Depression, Schizophrenia
Conditions
Keywords
Schizophrenia, Depression, Quetiapine
Brief summary
Aim of the study is to assess if the new compound Seroquel XR™ is non-inferior to Risperidone, considered as the reference drug for the treatment of depressive symptoms of schizophrenia. PLEASE NOTE: Seroquel SR and Seroquel XR refer to the same formulation. The SR designation was changed to XR after consultation with FDA.
Interventions
Uptitrated starting from 300 mg in the evening on day 0, then increasing to 600 mg and up to 800 mg in the following two evenings. Previous antipsychotic was taken at the full dose on day 0, half dose on day 1 and stopped from day 2. From day 3 onwards it was possible to adjust the Seroquel XR dose, depending on the clinical response and tolerability of the patient, within the range of 400-800 mg per day
DRUGRisperidone
Uptitrated starting from 1 mg bid (morning and evening) on day 0, then increasing to 2 mg bid and up to 3 mg in the following two days. As per the other arm, previous antipsychotic was taken at the full dose on day 0, half dose on day 1 and stopped from day 2. From day 2 onwards, it was allowed to adjust he dose of Risperidone depending on the clinical response and tolerability of the patient.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Provision of written informed consent * Patients who satisfy the criteria for diagnosis of schizophrenia or schizoaffective disorder according to DSM-IVTR * Baseline depressive symptoms, assessed by means of HAM-D (21-item) score ≥20, and HAM-D item 1 score ≥2
Exclusion criteria
* Any DSM-IV Axis I disorder other than schizophrenia and schizoaffective disorder * Patients treated with depot antipsychotic medications within 1 dosing interval before day 0; patients treated with other AP oral medications during the trial except for the switch period * Use of Clozapine within 28 days prior to enrollment or Clozapine non responders * Any significant clinical disorder that, in the opinion of the investigator, made the subject unsuitable to be given treatment with an investigational drug * An absolute neutrophil count (ANC) of ≤1.5 x 109 per liter * Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 of Calgary Depression Scale for Schizophrenia (CDSS) Score. | 12 week from baseline to last visit | The CDSS scale is used to assess the level of depression in schizophrenia and to estimate the severity of depressive symptoms. CDSS has 9 items rated on four-point scale: 0=absent; 1=mild; 2=moderate; 3=severe. Anchor point descriptions are provided to aid differentiation between each item score. The first eight items are rated on basis of patients' responses to questions; the 9 item is based on clinician's assessment. The sum score is derived by adding the point score of all items (from 0 to 27 points); total score 4-5 is considered for minor depression and 6-7 score for major depression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 of PANSS Score | 12 weeks from baseline to last visit | 30-item scale where each symptom is rated on a severity ranging from 1-7. Symptoms are categorized into 7 items referring to positive, 7 items referring to negative and 16 general psychotic. Total score range 30- 210, higher values represent worse outcome. Number of participants analyzed refers to valid for efficacy per protocol population. |
| - Change From Baseline to Week 12 of Clinical Global Impression (CGI- Severity of Illness) Score | 12 weeks from baseline to last visit | The CGI-S subset ranges from 1 to 7 such that a score of 1 indicates normal, not at all ill, while a score of 7 indicates among the most extremely ill of patients. The change from start of treatment (baseline V2) in the Severity of Illness will be calculated by subtracting the score at start of treatment (baseline V2) from the following visits |
| CGI- Global Improvement Mean Score at Week 12 | 12week: descriptive statistic of CGI by visit and treatment | The CGI-S subset ranges from 1 to 7 such that a score of 1 indicates normal, not at all ill, while a score of 7 indicates among the most extremely ill of patients. The change from start of treatment (baseline V2) in the Severity of Illness will be calculated by subtracting the score at start of treatment (baseline V2) from the following visits |
