PMID- 35594551 OWN - NLM STAT- MEDLINE DCOM- 20221014 LR - 20221201 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 31 IP - 20 DP - 2022 Oct 10 TI - A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. PG - 3393-3404 LID - 10.1093/hmg/ddac111 [doi] AB - PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners' Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P < 0.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen's d = -0.10, P = 0.518). However, several measures were associated with modest effect sizes (>/=0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P = 0.049) and central beta power (P = 0.039) 6 months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I. CI - (c) The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Srivastava, Siddharth AU - Srivastava S AUID- ORCID: 0000-0001-7008-1879 AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Jo, Booil AU - Jo B AD - Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA. FAU - Zhang, Bo AU - Zhang B AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Frazier, Thomas AU - Frazier T AD - Department of Psychology, John Carroll University, University Heights, OH 44118, USA. FAU - Gallagher, Anne Snow AU - Gallagher AS AD - Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Peck, Fleming AU - Peck F AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Levin, April R AU - Levin AR AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Mondal, Sangeeta AU - Mondal S AD - Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA. FAU - Li, Zetan AU - Li Z AD - Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA. FAU - Filip-Dhima, Rajna AU - Filip-Dhima R AD - Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Geisel, Gregory AU - Geisel G AD - Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Dies, Kira A AU - Dies KA AD - Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Diplock, Amelia AU - Diplock A AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. AD - Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Eng, Charis AU - Eng C AD - Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA. FAU - Hanna, Rabi AU - Hanna R AD - Department of Pediatrics, Hematology, Oncology, Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, OH 44195, USA. FAU - Sahin, Mustafa AU - Sahin M AUID- ORCID: 0000-0001-7044-2953 AD - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. AD - Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Hardan, Antonio AU - Hardan A AD - Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA. CN - Developmental Synaptopathies Consortium LA - eng SI - ClinicalTrials.gov/NCT02991807 GR - P50 HD105351/HD/NICHD NIH HHS/United States GR - K23 NS119666/NS/NINDS NIH HHS/United States GR - U54 NS092090/NS/NINDS NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - *Autistic Disorder/drug therapy MH - Double-Blind Method MH - Everolimus/adverse effects MH - *Hamartoma Syndrome, Multiple MH - Humans MH - PTEN Phosphohydrolase MH - TOR Serine-Threonine Kinases MH - Treatment Outcome PMC - PMC9558845 FIR - Sahin, Mustafa IR - Sahin M FIR - Eng, Charis IR - Eng C FIR - Hardan, Antonio IR - Hardan A FIR - Martinez-Agosto, Julian A IR - Martinez-Agosto JA FIR - Frazier, Thomas IR - Frazier T EDAT- 2022/05/21 06:00 MHDA- 2022/10/15 06:00 PMCR- 2022/05/20 CRDT- 2022/05/20 17:14 PHST- 2021/12/02 00:00 [received] PHST- 2022/03/24 00:00 [revised] PHST- 2022/04/03 00:00 [accepted] PHST- 2022/05/21 06:00 [pubmed] PHST- 2022/10/15 06:00 [medline] PHST- 2022/05/20 17:14 [entrez] PHST- 2022/05/20 00:00 [pmc-release] AID - 6589680 [pii] AID - ddac111 [pii] AID - 10.1093/hmg/ddac111 [doi] PST - ppublish SO - Hum Mol Genet. 2022 Oct 10;31(20):3393-3404. doi: 10.1093/hmg/ddac111.