Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)

NCT01289912 | Completed Phase 2 Results DMC

• 1 other identifier: 10-06-0247
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 2

Brief Summary

Tuberous Sclerosis Complex (TSC) is a multi-system disease, usually presenting with seizures, mental retardation and autism, and exhibiting a high variability in clinical findings both among and within families. Investigators are doing research in order to identify possible neurocognitive benefits from treatment with RAD001 or placebo for a six month period. There may also be potential for improvements in seizure frequency, sleep and autistic behaviors. We hope this trial will lead to a better understanding of TSC and to new forms of treatment, to benefit children and adults with TSC in the future. Individuals diagnosed with TSC will be asked to participate in this study if they are between the ages of 6 and 21 years of age and have an IQ of greater than or equal to 60. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals must have been on the same seizure medication(s), if applicable, for at least 6 months. Individuals must also be able to participate in neuropsychological testing and meet certain medical criteria. They will need to sign an informed consent. If enrolled in the study, participants will have a number of screening tests to help determine if they are eligible for participation in the clinical trial. If eligible for the treatment phase of the trial, they will be asked to take either the study drug or a placebo (pill with no medicine), which is determined by chance. The study involves about 9 visits, 3 of which can be done locally, over a six month period, as well as follow-up calls with our research nurse. Study visits will vary in length. Screening, three month and six month visits may last up to 8 hours, while all other visits will be less than 2 hours. The study visits include blood draws, laboratory tests and neuropsychological assessments. There is no fee to participate in this study. The study drug will be provided at no charge during the study. After all study data has been analyzed, families will be informed of the overall results. Treatment on this study may or may not improve a child's learning skills (neurocognition). Future patients may benefit from what is learned.

Conditions

Tuberous Sclerosis Complex

Keywords

Tuberous Sclerosis Complex; Autism; Neurocognition; RAD001; Everolimus; Afinitor; TSC

Outcome Measures

Primary Outcomes (3)

• Evaluation of the Safety of RAD001 on Neurocognition in Patients With TSC Compared With Placebo in Patients With TSC.

  Evaluation of the safety of RAD001 compared with placebo in patients with TSC focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.

  6 months

• Evaluation of the Efficacy of RAD001 on Neurocognition in Patients With TSC Compared With Placebo.

  Baseline and 6 month Timepoint scores are reported for the following primary outcome measures: 1. Peabody Picture Vocabulary Test 4 (PPVT-4; Receptive Language Measure). Scores reported as (mean, SD). Range=40-160, higher scores are better. 2. Expressive Vocabulary Test 2 (EVT-2; Expressive Language Measure). Scores reported as (mean, SD). Range=40-160, higher scores are better. 3. Wide Range Assessment of Memory and Learning 2 (WRAML2; Measure of Verbal Memory and Attention ). Scores reported as (mean, SD). Range=1-19, higher scores are better. 4. Vineland Adaptive Behavior Scales-II (VABS-II; Measure of Adaptive Behavior). Scores reported as (mean, SD). Range = 40-160, higher scores are better. 5. Purdue Pegboard Test (Measure of Fine Motor Speed and Coordination). Scores reported as (mean, SD). Range = 40-160, higher scores are better.

  6 months

• Evaluation of the Efficacy of RAD001 on Neurocognition (Cambridge Neuropsychological Test Automated Battery) in Patients With TSC Compared With Placebo.

  Scores are reported for baseline and 6 month timepoints on the Cambridge Neuropsychological Test Automated Battery (CANTAB) subscales below. For all subscales, scores are reported as the mean difference between the study subjects and a normative population matched for age, gender and IQ (e.g., subject subscale score - mean of matched normative group = reported score). Higher scores represent a better outcome. 1. Spatial Span (SSP) (spatial memory span) Range: -3 to 3 2. Spatial Working Memory (working memory) Range: -3 to 3 3. Pattern Recognition Memory (PRM) (visual pattern recognition memory) Range: -3 to 3 4. Spatial Recognition Memory (SRM) (spatial recognition memory) Range: -4 to 4 5. Rapid Visual Information Processing (RVIP) (sustained attention) Range: -4 to 4 6. Stockings of Cambridge (SOC) (spatial planning) Range: -4 to 4 7. Intra-Extra Dimensional Set Shift (IDED) (cognitive flexibility) Range: -5 to 5 8. Reaction Time (processing speed) Range: -5 to 5