| Change From Baseline to Week 12 of Drug Attitude Inventory 10 Item Scale (DAI 10) Score | 12 week from baseline to last visit | These items are presented as self-report statements with which the patient agrees or disagrees. Each response is scored as +1 if correct or -1 if incorrect. The final score is the grand total of the positive and negative points. A positive score means a positive subjective response. A negative total score means a negative subjective response |
| Change From Baseline to Week 12 of HAM-D Score | 12 weeks from baseline to last visit | 21-item scale for depression. Symptoms are rated finely (on a 5-point scale: absent; doubtful or trivial; mild: moderate severe) or coarsely (on a 3- point scale: absent; doubtful or mild; obvious, distinct, or severe).Total score range 0- 66, higher values represent worse outcome.Number of participants refers to valid for efficacy per protocol. Change:total score at week 12 minus total score at baseline. |
| Concomitant Use of Antidepressive Drugs From Baseline to Week 12 | 12 week from baseline to last visi | Number of concomitant users of antidepressive drugs during the study; the number of participants analyzed refers to safety population, that is to overall participants excluding 6 participants who did not assume any study drug administration |
| Change From Screening Visit to Week 12 of Prolactin Live | 12 week from screening visit to last visit | Plasma prolactin live was drawn prior to morning meal at the screening visit at the last visit |
| Body Mass Index (BMI) at Week 12 | 12 week | Patient weight and height have been be collected in order to assess the Body Mass Index (BMI). The mean BMI values reported are assessed after 12 weeks of treatment. |
| Change From Baseline in the Simpson Angus Scale (SAS) Total Score to Week 12 as an Indication of Neurological Side Effects Section | 12 weeks from baseline to last visit | Extrapyramidal Side Effects (EPS) will be assessed using the Simpson-Angus Scale (SAS; Simpson GN et al 1970) . The CRF is source data for these assessments and day 0 is considered as baseline. The SAS scale, containing 10 items, will be rated on a five-point scale where 0 is normal and 4 are severe symptoms. Min score =0, max score 40 Change from start of treatment (day 0) will be calculated as the visit score minus the score at start of treatment for each of the neurological assessments. |
Countries
Italy
Participant flow
Recruitment details
Adult male and female patients. with a diagnosis of schizophrenia or schizoaffective disorder (according to DSM-IVTR criteria). with depressive symptoms HAM-D baseline score ≥ 20. and HAM-D item 1 score ≥2.
Participants by arm
| Arm | Count |
|---|---|
| Seroquel XR Seroquel XR dose uptitrated starting from 300 mg in the evening on day 0, then increasing to 600 mg and up to 800 mg in the following two evenings. Previous antipsychotic was taken at the full dose on day 0, half dose on day 1 and stopped from day 2. From day 3 onwards it was possible to adjust the Seroquel XR dose, depending on the clinical response and tolerability of the patient, within the range of 400-800 mg per day | 107 |
| Risperidone Risperidone dose was uptitrated starting from 1 mg bid (morning and evening) on day 0, then increasing to 2 mg bid and up to 3 mg in the following two days. As per the other arm, previous antipsychotic was taken at the full dose on day 0, half dose on day 1 and stopped from day 2. From day 2 onwards, it was allowed to adjust he dose of Risperidone depending on the clinical response and tolerability of the patient. | 103 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 |
| Overall Study | Glycosylated Hemoglobin >8 | 1 | 0 |
| Overall Study | Known risperidone intolerance | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 4 |
| Overall Study | Low study drug dose | 0 | 1 |
| Overall Study | Past use of Seroquel -stopped due to AE | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 4 |
| Overall Study | Withdrawal by Subject | 6 | 10 |
Baseline characteristics
| Characteristic | Seroquel XR | Risperidone | Total |
|---|---|---|---|
| Age Continuous | 42.46 years STANDARD_DEVIATION 10.71 | 42.08 years STANDARD_DEVIATION 11.48 | 42.27 years STANDARD_DEVIATION 11.1 |
| Sex: Female, Male Female | 51 Participants | 40 Participants | 91 Participants |
| Sex: Female, Male Male | 56 Participants | 63 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / — | 21 / — |
| serious Total, serious adverse events | 4 / 109 | 4 / 107 |
Outcome results
Primary
Change From Baseline to Week 12 of Calgary Depression Scale for Schizophrenia (CDSS) Score.
