Healthy Controls, Narcolepsy With Cataplexy
Conditions
Keywords
Xyrem, narcolepsy with cataplexy, positron emission tomography, dopamine
Brief summary
The overall aim of this investigation is to establish whether an action of Xyrem® on the brain dopamine system in patients with narcolepsy, and in a comparison control group, might explain part of the anti-narcoleptic effect of the drug. Trial Objective is to establish, using positron emission tomography (PET), in Xyrem®-naïve narcolepsy with cataplexy patients, and in matched controls, whether a single dose of Xyrem® causes changes in striatal binding of 11C-raclopride and 11C-DTBZ that would suggest altered activity of brain dopamine neurones.
Interventions
DRUGXyrem
single 3.0 gram dose
Sponsors
Centre for Addiction and Mental Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Participants will be recruited to fill 2 separate study groups: 1) participants with a diagnosis of narcolepsy with cataplexy; 2) healthy controls.
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* current diagnosis of narcolepsy with cataplexy OR healthy control
Exclusion criteria
* use of any sedative hypnotics, tranquilizers, anticonvulsants, antihistamines (except non-sedating), benzodiazepines, clonidine or any medication known to affect dopamine at start of baseline period * significant unstable or uncontrolled medical/psychiatric disease * significant history of head trauma/surgery or seizure disorder * radiation exposure exceeding 20mSv in last 12 months * pregnancy * substance abuse/dependence (including alcohol) * have sleep apnea, or are shift workers * on a sodium-restricted diet * has ever taken Xyrem / sodium oxybate / GHB at any time * claustrophobia * metal implants / objects in the body that may interfere with MRI * succinic semialdehyde dehydrogenase deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [C-11]Raclopride BPND at 1 Hour Post Xyrem | 1 hour post Xyrem | BPND (Binding Potential) of \[C-11\]raclopride measures 1 hour after taking a single 3g dose of Xyrem. |
| % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | 1 hour post Xyrem | \[C-11\] raclopride is a radioligand that binds to the D2/3 dopamine receptor in the dopamine-rich striatum and which is sensitive to dopamine occupancy. % change was calculated as follows: (1 hour BPND - baseline BPND)/baseline BPND \*100; Mean % change represents the mean of each participant's individual % change within the group. |
| [C-11]Raclopride BPND at 7 Hours Post Xyrem | 7 hours post Xyrem | BPND (Binding Potential) of \[C-11\]raclopride measures 7 hours after taking a single 3g dose of Xyrem. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Gamma-hydroxybutyrate (GHB) Cmax | multiple time points from 0 to 7 hours post-Xyrem | The concentration of gammahydroxybutyrate in blood of participants who have received a single dose of Xyrem as measured by Cmax. |
| [C-11]DTBZ BPND at 5 Hours Post Xyrem | 5 hours post single Xyrem dose | Measurement of \[C-11\]DTBZ 5 hours after taking a single dose of 3g Xyrem |
| Duration of Drowsiness | observed after receiving single dose of Xyrem, up to 9 hours | Period of time when the participant was experiencing the sedative action of Xyrem. Data derived from self-report as well as anesthesiologist observation. |
| % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | 5 hours post single Xyrem dose | \[C-11\] DTBZ is a radioligand that binds to the vesicular monoamine transporter and which is sensitive to dopamine occupancy. % change was calculated as follows: (5 hour BPND - baseline BPND)/baseline BPND \*100; Mean % change represents the mean of each participant's individual % change within the group. |
| Blood Gamma-hydroxybutyrate (GHB) Concentration (AUC) | multiple time points from 0 to 7 hours post-Xyrem | The concentration of gammahydroxybutyrate in blood of participants who have received a single dose of Xyrem, as measured by Area Under the Curve. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Narcolepsy With Cataplexy patients given single dose of Xyrem
Xyrem: single 3.0 gram dose | 1 |
| Healthy Controls healthy controls given a single dose of Xyrem
Xyrem: single 3.0 gram dose | 10 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | due to technical difficulties, the 1 hour post PET scan was not completed at the one hour time point | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Healthy Controls | Narcolepsy With Cataplexy | Total |
|---|---|---|---|
| Age, Continuous | 29.6 years STANDARD_DEVIATION 8 | 52 years | 31.6 years STANDARD_DEVIATION 10 |
| [C-11]DTBZ BPND at Baseline Associative Striatum | 2.60 BPND (Binding Potential) STANDARD_DEVIATION 0.26 | 2.41 BPND (Binding Potential) | 2.58 BPND (Binding Potential) STANDARD_DEVIATION 0.25 |
