Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex (TSC)

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Brief Title

Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex (TSC)

Official Title

Everolimus (RAD001) Therapy for Epilepsy in Patients With Tuberous Sclerosis Complex

Brief Summary

      The goal of this study is to learn if the study drug RAD001 can reduced the number of
      epileptic seizures, and can be taken safety by people who have epilepsy associated with
      Tuberous Sclerosis Complex.
    

Detailed Description

      Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence at birth of 1 in
      6000. This disorder is characterized by the development of benign tumors in multiple organ
      systems, including the brain. The primary neurological manifestations of TSC are epilepsy,
      mental retardation and autism. Epilepsy is most common, occurring in 80-90% of patients, and
      often the seizures are severe, unremitting, and uncontrolled by current anticonvulsant
      medications. It is generally accepted that the seizures arise from cortical and subcortical
      tubers and surrounding tissue in the brain. These tubers are caused by mutations in the tumor
      suppressor genes TSC1 or TSC2. The protein products of these genes, hamartin and tuberin, act
      as negative regulators of the PI3K/PKB(Akt)/mTOR signaling pathway that regulates cell growth
      and proliferation Everolimus is an immunosuppressant drug that also inhibits mTOR signaling
      and is capable of reversing aberrant mTOR-dependent effects that occur when hamartin or
      tuberin are absent or defective. Thus, we hypothesize that drugs like everolimus may be
      therapeutically useful for the treatment of refractory epilepsy in patients with TSC.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Reduction in Seizure Frequency


Condition

Epilepsy

Intervention

Everolimus

Study Arms / Comparison Groups

 Everolimus
Description:  Subjects will be administered study drug if they meet study criteria after 4 weeks of baseline phase. The starting dose will be 5 mg/m2/day, rounded to the nearest 2.5 mg/dose, to be taken daily.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

January 2010

Completion Date

April 2016

Primary Completion Date

April 2016

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female individuals aged two years and older.

          -  History of epilepsy and at least eight reported seizures in previous 30 days prior to
             informed consent

          -  Failure of two or more approved antiepileptic drug therapies

          -  Clinically definite diagnosis of tuberous sclerosis (modified Gomez criteria or
             positive genetic test)

          -  Parents/Caregivers are English-speaking (primary or secondary language acceptable)

          -  If female and of child bearing potential, documentation of negative pregnancy test at
             time of informed consent. Sexually active pre-menopausal female or male patients must
             use adequate contraceptive measures, excluding use of estrogen-containing birth
             control contraceptive regimen while on study medication. Prior hysterectomy, tubal
             ligation, complete abstinence, barrier methods which include both a cervical diaphragm
             and spermicidal jelly, intrauterine devices (IUD), progesterone based contraceptives,
             or vasectomy in partner are all acceptable forms of contraception

          -  Adequate bone marrow function as shown by ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L,
             and Hb >9 g/dL

          -  Adequate liver function as shown by serum bilirubin ≤ 1.5 x upper limit of normal
             (ULN), ALT and AST ≤ 2.5x ULN, INR and PTT ≤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 renal function as shown by a serum creatinine ≤ 1.5 x ULN

          -  Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x
             ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only
             be included after initiation of appropriate lipid lowering medication

        Exclusion Criteria:

          -  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 < < 100 X 109/L ,
             absolute neutrophil count < 1.5 x 109/L)

          -  Patients currently receiving anticancer therapies or who have received anticancer
             therapies within 4 weeks of the start of study drug (including chemotherapy, radiation
             therapy, antibody based therapy, etc.)

          -  Patients, who have had a major surgery or significant traumatic injury within 4 weeks
             of start of study drug, 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 study

          -  Prior treatment with any investigational drug within the preceding 4 weeks prior to
             informed consent

          -  Patients receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent. Topical or inhaled corticosteroids are allowed

          -  Patients should not receive immunization with attenuated live vaccines within one week
             of informed consent or during study period

          -  Patients with coexisting malignancies within past 3 years, except for adequately
             treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

          -  Uncontrolled brain or leptomeningeal metastases, including patients who continue to
             require glucocorticoids for brain or leptomeningeal metastases

          -  Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as:

               -  Symptomatic congestive heart failure of New York heart Association Class III or
                  IV, unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within 6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia or any other clinically significant cardiac disease

               -  Severely impaired lung function defined as spirometry and DLCO that is 50% of the
                  normal predicted value and/or 02 saturation that is 88% or less at rest on room
                  air and/or requirement for continuous supplemental O2

               -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

               -  Active (acute or chronic) or uncontrolled severe infections

               -  Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis

                    -  A known history of HIV seropositivity

                    -  Impairment of gastrointestinal function or gastrointestinal disease that may
                       significantly alter the absorption of everolimus (e.g., ulcerative disease,
                       uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
                       bowel resection)

                    -  Patients with an active, bleeding diathesis

                    -  Female patients who are pregnant or breast feeding, or adults of
                       reproductive potential who are not using effective birth control methods.

                    -  Patients who have received prior treatment with an mTOR inhibitor
                       (sirolimus, temsirolimus, everolimus).

                    -  Patients with a known hypersensitivity to RAD001 (everolimus) or other
                       rapamycin (sirolimus, temsirolimus) or to its excipients

                    -  History of noncompliance to medical regimens
      

Gender

All

Ages

2 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Darcy Krueger, M.D. Ph.D, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01070316

Organization ID

2009-0998


Responsible Party

Sponsor

Study Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

 Novartis

Study Sponsor

Darcy Krueger, M.D. Ph.D, Principal Investigator, Children's Hospital Medical Center, Cincinnati


Verification Date

February 2017