The CDSS scale is used to assess the level of depression in schizophrenia and to estimate the severity of depressive symptoms. CDSS has 9 items rated on four-point scale: 0=absent; 1=mild; 2=moderate; 3=severe. Anchor point descriptions are provided to aid differentiation between each item score. The first eight items are rated on basis of patients' responses to questions; the 9 item is based on clinician's assessment. The sum score is derived by adding the point score of all items (from 0 to 27 points); total score 4-5 is considered for minor depression and 6-7 score for major depression.
Time frame: 12 week from baseline to last visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Baseline to Week 12 of Calgary Depression Scale for Schizophrenia (CDSS) Score. | 7.31 Score on a scale | Standard Deviation 6.1 |
| Risperidone | Change From Baseline to Week 12 of Calgary Depression Scale for Schizophrenia (CDSS) Score. | 5.53 Score on a scale | Standard Deviation 6.4 |
Secondary
Body Mass Index (BMI) at Week 12
Patient weight and height have been be collected in order to assess the Body Mass Index (BMI). The mean BMI values reported are assessed after 12 weeks of treatment.
Time frame: 12 week
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Body Mass Index (BMI) at Week 12 | 29.07 Kg/m^2 | Standard Deviation 6.65 |
| Risperidone | Body Mass Index (BMI) at Week 12 | 28.80 Kg/m^2 | Standard Deviation 5.31 |
Secondary
CGI- Global Improvement Mean Score at Week 12
The CGI-S subset ranges from 1 to 7 such that a score of 1 indicates normal, not at all ill, while a score of 7 indicates among the most extremely ill of patients. The change from start of treatment (baseline V2) in the Severity of Illness will be calculated by subtracting the score at start of treatment (baseline V2) from the following visits
Time frame: 12week: descriptive statistic of CGI by visit and treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | CGI- Global Improvement Mean Score at Week 12 | 91 score on a scale | Standard Deviation 4.47 |
| Risperidone | CGI- Global Improvement Mean Score at Week 12 | 88 score on a scale | Standard Deviation 4.55 |
Secondary
Change From Baseline in the Simpson Angus Scale (SAS) Total Score to Week 12 as an Indication of Neurological Side Effects Section
Extrapyramidal Side Effects (EPS) will be assessed using the Simpson-Angus Scale (SAS; Simpson GN et al 1970) . The CRF is source data for these assessments and day 0 is considered as baseline. The SAS scale, containing 10 items, will be rated on a five-point scale where 0 is normal and 4 are severe symptoms. Min score =0, max score 40 Change from start of treatment (day 0) will be calculated as the visit score minus the score at start of treatment for each of the neurological assessments.