  6 months

Secondary Outcomes (5)

• Comparison of Absolute Change From Baseline in Frequency of Epileptiform Events Between Patients Taking RAD001 vs. Placebo

  6 months

• Comparison of Sleep Disturbances Between Patients Taking RAD001 vs. Placebo

  6 months

• Comparison of Autism Spectrum Disorders Features Between Patients Taking RAD001 vs. Placebo

  6 months

• Comparison of Academic Skills Between Patients Taking RAD001 vs. Placebo

  6 months

• Comparison of Behavioral Problems Between Patients Taking RAD001 vs Placebo

  6 months

Study Arms (2)

RAD001

EXPERIMENTAL

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.

Drug: RAD001

Placebo

PLACEBO COMPARATOR

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.

Drug: Placebo

Interventions

RAD001 DRUG

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 in the morning after a light, nonfat breakfast.

Also known as: Everolimus, Afinitor

RAD001

Placebo DRUG

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 in the morning after a light, nonfat breakfast.

Placebo

Eligibility Criteria

• Age: 6 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Male or female patients ages 6 to 21 years of age.
• IQ ≥60.
• Ability to participate in direct neuropsychological and developmental testing.
• English as primary language.
• Diagnosis of tuberous sclerosis complex confirmed by genetic testing and/or clinically definite diagnosis of tuberous sclerosis complex according to the modified Gomez criteria and an IQ\>60.
• Stable anti-epileptic drugs (no changes in medications except dose for \>6 months).
• Adequate renal function. The GFR would 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
• If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, excluding estrogen containing contraceptives, while on study. Abstinence will be considered an adequate contraceptive measure.
• 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 at time of randomization.)
• Adequate liver function as shown by:
• serum bilirubin ≤ 1.5 x ULN
• ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
• Written informed consent according to local guidelines.

You may not qualify if:

• Change of one or more antiepileptic medication in the past 6 months.
• Prior exposure to the systemic use of an mTOR inhibitor.
• Exposure to any investigational agent in the 30 days prior to randomization.
• Neurosurgery within 6 months.
• Known impaired lung function (e.g.FEV1 or DLCO \<70% of predicted), if not resolved or if resolved within past 24 months.
• Significant hematological or hepatic abnormality (i.e. transaminase levels \> 2.5 x ULN or serum bilirubin \> 1.5 x ULN, hemoglobin \< 9 g/dL, platelets \< 80,000/ mm3, absolute neutrophil count \< 1,000/mm3).
• Serum creatinine \> 1.5 x ULN.
• Uncontrolled hyperlipidemia: Fasting serum cholesterol \> 300 mg/dL OR \> 7.75 mmol/L AND Fasting triglycerides \> 2.5 x ULN.
• Uncontrolled diabetes mellitus as defined by fasting serum glucose \> 1.5 x ULN.
• Patients with bleeding diathesis or on oral anti-vitamin K medication (except low dose warfarin).
• Patients with known history of HIV seropositivity.
• Pregnancy or breast feeding.
• Active infection at date of randomization.
• Prior history of organ transplant.
• Recent surgery (involving entry into a body cavity or requiring sutures) within the 4 weeks prior to randomization.

Sponsors & Collaborators

• Mustafa Sahin: lead
• Tuberous Sclerosis Alliance: collaborator
• Autism Speaks: collaborator
• Novartis Pharmaceuticals: collaborator
• Seizure Tracker LLC: collaborator

Study Sites (2)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Related Links

• Tuberous Sclerosis Alliance

MeSH Terms

Conditions

Tuberous Sclerosis; Autistic Disorder

Interventions

Everolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Mustafa Sahin
• Organization: Boston Children's Hospital

Mustafa.Sahin@childrens.harvard.edu

617-355-8994

Study Officials

• Mustafa Sahin, MD, PhD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: February 2, 2011
• First Posted: February 4, 2011
• Study Start: January 1, 2011
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: January 25, 2018
• Results First Posted: January 25, 2018

Record last verified: 2018-01

Locations

US (2)