WithdrawnNCT06080165Updated Jul 10, 2024

Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

A Phase 1/2 interventional study of Sirolimus and Placebo in PTEN Gene Mutation, PTEN Hamartoma Tumor Syndrome and PTEN Hamartoma Syndrome, sponsored by Stanford University. Withdrawn at 3 sites in United States. Open to participants aged 5 Years to 45 Years. Per ClinicalTrials.gov, last updated 2024-07-10.

Sponsored by Stanford University · Phase 1/2, Interventional, and Treatment

Why this study was withdrawn

Investigator decided not to proceed with the trial.

Phase: Phase 1/2
Study type: Interventional
Enrollment: 0
Allocation: Randomized
Ages: 5 Years to 45 Years
Sex: All

Study 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.

Conditions studied

PTEN Gene Mutation
PTEN Hamartoma Tumor Syndrome
PTEN Hamartoma Syndrome

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Keywords

Sirolimus
Rapamune

Who can participate

Ages eligible: 5 Years to 45 Years
Sexes eligible: All
Accepts healthy volunteers: No

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;
No planned changes in school placement in children and adolescents;
Availability of reliable transportation to attend clinic visits;
availability of a trustworthy informant who interacts with subject on a regular basis;
Ability to participate in the testing procedures to the extent that valid standard scores and biological samples can be obtained.

Exclusion criteria

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.

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 0 participants (actual)

Study arms

Experimental
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.
Drug: Sirolimus
Placebo comparator
Placebo
matching placebo
Drug: Placebo

Interventions

DrugSirolimus
Experimental: 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 clinical labs of sirolimus levels. 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.
Also known as: Rapamune
DrugPlacebo
matching placebo

What researchers measure

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

Clinical Global Impression Improvement (CGI-I) Scale changes during treatment.
Time frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Change from baseline on parent rated Stanford Social Dimensions Scale (SSDS)
Time frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6

Other outcomes

Change from baseline on Brief Observation of Social Communication Change (BOSCC)
Time frame: Month 6
Change from baseline on Neurobehavioral Evaluation Tool (NET) Social Communication and Interaction subscale
Time frame: Month 3, Month 6
Change from baseline on the Reading the Mind in the Eyes Test (RMET)
Time frame: Month 6
Change from baseline on Purdue Pegboard (PP) Test
Time frame: Month 6
Change from baseline on parent rated Dimensional Assessment of Restricted/Repetitive Behaviors (DARB)
Time frame: Month 3, Month 6
Change from baseline on Vineland Adaptive Behavior Scales (VABS-III)
Time frame: Month 3, Month 6
Change from baseline on Wide Range Assessment of Memory and Learning-2 (WRAML-2)
Time frame: Month 6
Change from baseline on Clinical Global Impression Improvement (CGI-I) Scale changes during treatment.
Time frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6
Change from baseline on parent reported Child or Adult Behavioral Checklist
Time frame: Month 3, Month 6
Change from baseline on complete blood count (CBC) with differential as measured by peripheral blood
Time frame: Month 1, Month 3, Month 5, Month 6
Change from baseline on comprehensive metabolic panel as measured by peripheral blood
Time frame: Month 1, Month 3, Month 5, Month 6
Change from baseline on lipid profile as measured by peripheral blood.
Time frame: Month 1, Month 3, Month 5, Month 6

Study locations

3 sites

Stanford University
Stanford, California 94305, United States
Boston Children's Hospital
Boston, Massachusetts 02115, United States
Cleveland Clinic
Cleveland, Ohio 44195, United States

References and documents

Individual participant data

Plan to share: Yes — Data will be on the National Institute of Mental Health Data Archive (NDA).

No publications or documents are linked to this record.

Registry details

Key details

Study ID: NCT06080165
Lead sponsor: Stanford University
Responsible party: Antonio Hardan (Professor, Stanford University) — Principal investigator
First posted: Oct 12, 2023
Start date: Jul 2024 (estimated)
Primary completion: Jun 2028 (estimated)
Completion: Jun 2028 (estimated)
Last update: Jul 10, 2024

Study contacts

Antonio Hardan, MD

principal investigator · Stanford University

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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