: Placebo
description: Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.
Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.
arm group label: Placebo
criteria: 
gender: All
minimum age: 5 Years
maximum age: 45 Years
healthy volunteers: No
last name: Mustafa Sahin, MD, PhD
role: Principal Investigator
affiliation: Boston Children's Hospital
facility: 
facility: 
facility: 
country: United States
url: http://www.rarediseasesnetwork.org/cms/dsc
description: Developmental Synaptopathies Consortium
responsible party type: Principal Investigator
investigator affiliation: Boston Children's Hospital
investigator full name: Mustafa Sahin
investigator title: Director, Translational Neuroscience Center/ Professor of Neurology, Harvard Medical School
mesh term: Hamartoma
mesh term: Neoplasms
mesh term: Hamartoma Syndrome, Multiple
mesh term: Syndrome
mesh term: Everolimus
sharing ipd: Yes
ipd description: Data will be shared with the National Database of Autism Research (NDAR)
submitted: May 6, 2022
returned: June 2, 2022
submitted: August 18, 2022
returned: September 12, 2022
submitted: December 1, 2022
returned: December 21, 2022
submitted: January 10, 2023
returned: February 3, 2023
submitted: May 11, 2023
returned: May 11, 2023