A randomized controlled trial of Everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome
PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mTOR (mechanistic target of rapamycin) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in h...
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| Veröffentlicht in: | Human molecular genetics 2022-10, Vol.31 (20), p.3393-3404 |
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| creator | Srivastava, Siddharth Jo, Booil Zhang, Bo Frazier, Thomas Gallagher, Anne Snow Peck, Fleming Levin, April R Mondal, Sangeeta Li, Zetan Filip-Dhima, Rajna Geisel, Gregory Dies, Kira A Diplock, Amelia Eng, Charis Hanna, Rabi Sahin, Mustafa Hardan, Antonio |
| description | PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mTOR (mechanistic target of rapamycin) 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 |
| doi_str_mv | 10.1093/hmg/ddac111 |
| format | Article |
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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) six 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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddac111</identifier><identifier>PMID: 35594551</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Original</subject><ispartof>Human molecular genetics, 2022-10, Vol.31 (20), p.3393-3404</ispartof><rights>The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-6189ed238fa832391cd83783e578263673383ec64406b6a5204bdbed89c728b53</citedby><cites>FETCH-LOGICAL-c447t-6189ed238fa832391cd83783e578263673383ec64406b6a5204bdbed89c728b53</cites><orcidid>0000-0001-7008-1879 ; 0000-0001-7044-2953</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35594551$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Srivastava, Siddharth</creatorcontrib><creatorcontrib>Jo, Booil</creatorcontrib><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Frazier, Thomas</creatorcontrib><creatorcontrib>Gallagher, Anne Snow</creatorcontrib><creatorcontrib>Peck, Fleming</creatorcontrib><creatorcontrib>Levin, April R</creatorcontrib><creatorcontrib>Mondal, Sangeeta</creatorcontrib><creatorcontrib>Li, Zetan</creatorcontrib><creatorcontrib>Filip-Dhima, Rajna</creatorcontrib><creatorcontrib>Geisel, Gregory</creatorcontrib><creatorcontrib>Dies, Kira A</creatorcontrib><creatorcontrib>Diplock, Amelia</creatorcontrib><creatorcontrib>Eng, Charis</creatorcontrib><creatorcontrib>Hanna, Rabi</creatorcontrib><creatorcontrib>Sahin, Mustafa</creatorcontrib><creatorcontrib>Hardan, Antonio</creatorcontrib><creatorcontrib>the Developmental Synaptopathies Consortium</creatorcontrib><title>A randomized controlled trial of Everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mTOR (mechanistic target of rapamycin) 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) six 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. 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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) six 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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>35594551</pmid><doi>10.1093/hmg/ddac111</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-7008-1879</orcidid><orcidid>https://orcid.org/0000-0001-7044-2953</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Original |
| title | A randomized controlled trial of Everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome |
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