Schizophrenia
Conditions
Keywords
MMN, EEG, P50, gamma power, P300, auditory gating
Brief summary
This is a phase 1, double-blind, placebo-controlled, 3 period cross-over study to evaluate CVN058 target engagement by measuring auditory evoked potential mismatch negativity (MMN) downstream to 5-hydroxytryptamine receptor 3 (5-HT3) as a pharmacodynamic (PD) marker.
Detailed description
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 treatment sequences (Table 2.a) to receive 1 of 3 dose regimens in each period: a single oral administration of CVN058 (15 mg or 150 mg) or matching placebo. The sequence will determine the order in which a subject will take each of the 3 regimens. Discontinued subjects may be replaced at the discretion of the sponsor so that approximately 20 completed subjects are available for analysis. The study includes three 1-day treatment periods, with a minimum of 7-day washout, maximum 10 day washout (2 total washouts, after Periods 1 and 2) between periods, and a 7-10 day follow-up call post dosing of the last period. Subjects may be inpatients or outpatients at the discretion of the Investigator.
Interventions
DRUGCVN058
CVN058 will be given at two doses, a low does and a high dose
OTHERPlacebo comparator
inactive placebo
Sponsors
Cerevance Alpha, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind, placebo controlled.
Intervention model description
Male and female subjects with schizophrenia, age 18 to 50 years old, inclusive, will be randomized to 1 of 6 treatment sequences to receive 1 of 3 dose regimens in each period; a single oral administration of CVN058, or a matching placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Subjects 18 to 50 years of age, inclusive, at the time of informed consent. * The subject weighs at least 50 kg and has a body mass index (BMI) between 18 and 40 kg/m2 inclusive at Screening. * Subject meets schizophrenia criteria as defined by the Diagnostic & Statistical Manual of mental Disorders, 5th Edition (DSM-V). * Subjects are on a stable dose of antipsychotic medication(s) for at least 2 months prior to - Screening as documented by medical history and assessed by site staff. * Subject has a Positive and Negative Syndrome Scale (PANSS) total score of \<95.
Exclusion criteria
* Subject currently receiving treatment with any excluded medication or dietary supplement. * Subjects who have a history of gastrointestinal disease that would influence the absorption of study drug or have a history of any surgical intervention known to impact absorption (e.g., bariatric surgery or bowel resection). * Subjects having clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis) outside the reference range for the testing laboratory, unless the results are deemed to be not clinically significant (NCS) by the investigator at Screening. * Subjects with moderate to severe substance use disorder, unstable mood or anxiety disorder. * Subject has a current diagnosis of a significant psychiatric illness other than schizophrenia per DSM-V and is in an acute phase/episode. * Subject has clinically meaningful hearing loss.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level | 1.5 hours post-dose on Day 1 | MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball task. Participants were repeatedly exposed to auditory tones and a small proportion of those tones (the deviant stimuli) differ from the others (the standard stimuli) in their frequency or duration. Typically, the tones are presented, and the evoked potentials are recorded while participants are engaged on a different task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of the negative component in the evoked potential occurring at around 200 msec. MMN is the difference in amplitude between deviant and standard stimuli responses and considered to represent an aspect of pre-attentive novelty detection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Screening through 30 days post-dose, up to 58 days | An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. TEAEs are defined as any event with onset during or after the first dose of study treatment (active or placebo) |
Countries
United States
Participant flow
Recruitment details
A total of 22 eligible participants with schizophrenia including schizoaffective disorder. Eligible participants were randomized to 6 treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence ABC Participants were randomized to receive single oral dose of Placebo in treatment period 1 followed by CVN058 15 milligrams (mg) in treatment period 2 followed by CVN058 150 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 3 |
| Treatment Sequence BAC Participants were randomized to receive single oral dose of CVN058 15 mg in treatment period 1 followed by Placebo in treatment period 2 followed by CVN058 150 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 3 |
| Treatment Sequence CAB Participants were randomized to receive single oral dose of CVN058 150 mg in treatment period 1 followed by Placebo in treatment period 2 followed by CVN058 15 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 4 |
| Treatment Sequence ACB Participants were randomized to receive single oral dose of CVN058 15 mg in treatment period 1 followed by Placebo in treatment period 2 followed by CVN058 150 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 4 |
| Treatment Sequence BCA Participants were randomized to receive single oral dose of Placebo in treatment period 1 followed by CVN058 150 mg in treatment period 2 and CVN058 15 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 4 |
| Treatment Sequence CBA Participants were randomized to receive single oral dose of CVN058 150 mg in treatment period 1 followed by Placebo in treatment period 2 and CVN058 15 mg in treatment period 3. Each treatment period was followed by a washout-period of 7 days. | 4 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence ABC | Total | Treatment Sequence CBA | Treatment Sequence BCA | Treatment Sequence ACB | Treatment Sequence CAB | Treatment Sequence BAC |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.0 Years STANDARD_DEVIATION 4 | 35.2 Years STANDARD_DEVIATION 8.06 | 36.3 Years STANDARD_DEVIATION 8.54 | 32.5 Years STANDARD_DEVIATION 14.15 | 39.0 Years STANDARD_DEVIATION 6.63 | 35.0 Years STANDARD_DEVIATION 6.06 | 32.0 Years STANDARD_DEVIATION 8.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 9 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 13 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants | 9 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 0 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 2 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 17 Participants | 4 Participants | 4 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 13 | 0 / 8 | 0 / 19 |
| other Total, other adverse events | 1 / 20 | 1 / 13 | 1 / 8 | 4 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 13 | 0 / 8 | 0 / 19 |
Outcome results
Primary
Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level
MMN is a pre-attentive auditory component elicited by deviant stimuli in an auditory oddball task. Participants were repeatedly exposed to auditory tones and a small proportion of those tones (the deviant stimuli) differ from the others (the standard stimuli) in their frequency or duration. Typically, the tones are presented, and the evoked potentials are recorded while participants are engaged on a different task, such as reading. Normally, the occurrence of a deviant stimulus increases the amplitude of the negative component in the evoked potential occurring at around 200 msec. MMN is the difference in amplitude between deviant and standard stimuli responses and considered to represent an aspect of pre-attentive novelty detection.
Time frame: 1.5 hours post-dose on Day 1
Population: Pharmacodynamic Population consisted of all participants who received study drug and had measurements in both the placebo-dosed period and at least one (1) CVN058-dosed period for at least one (1) electroencephalography (EEG)/evoked response endpoint. Only those participants with data available at specified time points has been presented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level | -0.551 microvolts | Standard Deviation 0.7303 |
| 15mg CVN058 | Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level | -0.749 microvolts | Standard Deviation 0.726 |
| 75mg CVN058 | Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level | -0.386 microvolts | Standard Deviation 0.5682 |
| 150 mg CVN058 | Mean Amplitude of Duration of Auditory Mismatch Negativity (MMN) by Dose Level | -1.084 microvolts | Standard Deviation 0.7632 |
Secondary
Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgement. TEAEs are defined as any event with onset during or after the first dose of study treatment (active or placebo)
Time frame: Screening through 30 days post-dose, up to 58 days
Population: Safety Population consisted of all participants who were randomized and received study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 1 Participants |
| Placebo | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| 15mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| 15mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 1 Participants |
| 75mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 1 Participants |
| 75mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |
| 150 mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAE | 4 Participants |
| 150 mg CVN058 | Number of Participants Reporting Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any SAE | 0 Participants |