| [C-11]DTBZ BPND at Baseline Limbic Striatum | 1.85 BPND (Binding Potential) STANDARD_DEVIATION 0.19 | 1.68 BPND (Binding Potential) | 1.84 BPND (Binding Potential) STANDARD_DEVIATION 0.18 |
| [C-11]DTBZ BPND at Baseline Sensorimotor Striatum | 3.05 BPND (Binding Potential) STANDARD_DEVIATION 0.38 | 2.49 BPND (Binding Potential) | 3.00 BPND (Binding Potential) STANDARD_DEVIATION 0.4 |
| [C-11]raclopride BPND at Baseline Associative Striatum | 3.63 BPND (Binding Potential) STANDARD_DEVIATION 0.32 | 3.06 BPND (Binding Potential) | 3.58 BPND (Binding Potential) STANDARD_DEVIATION 0.35 |
| [C-11]raclopride BPND at Baseline Limbic Striatum | 2.83 BPND (Binding Potential) STANDARD_DEVIATION 0.19 | 2.59 BPND (Binding Potential) | 2.80 BPND (Binding Potential) STANDARD_DEVIATION 0.19 |
| [C-11]raclopride BPND at Baseline Sensorimotor Striatum | 4.04 BPND (Binding Potential) STANDARD_DEVIATION 0.43 | 3.11 BPND (Binding Potential) | 3.96 BPND (Binding Potential) STANDARD_DEVIATION 0.49 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 1 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Canada | 10 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 0 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 15 |
| other Total, other adverse events | 0 / 2 | 4 / 15 |
| serious Total, serious adverse events | 0 / 2 | 0 / 15 |
Outcome results
Primary
[C-11]Raclopride BPND at 1 Hour Post Xyrem
BPND (Binding Potential) of \[C-11\]raclopride measures 1 hour after taking a single 3g dose of Xyrem.
Time frame: 1 hour post Xyrem
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Limbic Striatum | 2.94 BPND (Binding Potential) | — |
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Associate Striatum | 3.80 BPND (Binding Potential) | — |
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Sensorimotor Striatum | 3.87 BPND (Binding Potential) | — |
| Healthy Controls | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Limbic Striatum | 3.01 BPND (Binding Potential) | Standard Deviation 0.28 |
| Healthy Controls | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Associate Striatum | 3.70 BPND (Binding Potential) | Standard Deviation 0.33 |
| Healthy Controls | [C-11]Raclopride BPND at 1 Hour Post Xyrem | Sensorimotor Striatum | 4.11 BPND (Binding Potential) | Standard Deviation 0.49 |
p-value: 0.31repeated measures ANOVA
Primary
[C-11]Raclopride BPND at 7 Hours Post Xyrem
BPND (Binding Potential) of \[C-11\]raclopride measures 7 hours after taking a single 3g dose of Xyrem.
Time frame: 7 hours post Xyrem
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Limbic Striatum | 2.33 BPND (Binding Potential) | — |
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Associate Striatum | 2.83 BPND (Binding Potential) | — |
| Narcolepsy With Cataplexy | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Sensorimotor Striatum | 2.75 BPND (Binding Potential) | — |
| Healthy Controls | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Associate Striatum | 3.62 BPND (Binding Potential) | Standard Deviation 0.29 |
| Healthy Controls | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Limbic Striatum | 2.76 BPND (Binding Potential) | Standard Deviation 0.18 |
| Healthy Controls | [C-11]Raclopride BPND at 7 Hours Post Xyrem | Sensorimotor Striatum | 4.06 BPND (Binding Potential) | Standard Deviation 0.4 |
Primary
% Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem
\[C-11\] raclopride is a radioligand that binds to the D2/3 dopamine receptor in the dopamine-rich striatum and which is sensitive to dopamine occupancy. % change was calculated as follows: (1 hour BPND - baseline BPND)/baseline BPND \*100; Mean % change represents the mean of each participant's individual % change within the group.
Time frame: 1 hour post Xyrem
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Limbic Stiatum | 13.27 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Associative Striatum | 23.88 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Sensorimotor Striatum | 24.43 percentage change from baseline | — |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Limbic Stiatum | 6.49 percentage change from baseline | Standard Deviation 8.6 |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Associative Striatum | 2.11 percentage change from baseline | Standard Deviation 8.59 |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Sensorimotor Striatum | 1.93 percentage change from baseline | Standard Deviation 8.85 |
Primary
% Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem
\[C-11\] raclopride is a radioligand that binds to the D2/3 dopamine receptor in the dopamine-rich striatum and which is sensitive to dopamine occupancy. % change was calculated as follows: (7 hours BPND - baseline BPND)/baseline BPND \*100; Mean % change represents the mean of each participant's individual % change within the group.
