A pilot open label, single dose trial of fenobam in adults with fragile X syndrome methods
Aim. Evidence-backed execution summary for A pilot open label, single dose trial of fenobam in adults with fragile X syndrome methods from A pilot open label, single dose trial of fenobam in adults with fragile X syndrome.
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human
Subject model for the experiment.
- Use
- confirm full cohort details in the source paper
METHODS
reagent used in the protocol.
- Use
- Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclusion criteria required a DNA based diagnosis of FXS, stable medication doses for at least 6 weeks before study, and ability to tolerate an i...
DISCUSSION
reagent used in the protocol.
- Use
- Fenobam peak concentrations occurred later than expected based on prior pharmacokinetic results and thus the PPI was done when values were still increasing on the pharmacokinetic curve. Therefore, the PPI results presented may represent an underestimate of the effect of fenobam on PPI that would have been measured i...
DISCUSSION
reagent used in the protocol.
- Use
- Limitations of this study include the lack of placebo control, the small sample size, and the biasing of the subject sample to include only those who were higher functioning behaviourally and less anxious so that they would be able to tolerate the study procedures, including the intravenous catheter. More anxious in...
METHODS
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclusion criteria required a DNA based diagnosis of FXS, stable medication doses for at least 6 weeks before study, and ability to tolerate an i...
- Use
- Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclusion criteria required a DNA based diagnosis of FXS, stable medication doses for at least 6 weeks before study, and ability to tolerate an i...
RESULTS
‡Side effects and clinical improvement were characterised by observations at designated time points (0,15, 30, 45, 60, 120, 180, 240, 300, 360 min) by the principal investigator (PI) and by formal questioning of the subject/guardian throughout the visit for the occurrence of central nervous system (CNS) side e...
- Use
- ‡Side effects and clinical improvement were characterised by observations at designated time points (0,15, 30, 45, 60, 120, 180, 240, 300, 360 min) by the principal investigator (PI) and by formal questioning of the subject/guardian throughout the visit for the occurrence of central nervous system (CNS) side e...
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Open quote workflowStep-by-step procedure
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Methods:
Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.
METHODS
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclusion criteria required a DNA based diagnosis of FXS, stable medication doses for at least 6 weeks before study, and ability to tolerate an intravenous catheter (IV) for 6 h for pharmacokinetic studies. Exclusion criteria included concurrent treatment with lithium, typical antipsychotics, tricyclic antidepressants, NMDA antagonists or enzyme inducing anticonvulsants, concurrent or recent initiation of cognitive behavioural therapy, significant disease in another organ system, hearing or vision impairments, psychosis, major depressive symptoms, pregnancy, drug abuse disorder, Tourette syndrome, and significant abnormalities in baseline laboratory tests. Subjects with well controlled seizures were not excluded alt...
METHODS
At the screening visit medical history, exam, vital signs, laboratory testing including routine chemistries, blood counts, thyroid functions, electrocardiogram (ECG), and a pregnancy test (females) were evaluated, and baseline CPT (Carolina Project Fragile X continuous performance test) and prepulse inhibition (PPI) outcome measures were obtained. At the treatment visit, 14-28 days after screening, an IV was inserted for blood drawing and the subject received the study medication orally. Blood for pharmacokinetic testing, blood pressure, heart rate and side effect screening was obtained at 0, 15, 30, 45, 60, 120, 180, 240, 300, and 360 min after dosing. Our side effects screening protocol involved asking both the subject and family members if the subject was having any of a structured list of symptoms relevant to potential effects of fenobam (aggression, fatigue, hyperactivity,...
METHODS
PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PPI at 120 ms has excellent test-retest reliability with intraclass correlations of 0.85 for FXS and 0.88 for controls; (3) PPI is responsive to medication effects; (4) PPI in the mouse model of FXS can be corrected with MPEP; and (5) PPI represents an electrophysiological measure that is expected to be less amenable to placebo effects than other measures. The PPI protocol used for this study was a slightly modified version of the procedure previously described. Startle stimuli (SS) were 50 ms 105 db SPL white noise pulses and acoustic prepulses (PP) are 25 ms 75 db SPL 1 kHz tones. These trials are delivered while participants watch a silent movie to maintain compliance and interest in the procedure. Test-ret...