Time frame: 12 weeks from baseline to last visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Baseline in the Simpson Angus Scale (SAS) Total Score to Week 12 as an Indication of Neurological Side Effects Section | 2.74 score on scale | Standard Deviation 5.29 |
| Risperidone | Change From Baseline in the Simpson Angus Scale (SAS) Total Score to Week 12 as an Indication of Neurological Side Effects Section | 3.88 score on scale | Standard Deviation 5.24 |
Secondary
- Change From Baseline to Week 12 of Clinical Global Impression (CGI- Severity of Illness) Score
The CGI-S subset ranges from 1 to 7 such that a score of 1 indicates normal, not at all ill, while a score of 7 indicates among the most extremely ill of patients. The change from start of treatment (baseline V2) in the Severity of Illness will be calculated by subtracting the score at start of treatment (baseline V2) from the following visits
Time frame: 12 weeks from baseline to last visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | - Change From Baseline to Week 12 of Clinical Global Impression (CGI- Severity of Illness) Score | -1.50 Score on scale | Standard Deviation 1.33 |
| Risperidone | - Change From Baseline to Week 12 of Clinical Global Impression (CGI- Severity of Illness) Score | -1.04 Score on scale | Standard Deviation 1.31 |
Secondary
Change From Baseline to Week 12 of Drug Attitude Inventory 10 Item Scale (DAI 10) Score
These items are presented as self-report statements with which the patient agrees or disagrees. Each response is scored as +1 if correct or -1 if incorrect. The final score is the grand total of the positive and negative points. A positive score means a positive subjective response. A negative total score means a negative subjective response
Time frame: 12 week from baseline to last visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Baseline to Week 12 of Drug Attitude Inventory 10 Item Scale (DAI 10) Score | 86.38 score on scale | Standard Deviation 4.12 |
| Risperidone | Change From Baseline to Week 12 of Drug Attitude Inventory 10 Item Scale (DAI 10) Score | 76.64 score on scale | Standard Deviation 4.7 |
Secondary
Change From Baseline to Week 12 of HAM-D Score
21-item scale for depression. Symptoms are rated finely (on a 5-point scale: absent; doubtful or trivial; mild: moderate severe) or coarsely (on a 3- point scale: absent; doubtful or mild; obvious, distinct, or severe).Total score range 0- 66, higher values represent worse outcome.Number of participants refers to valid for efficacy per protocol. Change:total score at week 12 minus total score at baseline.
Time frame: 12 weeks from baseline to last visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Baseline to Week 12 of HAM-D Score | -29.83 Score on scale | Standard Deviation 10.13 |
| Risperidone | Change From Baseline to Week 12 of HAM-D Score | -23.02 Score on scale | Standard Deviation 10.33 |
Secondary
Change From Baseline to Week 12 of PANSS Score
30-item scale where each symptom is rated on a severity ranging from 1-7. Symptoms are categorized into 7 items referring to positive, 7 items referring to negative and 16 general psychotic. Total score range 30- 210, higher values represent worse outcome. Number of participants analyzed refers to valid for efficacy per protocol population.
Time frame: 12 weeks from baseline to last visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Baseline to Week 12 of PANSS Score | 102.26 score on scale | Standard Deviation 24.14 |
| Risperidone | Change From Baseline to Week 12 of PANSS Score | 100.51 score on scale | Standard Deviation 25.65 |
Secondary
Change From Screening Visit to Week 12 of Prolactin Live
Plasma prolactin live was drawn prior to morning meal at the screening visit at the last visit
Time frame: 12 week from screening visit to last visit
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Seroquel XR | Change From Screening Visit to Week 12 of Prolactin Live | 61.20 KG | Standard Deviation 29.77 |
| Risperidone | Change From Screening Visit to Week 12 of Prolactin Live | 90.80 KG | Standard Deviation 55.78 |
Secondary
Concomitant Use of Antidepressive Drugs From Baseline to Week 12
Number of concomitant users of antidepressive drugs during the study; the number of participants analyzed refers to safety population, that is to overall participants excluding 6 participants who did not assume any study drug administration
Time frame: 12 week from baseline to last visi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Seroquel XR | Concomitant Use of Antidepressive Drugs From Baseline to Week 12 | 12 Participants |
| Risperidone | Concomitant Use of Antidepressive Drugs From Baseline to Week 12 | 11 Participants |
Secondary
Concomitant Use of Antidepressive Drugs From Baseline to Week 12
Number of concomitant users of antidepressive drugs during the study; the number of participants analyzed refers to ITT/safety population, that is to overall participants excluding the 6 participants who did not assume any study drug administration
Time frame: Change of drug use from baseline to last visi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Seroquel XR | Concomitant Use of Antidepressive Drugs From Baseline to Week 12 | 14 Participants |
| Risperidone | Concomitant Use of Antidepressive Drugs From Baseline to Week 12 | 17 Participants |