A Randomized Controlled Double-Blind Trial of Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations
Overview
- Phase
- Phase 1
- Intervention
- Sirolimus
- Conditions
- PTEN Gene Mutation
- Sponsor
- Stanford University
- Locations
- 3
- Primary Endpoint
- Change from baseline in parent rated Social Responsiveness Scale, Second Edition Total Scores (SRS-2) total scores during treatment.
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
The goal of this study is to examine the safety and treatment effects of sirolimus for targeting social communication deficits in people with genetic disorders associated with PTEN germline mutations, which are often referred to as PTEN Harmartoma Tumor Syndrome (PHTS). The mechanism of sirolimus in the body has shown promise for helping to improve social communication skills in case reports of people with PHTS. Everolimus, a closely related compound, also showed benefits in social communication skills in a previous pilot trial in people with PHTS. This is a 6 month double-blind trial followed by at 6 month open label extension trial.
Investigators
Antonio Hardan
Professor
Stanford University
Eligibility Criteria
Inclusion Criteria
- •Inclusion Criteria: All participants will meet the following selection criteria:
- •Male or female outpatients between 5.00 and 45.99 years of age
- •PHTS confirmed by genetic testing;
- •Fluent in English
- •at least moderate severity of social skill deficits based on a social responsiveness scale t score ≥ 60
- •Stable psychotropic and anti-epileptic medications for at least 4 weeks with the exception of fluoxetine which should be stable for at least 8 weeks
- •Adequate Liver function (SGOT, SGPT, TBili, Alk Phos all\<3x normal); HCT\>27%; WBC \> 3.0, ANC \>1,500, and platelets \>100,000
- •adequate renal function with a GFR ≥ 50 ml/min/m2 as determined by the Schwartz Formula for children and MDRD for adults (www.nkdep.nih.gov/professionals/gfr_calculators/index)
- •Negative urine pregnancy test for females and no plans to become pregnant or conceive a child while participating in the study. The effects of mTOR inhibitors on the developing fetus at the doses used in this study are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of the study. Because of the possibility of drug interactions and the potential effect of female hormones on the growth of kidney angiomyolipomas and lymphangioleiomyomatosis, estrogen-containing oral contraceptives are not recommended in women enrolled in this study, so an effective non-estrogen or barrier method of contraception must be used.
- •Medically stable with no active medical problems such as unstable seizures or cardiovascular disease or cancer that is not in remission as evidenced by medical history; -No anticipated changes in frequency and intensity of existing interventions such as behavioral and developmental treatments, in home services, or speech therapy;
Exclusion Criteria
- •Participants will be excluded if one of the following is met:
- •Significant medical illness, such as endocrinopathies, cardiovascular disease, or severe chronic malnutrition;
- •Pregnancy, planned pregnancy, or unwillingness to use adequate contraception;
- •Planned changes to concomitant medications;
- •Concomitant therapy, or prior use within 3 months of the baseline visit, with an agent with known or possible anti-mTOR activity or concomitant therapy with strong inhibitors (e.g., cyclosporine and ketoconazole) or inducers of CYP3A;
- •Active infection at time of enrollment;
- •Participation in a clinical trial in the 30 days prior to study entry;
- •Major surgery, radiation therapy or stereotactic radio-surgery within previous 4 weeks at time of enrollment; and
- •Neurosurgery within prior 6 months at time of enrollment.
Arms & Interventions
Sirolimus
Participants that are 5 to 12.99 years old will start at 1 mg/m2/dose. Participants that are 13 to 45.99 years old and \< 39.99 kg in weight will also start on 1 mg/day. Participants that are 13 to 45.99 years old and \> 40 kg in weight will start on 2 mg/day. The target blood level will be 5-15 ng/ml with dose adjustment based on sirolimus levels obtained every 2 to 3 weeks after every dose change.
Intervention: Sirolimus
Placebo
matching placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Change from baseline in parent rated Social Responsiveness Scale, Second Edition Total Scores (SRS-2) total scores during treatment.
Time Frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Secondary Outcomes
- Change from baseline on parent rated Stanford Social Dimensions Scale (SSDS)(Month 1, Month 2, Month 3, Month 4, Month 5, Month 6)
- Clinical Global Impression Improvement (CGI-I) Scale changes during treatment.(Month 1, Month 2, Month 3, Month 4, Month 5, Month 6)