Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.
Adolescent
Adult
Cognition
/ drug effects
Cross-Over Studies
Cyclic Nucleotide Phosphodiesterases, Type 4
/ metabolism
Fragile X Mental Retardation Protein
/ genetics
Fragile X Syndrome
/ drug therapy
Humans
Language Tests
Male
Phosphodiesterase 4 Inhibitors
/ therapeutic use
Placebos
/ administration & dosage
Psychometrics
/ statistics & numerical data
Treatment Outcome
Young Adult
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
24
11
2020
accepted:
15
03
2021
pubmed:
1
5
2021
medline:
24
6
2021
entrez:
30
4
2021
Statut:
ppublish
Résumé
The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.
Identifiants
pubmed: 33927413
doi: 10.1038/s41591-021-01321-w
pii: 10.1038/s41591-021-01321-w
doi:
Substances chimiques
FMR1 protein, human
0
Phosphodiesterase 4 Inhibitors
0
Placebos
0
Fragile X Mental Retardation Protein
139135-51-6
Cyclic Nucleotide Phosphodiesterases, Type 4
EC 3.1.4.17
PDE4D protein, human
EC 3.1.4.17
Banques de données
ClinicalTrials.gov
['NCT03569631']
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
862-870Subventions
Organisme : NICHD NIH HHS
ID : R01 HD076189
Pays : United States
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