Schizophrenia
Conditions
Keywords
Schizophrenia, Antipsychotic, Zicronapine, Lu 31-310
Brief summary
The main purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of once weekly dosing of zicronapine, compared to daily dosing of zicronapine.
Detailed description
The study includes 2 treatment periods. The open-label run-in period will begin at patient enrolment and continue for 3 weeks, during which all patients will receive once daily treatment with zicronapine. The double-blind period will begin at patient randomization and continue for 5 weeks, during which the patients will be assigned to one group receiving once daily treatment with zicronapine and 3 groups receiving once weekly treatment with zicronapine.
Interventions
DRUGZicronapine open-label lead-in 10 mg daily
Encapsulated tablet ,10 mg, once daily, open-label
DRUGZicronapine 10 mg daily
Encapsulated tablet, 10 mg, once daily, double-blind
DRUGZicronapine 20 mg once weekly
Encapsulated tablet, 20 mg, once weekly (on day 1 of each 7 day cycle), double-blind
DRUGZicronapine 30 mg once weekly
Encapsulated tablet, 30 mg, once weekly (on day 1 of each 7 day cycle), double-blind
DRUGZicronapine 45 mg once weekly
Encapsulated tablet, 45 mg, once weekly (on day 1 of each 7 day cycle), double-blind
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) * A score of \<=4 (moderately ill) on Clinical Global Impression - Severity of Illness (CGI-S) scale * A total score \>=60 on Positive and Negative Syndrome Scale (PANSS) * A score of \<=4 (moderate) on PANSS items: P7 (hostility) AND G8 (uncooperativeness)
Exclusion criteria
* Acute exacerbation requiring hospitalization within the last 3 months OR requiring change of antipsychotic medication within the last 4 weeks * Diagnosis or history of substance dependence or substance abuse according to DSM-IV-TR within the last 3 months * Significant risk of harming himself/herself or others * Positive serology for hepatitis A, B, C, or HIV * Present condition that might compromise liver function * Medical or neurological disorder or treatment that could interfere with study treatment or compliance * Previous exposure to zicronapine Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 11 weeks for open-label period; 13 weeks for double-blind period | Number of patients with treatment-emergent adverse events during each of the two study periods plus corresponding safety follow-up period. Open-label period: 3 weeks post-baseline plus 8 weeks safety follow-up (11 weeks total); Double-blind period: 5 weeks post-randomization plus 8 weeks safety follow-up (13 weeks total) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period) | The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome). |
| Clinical Global Impression Severity Scale (CGI-S) Change From Baseline | 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period) | The CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses their clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients). |
| Clinical Global Impression Improvement Scale (CGI-I) | 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period) | The CGI-I provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). In all cases, the assessment is made independent of whether the rater believes the improvement is drug-related or not. |
Countries
United States
Participant flow
Pre-assignment details
46 patients were initially enrolled in a 3-week open-label study period. The 42 patients who completed the open-label period were subsequently randomized to a 5-week double-blind period.
Participants by arm
| Arm | Count |
|---|---|
| Zicronapine Open-label 10 mg Daily Zicronapine open-label 10 mg daily: Encapsulated tablet ,10 mg, once daily, open-label | 4 |
| Zicronapine 10 mg Daily Zicronapine basis dose 10 mg daily: Encapsulated tablet, 10 mg, once daily, double-blind | 11 |
| Zicronapine 20 mg Once Weekly Zicronapine low dose 20 mg once weekly: Encapsulated tablet, 20 mg, once weekly (on day 1 of each 7 day cycle), double-blind | 10 |
| Zicronapine 30 mg Once Weekly Zicronapine med dose 30 mg once weekly: Encapsulated tablet, 30 mg, once weekly (on day 1 of each 7 day cycle), double-blind | 11 |