Time frame: 7 hours post Xyrem
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Limbic Striatum | -10.13 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Associative Striatum | -7.50 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Sensorimotor Striatum | -11.56 percentage change from baseline | — |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Limbic Striatum | -2.07 percentage change from baseline | Standard Deviation 8.24 |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Associative Striatum | 0.17 percentage change from baseline | Standard Deviation 7.42 |
| Healthy Controls | % Change in PET [C11]Raclopride Binding From Baseline After Single Dose of Xyrem | Sensorimotor Striatum | 0.72 percentage change from baseline | Standard Deviation 7.64 |
Secondary
Blood Gamma-hydroxybutyrate (GHB) Cmax
The concentration of gammahydroxybutyrate in blood of participants who have received a single dose of Xyrem as measured by Cmax.
Time frame: multiple time points from 0 to 7 hours post-Xyrem
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Narcolepsy With Cataplexy | Blood Gamma-hydroxybutyrate (GHB) Cmax | 107 mg/ml | — |
| Healthy Controls | Blood Gamma-hydroxybutyrate (GHB) Cmax | 107.37 mg/ml | Standard Deviation 32.95 |
Secondary
Blood Gamma-hydroxybutyrate (GHB) Concentration (AUC)
The concentration of gammahydroxybutyrate in blood of participants who have received a single dose of Xyrem, as measured by Area Under the Curve.
Time frame: multiple time points from 0 to 7 hours post-Xyrem
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Narcolepsy With Cataplexy | Blood Gamma-hydroxybutyrate (GHB) Concentration (AUC) | 187.03 AUC (ug/ml*hr) | — |
| Healthy Controls | Blood Gamma-hydroxybutyrate (GHB) Concentration (AUC) | 178.49 AUC (ug/ml*hr) | Standard Deviation 52.12 |
Secondary
[C-11]DTBZ BPND at 5 Hours Post Xyrem
Measurement of \[C-11\]DTBZ 5 hours after taking a single dose of 3g Xyrem
Time frame: 5 hours post single Xyrem dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Limbic Striatum | 1.71 BPND (binding potential) | — |
| Narcolepsy With Cataplexy | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Associative Striatum | 2.56 BPND (binding potential) | — |
| Narcolepsy With Cataplexy | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Sensorimotor Striatum | 2.65 BPND (binding potential) | — |
| Healthy Controls | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Associative Striatum | 2.65 BPND (binding potential) | Standard Deviation 0.4 |
| Healthy Controls | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Limbic Striatum | 1.82 BPND (binding potential) | Standard Deviation 0.24 |
| Healthy Controls | [C-11]DTBZ BPND at 5 Hours Post Xyrem | Sensorimotor Striatum | 3.12 BPND (binding potential) | Standard Deviation 0.53 |
Secondary
% Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem
\[C-11\] DTBZ is a radioligand that binds to the vesicular monoamine transporter and which is sensitive to dopamine occupancy. % change was calculated as follows: (5 hour BPND - baseline BPND)/baseline BPND \*100; Mean % change represents the mean of each participant's individual % change within the group.
Time frame: 5 hours post single Xyrem dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Narcolepsy With Cataplexy | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Limbic Striatum | 2.00 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Associative Striatum | 6.10 percentage change from baseline | — |
| Narcolepsy With Cataplexy | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Sensorimotor Striatum | 6.51 percentage change from baseline | — |
| Healthy Controls | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Limbic Striatum | -1.98 percentage change from baseline | Standard Deviation 9.2 |
| Healthy Controls | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Associative Striatum | 2.04 percentage change from baseline | Standard Deviation 11.84 |
| Healthy Controls | % Change in PET [C-11] Dihydrotetrabenazine (DTBZ) Binding From Baseline to Five Hours Post Xyrem | Sensorimotor Striatum | 2.47 percentage change from baseline | Standard Deviation 12.09 |
p-value: 0.748repeated measures ANOVA
Secondary
Duration of Drowsiness
Period of time when the participant was experiencing the sedative action of Xyrem. Data derived from self-report as well as anesthesiologist observation.
Time frame: observed after receiving single dose of Xyrem, up to 9 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Narcolepsy With Cataplexy | Duration of Drowsiness | 220.20 minutes |
| Healthy Controls | Duration of Drowsiness | 92.4 minutes |