RESULTS
‡Side effects and clinical improvement were characterised by observations at designated time points (0,15, 30, 45, 60, 120, 180, 240, 300, 360 min) by the principal investigator (PI) and by formal questioning of the subject/guardian throughout the visit for the occurrence of central nervous system (CNS) side effects relevant to fenobam from a checklist (see Methods) new, or worsening of existing signs, symptoms or behaviours.
DISCUSSION
Fenobam peak concentrations occurred later than expected based on prior pharmacokinetic results and thus the PPI was done when values were still increasing on the pharmacokinetic curve. Therefore, the PPI results presented may represent an underestimate of the effect of fenobam on PPI that would have been measured if PPI was done at 2-3 h post-dose. Further, correlations between PPI and fenobam values may have been masked due to variable rates of increase in different subjects. In future study design for fenobam trials, PPI should be administered 2-3 h post-dose to optimise drug impact. The PPI results shown here are consistent with a recent study using eyeblink startle PPI methodology, similar to methods used in human studies, which demonstrated a significant PPI deficit in the fmr1 knockout mouse that was rescued to wild-type levels by MPEP, an mGluR5 antagonist.
Measurement outputs
What raw and processed outputs should exist?
Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
At the screening visit medical history, exam, vital signs, laboratory testing including routine chemistries, blood counts, thyroid functions, electrocardiogram (ECG), and a preg...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PP...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
The Carolina Fragile X Project Continuous Performance Test (FXCPT), developed for individuals with cognitive impairment, was chosen to assess attention, impulsivity, and inhibit...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Analysis plan
How should the outputs become interpretable results?
Acquisition
Collect raw experimental outputs with enough metadata to preserve sample identity, condition, and timing.
inferred from protocolPreprocessing / cleaning
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC).
from paperScoring or quantification
Quantify the primary readouts for this experiment: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect...; At the screening visit medical history, exam, vital signs, laboratory testing including routine chemistries, blood counts, thyroid functions, electrocardiogram (ECG), and a preg...; PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PP...; The Carolina Fragile X Project Continuous Performance Test (FXCPT), developed for individuals with cognitive impairment, was chosen to assess attention, impulsivity, and inhibit....
from paperStatistical comparison
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclu...; PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PP...; The Carolina Fragile X Project Continuous Performance Test (FXCPT), developed for individuals with cognitive impairment, was chosen to assess attention, impulsivity, and inhibit...; For statistical analysis of PPI data, a positive response was defined as a 20% or greater improvement over baseline. One sample exact binomial 95% confidence interval was comput...
from paperReporting output
Report representative outputs alongside summary comparisons for Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect..., At the screening visit medical history, exam, vital signs, laboratory testing including routine chemistries, blood counts, thyroid functions, electrocardiogram (ECG), and a preg..., PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PP..., The Carolina Fragile X Project Continuous Performance Test (FXCPT), developed for individuals with cognitive impairment, was chosen to assess attention, impulsivity, and inhibit....
inferred from protocolStructured statistical methods
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclu...; PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PP...; The Carolina Fragile X Project Continuous Performance Test (FXCPT), developed for individuals with cognitive impairment, was chosen to assess attention, impulsivity, and inhibit...; For statistical analysis of PPI data, a positive response was defined as a 20% or greater improvement over baseline. One sample exact binomial 95% confidence interval was comput...
source structuredSource and audit
What supports the facts on this page?
Evidence quotes (6)
Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.