| Zicronapine 45 mg Once Weekly Zicronapine high dose 45 mg once weekly: Encapsulated tablet, 45 mg, once weekly (on day 1 of each 7 day cycle), double-blind | 10 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double-blind | Administrative or other | 0 | 0 | 0 | 1 | 1 |
| Double-blind | Adverse Event | 0 | 1 | 2 | 2 | 0 |
| Double-blind | Protocol Violation | 0 | 0 | 0 | 0 | 1 |
| Double-blind | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
| Open-label | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Open-label | Withdrawal by Subject | 3 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Zicronapine 10 mg Daily | Zicronapine 20 mg Once Weekly | Zicronapine 30 mg Once Weekly | Zicronapine 45 mg Once Weekly | Zicronapine Open-label 10 mg Daily | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 42.7 years STANDARD_DEVIATION 11.7 | 47.8 years STANDARD_DEVIATION 6.4 | 50.8 years STANDARD_DEVIATION 5 | 50.1 years STANDARD_DEVIATION 4.8 | 38.5 years STANDARD_DEVIATION 6.6 | 47.0 years STANDARD_DEVIATION 8.3 |
| BMI | 31.3 kg/m2 STANDARD_DEVIATION 7.1 | 31.6 kg/m2 STANDARD_DEVIATION 5.9 | 28.6 kg/m2 STANDARD_DEVIATION 4.2 | 32.2 kg/m2 STANDARD_DEVIATION 5.2 | 30.0 kg/m2 STANDARD_DEVIATION 5.5 | 30.4 kg/m2 STANDARD_DEVIATION 5.3 |
| Height | 169.5 cm STANDARD_DEVIATION 8.3 | 170.1 cm STANDARD_DEVIATION 9.7 | 174.6 cm STANDARD_DEVIATION 10.3 | 170.9 cm STANDARD_DEVIATION 11.7 | 176.3 cm STANDARD_DEVIATION 9.4 | 171.8 cm STANDARD_DEVIATION 9.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 5 Participants | 8 Participants | 7 Participants | 1 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 16 Participants |
| Region of Enrollment United States | 11 participants | 10 participants | 11 participants | 10 participants | 4 participants | 46 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 1 Participants | 17 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 7 Participants | 6 Participants | 3 Participants | 29 Participants |
| Waist circumference | 99.8 cm STANDARD_DEVIATION 16.4 | 101.8 cm STANDARD_DEVIATION 14.1 | 101.1 cm STANDARD_DEVIATION 13.1 | 106.5 cm STANDARD_DEVIATION 12.5 | 98.7 cm STANDARD_DEVIATION 16.2 | 103.3 cm STANDARD_DEVIATION 13.2 |
| Weight | 90.0 kg STANDARD_DEVIATION 21.1 | 91.5 kg STANDARD_DEVIATION 19.2 | 87.5 kg STANDARD_DEVIATION 17.5 | 93.8 kg STANDARD_DEVIATION 16.8 | 94.7 kg STANDARD_DEVIATION 27.5 | 89.7 kg STANDARD_DEVIATION 18 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 46 | 8 / 11 | 4 / 10 | 4 / 11 | 9 / 10 |
| serious Total, serious adverse events | 0 / 46 | 0 / 11 | 1 / 10 | 1 / 11 | 1 / 10 |
Outcome results
Primary
Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Number of patients with treatment-emergent adverse events during each of the two study periods plus corresponding safety follow-up period. Open-label period: 3 weeks post-baseline plus 8 weeks safety follow-up (11 weeks total); Double-blind period: 5 weeks post-randomization plus 8 weeks safety follow-up (13 weeks total)
Time frame: 11 weeks for open-label period; 13 weeks for double-blind period
Population: Adverse events for the 46 patients enrolled in the open-label period are reported in the first (open-label) study arm. Adverse events for the 42 patients (out of the 46 enrolled) who were subsequently randomized to the double-blind period are reported across the last four (randomized) study arms.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zicronapine Open-label 10 mg Daily | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 12 participants |
| Zicronapine Basis Dose 10 mg Daily | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 8 participants |
| Zicronapine Low Dose 20 mg Once Weekly | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 4 participants |
| Zicronapine Med Dose 30 mg Once Weekly | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 4 participants |
| Zicronapine High Dose 45 mg Once Weekly | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 9 participants |
Secondary
Clinical Global Impression Improvement Scale (CGI-I)
The CGI-I provides the clinician's impression of the patient's improvement (or worsening). The clinician assesses the patient's condition relative to a baseline on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). In all cases, the assessment is made independent of whether the rater believes the improvement is drug-related or not.
