A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations

Antonio Y Hardan; Booil Jo; Thomas W Frazier; Patricia Klaas; Robyn M Busch; Kira A Dies; Rajna Filip-Dhima; Anne V Snow; Charis Eng; Rabi Hanna; Bo Zhang; Mustafa Sahin

doi:10.1016/j.conctc.2021.100733

A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations

Contemp Clin Trials Commun. 2021 Feb 6:21:100733. doi: 10.1016/j.conctc.2021.100733. eCollection 2021 Mar.

Authors

Antonio Y Hardan¹, Booil Jo¹, Thomas W Frazier^{2

3

4}, Patricia Klaas⁵, Robyn M Busch^{4

5

6}, Kira A Dies^{7

8}, Rajna Filip-Dhima^{7

8}, Anne V Snow⁹, Charis Eng^{4

6

10

11

12}, Rabi Hanna^{6

9}, Bo Zhang⁷, Mustafa Sahin^{7

8}

Affiliations

¹ Department of Psychiatry and Behavioral Science, Stanford University, Stanford, CA, USA.
² Autism Speaks, New York, NY, USA.
³ Department of Psychology, John Carroll University, Cleveland Heights, Ohio, USA.
⁴ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ F.M. Kirby Neurobiology Center, Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Pediatric Hematology Oncology and Bone Marrow Transplantation, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
¹¹ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹² Germline High Risk Cancer Focus Group, Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Abstract

This randomized, double-blind controlled trial of everolimus in individuals with germline phosphatase and tensin homolog mutations (PTEN) was designed to evaluate the safety of everolimus compared with placebo and to evaluate the efficacy of everolimus on neurocognition and behavior compared to placebo as measured by standardized neurocognitive and motor measures as well as behavioral questionnaires. The safety profile of everolimus is characterized by manageable adverse events that are generally reversible and non-cumulative. The primary safety endpoint of this study was drop-out rate due to side effects, comparing everolimus versus placebo. We also sought to determine the frequency of adverse events by type and severity. The main efficacy endpoint was a neurocognitive composite computed in two ways: 1) an average for working memory, processing speed, and fine motor subtests; and 2) the same average as above except weighted 2/3, and an additional average based on all other available neurocognitive testing measures assessing the additional domains of nonverbal ability, visuomotor skills, verbal learning, and receptive and expressive language, weighted 1/3. Secondary efficacy endpoints examined the effect of everolimus on overall global clinical improvement, autism symptoms, behavioral problems, and adaptive abilities as measured by validated, standardized instruments. We predicted that the rate of adverse events would be no more than 10% higher in the everolimus group compared to placebo, and overall severity of side effects would be minimal. We also expected that individuals receiving everolimus would show more improvement, relative to those taking placebo, on the composite neurocognitive index.

Keywords: Autism spectrum disorder; Everolimus; Neurobehavior and neurocognition; PTEN hamartoma tumor syndrome; Randomized controlled trial.

Abstract

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