Subjects were recruited from fragile X clinics at Rush University Medical Center (RUMC) and the MIND Institute at University of California at Davis Medical Center (UCDMC). Inclusion criteria required a DNA based diagnosis of FXS, stable medication doses for at least 6 weeks before study, and ability to tolerate an intravenous catheter (IV) for 6 h for pharmacokinetic studies. Exclusion criteria included concurrent treatment with lithium, typical antipsychotics, tricyclic antidepressants, NMDA antagonists or enzyme inducing anticonvulsants, concurrent or recent initiation of cognitive behavioural therapy, significant disease in another organ system, hearing or vision impairments, psychosis, major depressive symptoms, pregnancy, drug abuse disorder, Tourette syndrome, and significant abnormalities in baseline laboratory tests. Subjects with well controlled seizures were not excluded although none of the subjects enrolled had a seizure history. Informed written consent was obtained from either the subject or the parent before participation. Assent from the subject was obtained when the subject was not his/her own legal guardian. The study was approved by the institutional review bo...
At the screening visit medical history, exam, vital signs, laboratory testing including routine chemistries, blood counts, thyroid functions, electrocardiogram (ECG), and a pregnancy test (females) were evaluated, and baseline CPT (Carolina Project Fragile X continuous performance test) and prepulse inhibition (PPI) outcome measures were obtained. At the treatment visit, 14-28 days after screening, an IV was inserted for blood drawing and the subject received the study medication orally. Blood for pharmacokinetic testing, blood pressure, heart rate and side effect screening was obtained at 0, 15, 30, 45, 60, 120, 180, 240, 300, and 360 min after dosing. Our side effects screening protocol involved asking both the subject and family members if the subject was having any of a structured list of symptoms relevant to potential effects of fenobam (aggression, fatigue, hyperactivity, anxiety and fidgetiness, increase in self stimulation, odd behaviour, inappropriate laughter, dizziness, vertigo, nausea, paraesthesia, and headache), and direct observation by the physician and family for the above symptoms and other behavioural changes. Subjects were all verbal and sufficiently hi...
PPI was chosen as an outcome measure to assess sensorimotor gating and inhibitory control because: (1) there is significant deficit of PPI in males and females with FXS; (2) PPI at 120 ms has excellent test-retest reliability with intraclass correlations of 0.85 for FXS and 0.88 for controls; (3) PPI is responsive to medication effects; (4) PPI in the mouse model of FXS can be corrected with MPEP; and (5) PPI represents an electrophysiological measure that is expected to be less amenable to placebo effects than other measures. The PPI protocol used for this study was a slightly modified version of the procedure previously described. Startle stimuli (SS) were 50 ms 105 db SPL white noise pulses and acoustic prepulses (PP) are 25 ms 75 db SPL 1 kHz tones. These trials are delivered while participants watch a silent movie to maintain compliance and interest in the procedure. Test-retest studies have demonstrated good to excellent reliability for PPI at 120 ms and 240 ms, but inadequate reliability for PPI at 60 ms. Therefore, for the current study, we eliminated the 60 ms trial type and added two trials per type, resulting in a protocol with 30 total trials (10 with SS alone, 1...
‡Side effects and clinical improvement were characterised by observations at designated time points (0,15, 30, 45, 60, 120, 180, 240, 300, 360 min) by the principal investigator (PI) and by formal questioning of the subject/guardian throughout the visit for the occurrence of central nervous system (CNS) side effects relevant to fenobam from a checklist (see Methods) new, or worsening of existing signs, symptoms or behaviours.
Fenobam peak concentrations occurred later than expected based on prior pharmacokinetic results and thus the PPI was done when values were still increasing on the pharmacokinetic curve. Therefore, the PPI results presented may represent an underestimate of the effect of fenobam on PPI that would have been measured if PPI was done at 2-3 h post-dose. Further, correlations between PPI and fenobam values may have been masked due to variable rates of increase in different subjects. In future study design for fenobam trials, PPI should be administered 2-3 h post-dose to optimise drug impact. The PPI results shown here are consistent with a recent study using eyeblink startle PPI methodology, similar to methods used in human studies, which demonstrated a significant PPI deficit in the fmr1 knockout mouse that was rescued to wild-type levels by MPEP, an mGluR5 antagonist.
Machine-readable layer
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