Time frame: 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period)
Population: All patients who were randomized to the double-blind study period, who took at least one dose of drug, and who had at least one valid PANSS assessment were included in the full analysis set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zicronapine Open-label 10 mg Daily | Clinical Global Impression Improvement Scale (CGI-I) | 2.9 units on a scale | Standard Deviation 0.6 |
| Zicronapine Basis Dose 10 mg Daily | Clinical Global Impression Improvement Scale (CGI-I) | 3.4 units on a scale | Standard Deviation 1.1 |
| Zicronapine Low Dose 20 mg Once Weekly | Clinical Global Impression Improvement Scale (CGI-I) | 3.0 units on a scale | Standard Deviation 0.6 |
| Zicronapine Med Dose 30 mg Once Weekly | Clinical Global Impression Improvement Scale (CGI-I) | 2.9 units on a scale | Standard Deviation 1.1 |
Secondary
Clinical Global Impression Severity Scale (CGI-S) Change From Baseline
The CGI-S provides the clinician's impression of the patient's current state of mental illness. The clinician uses their clinical experience of this patient population to rate the severity of the patient's current mental illness on a 7-point scale ranging from 1 (normal - not at all ill) to 7 (among the most extremely ill patients).
Time frame: 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period)
Population: All patients who were randomized to the double-blind study period, who took at least one dose of drug, and who had at least one valid PANSS assessment were included in the full analysis set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zicronapine Open-label 10 mg Daily | Clinical Global Impression Severity Scale (CGI-S) Change From Baseline | -0.5 units on a scale | Standard Error 0.2 |
| Zicronapine Basis Dose 10 mg Daily | Clinical Global Impression Severity Scale (CGI-S) Change From Baseline | -0.5 units on a scale | Standard Error 0.2 |
| Zicronapine Low Dose 20 mg Once Weekly | Clinical Global Impression Severity Scale (CGI-S) Change From Baseline | -0.2 units on a scale | Standard Error 0.2 |
| Zicronapine Med Dose 30 mg Once Weekly | Clinical Global Impression Severity Scale (CGI-S) Change From Baseline | -0.7 units on a scale | Standard Error 0.2 |
Secondary
Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline
The PANSS consisted of three subscales that contained a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 that indicated the absence of symptoms and a score of 7 indicated extremely severe symptoms. The PANSS total score was the sum of the rating scores for 7 positive subscale items, 7 negative subscale items, and 16 general psychopathology subscale items from the PANSS panel. PANSS Total Score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
Time frame: 8 weeks post-baseline (3 weeks open-label period plus 5 weeks double-blind period)
Population: All patients who were randomized to the double-blind study period, who took at least one dose of drug, and who had at least one valid PANSS assessment were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zicronapine Open-label 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS total | -8.0 units on a scale | Standard Error 2.7 |
| Zicronapine Open-label 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Positive Symptoms | -1.5 units on a scale | Standard Error 1.1 |
| Zicronapine Open-label 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Negative Symptoms | -2.9 units on a scale | Standard Error 1 |
| Zicronapine Open-label 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS General Psychopathology | -5.2 units on a scale | Standard Error 1.2 |
| Zicronapine Basis Dose 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Positive Symptoms | -0.8 units on a scale | Standard Error 1 |
| Zicronapine Basis Dose 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Negative Symptoms | -2.8 units on a scale | Standard Error 1 |
| Zicronapine Basis Dose 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS General Psychopathology | -5.5 units on a scale | Standard Error 1.2 |
| Zicronapine Basis Dose 10 mg Daily | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS total | -8.7 units on a scale | Standard Error 2.5 |
| Zicronapine Low Dose 20 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Negative Symptoms | -2.0 units on a scale | Standard Error 1 |
| Zicronapine Low Dose 20 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Positive Symptoms | -1.8 units on a scale | Standard Error 1.1 |
| Zicronapine Low Dose 20 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS General Psychopathology | -6.4 units on a scale | Standard Error 1.3 |
| Zicronapine Low Dose 20 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS total | -10.6 units on a scale | Standard Error 2.6 |
| Zicronapine Med Dose 30 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS General Psychopathology | -6.2 units on a scale | Standard Error 1.2 |
| Zicronapine Med Dose 30 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Positive Symptoms | -2.6 units on a scale | Standard Error 1 |
| Zicronapine Med Dose 30 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS total | -12.2 units on a scale | Standard Error 2.5 |
| Zicronapine Med Dose 30 mg Once Weekly | Positive and Negative Syndrome Scale (PANSS) Total and Subscales Change From Baseline | PANSS Negative Symptoms | -3.1 units on a scale | Standard Error 1 |