Efficacy Study of Early Onset of Antipsychotic Drug Action in Schizophrenia - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions:	Schizophrenia Schizoaffective Disorder Schizophreniform Disorder
Interventions:	Drug: olanzapine Drug: risperidone

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Study Period I was the screening period prior to enrollment. Study Period II was a 2-week open-label lead-in period of risperidone 2-6mg/day, at which time determination of early onset status was determined. Study Period III was a 10-week, double-blind therapy period.

Reporting Groups

	Description
NEO-OLZ	Olanzapine for not early onset response (NEO) patients. Olanzapine: 10-20 mg, oral, daily for 10 weeks
NEO-RIS	Risperidone for not early onset response (NEO) patients. Risperidone: 2-6 mg, oral, daily for 10 weeks
EO-RIS	Risperidone for early onset response (EO) patients. Risperidone: 2-6 mg, oral, daily for 10 weeks
Risperiodone Open-Label Lead-In	All patients completed a 2-week open-label risperidone lead-in period. This group contains all patients who started Study Period II. Risperidone: 2-6 mg, oral, daily

Participant Flow for 2 periods

Period 1: Study Period II

	NEO-OLZ	NEO-RIS	EO-RIS	Risperiodone Open-Label Lead-In
STARTED	0	0	0	628
COMPLETED	0	0	0	522
NOT COMPLETED	0	0	0	106
Lost to Follow-up	0	0	0	35
Withdrawal by Subject	0	0	0	20
Adverse Event	0	0	0	16
Physician Decision	0	0	0	13
Entry Criteria Not Met	0	0	0	6
Protocol Violation	0	0	0	6
Lack of Efficacy	0	0	0	7
Sponsor Decision	0	0	0	2
Parent/Caregiver Decision	0	0	0	1

Period 2: Study Period III

	NEO-OLZ	NEO-RIS	EO-RIS
STARTED	186	192	144
COMPLETED	126	134	100
NOT COMPLETED	60	58	44
Lost to Follow-up	14	16	14
Withdrawal by Subject	18	14	12
Adverse Event	9	10	8
Protocol Violation	3	8	2
Physician Decision	6	5	0
Entry Criteria Not Met	4	1	3
Lack of Efficacy	4	4	2
Parent/Caregiver Decision	0	0	2
Sponsor Decision	1	0	1
Clinical Relapse	1	0	0

Baseline Characteristics

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Reporting Groups

	Description
NEO-OLZ	Olanzapine for not early onset response (NEO) patients. Olanzapine: 10-20 mg, oral, daily for 10 weeks
NEO-RIS	Risperidone for not early onset response (NEO) patients. Risperidone: 2-6 mg, oral, daily for 10 weeks
EO-RIS	Risperidone for early onset response (EO) patients. Risperidone: 2-6 mg, oral, daily for 10 weeks

Baseline Measures

	NEO-OLZ	NEO-RIS	EO-RIS	Total
Number of Participants [units: participants]	186	192	144	522
Age [units: years] Mean ± Standard Deviation	41.84 ± 10.92	41.87 ± 11.34	41.83 ± 10.88	41.85 ± 11.04
Gender [units: participants]
Female	66	76	58	200
Male	120	116	86	322
Race/Ethnicity, Customized [units: participants]
American Indian or Alaska Native	1	2	1	4
Asian	3	0	0	3
Black or African American	88	92	54	234
White	80	80	74	234
Hispanic	14	18	15	47
Region of Enrollment [units: participants]
United States	173	176	130	479
Argentina	4	5	9	18
Russian Federation	9	11	5	25
Diagnosis [units: participants]
Schizophrenia/Schizophreniform Disorder	140	144	114	398
Schizoaffective Bipolar Disorder	31	25	21	77
Schizoaffective Depression	15	23	9	47
Abnormal Involuntary Movement Scale - Non-Global Total Score ^[1] [units: units on a scale] Mean ± Standard Deviation	0.67 ± 1.82	0.49 ± 1.48	0.44 ± 1.38	0.54 ± 1.58
Barnes Akathisia Rating Scale Total Score ^[2] [units: units on a scale] Mean ± Standard Deviation	0.80 ± 1.81	0.95 ± 1.97	0.54 ± 1.64	0.78 ± 1.83
Modified Simpson-Angus Scale ^[3] [units: units on a scale] Mean ± Standard Deviation	0.12 ± 0.29	0.14 ± 0.29	0.13 ± 0.82	0.13 ± 0.50
Montgomery-Asberg Depression Rating Scale (MADRS) - Total Score ^[4] [units: units on a scale] Mean ± Standard Deviation	13.52 ± 7.98	12.49 ± 8.44	7.29 ± 6.07	11.42 ± 8.09
Positive and Negative Syndrome Scale (PANSS) - Negative Subscale ^[5] [units: units on a scale] Mean ± Standard Deviation	21.18 ± 4.96	20.94 ± 5.30	15.83 ± 3.90	19.62 ± 5.36
Positive and Negative Syndrome Scale (PANSS) - Positive Subscale ^[6] [units: units on a scale] Mean ± Standard Deviation	21.50 ± 4.49	20.95 ± 4.65	15.37 ± 3.97	19.61 ± 5.13
Positive and Negative Syndrome Scale (PANSS) - Total Score ^[7] [units: units on a scale] Mean ± Standard Deviation	84.91 ± 13.81	84.05 ± 14.81	61.67 ± 12.85	78.21 ± 17.24

[1]	A 12-item instrument assesses observed abnormal movements in different parts of body. Ten items are scored in a 5-point scale (0 = none/normal, 4 = severe) which evaluates abnormal movements in three main anatomic areas (orofacial area, extremities, and trunk). Two items are yes/no questions regarding dentures. Total scores range from 0 to 42.
[2]	Evaluates akathisia associated with use of antipsychotic medications, includes objective and subjective component plus global impression rating for overall disorder. Components rated on scale of 0 to 3 for objective and subjective items and 0 to 5 for global clinical assessment, for total score of 0 (absence of akathisia) to 11 (severe akathisia).
[3]	Measures neuroleptic-induced parkinsonism. Total score consists of the sum of 10 items: 7 items (items 1, 3, 4, 7, 8, 9, 10) rated on a 4-point severity scale where 0=normal and 4=extreme, and 3 items (items 2, 5, 6) rated on a 2-point severity scale where 0=normal and 2=definitely abnormal/present. The total score ranges from 0 to 34.
[4]	Measures the overall severity of depressive symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms).
[5]	Assesses negative symptoms associated with schizophrenia. 7 items make up the Negative scale (ex. blunted affect, emotional withdrawal, poor rapport, and passive/apathetic social withdrawal). Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total Negative Subscale scores range from 7 to 49.
[6]	Assesses positive symptoms associated with schizophrenia. 7 items make up the Positive scale (ex. delusions, conceptual disorganization, and hallucinatory behavior). Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total Positive Subscale scores range from 7 to 49.
[7]	Assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210.

Outcome Measures

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1. Primary:

Changes From Study Period II Baseline (Week 0) to Weeks 3, 4, 6, 8, and 12 in Positive and Negative Syndrome Scale (PANSS) Total Score in Early Onset Response and Not Early Onset Response-Risperidone Patients [ Time Frame: Weeks 0, 3, 4, 6, 8, 12 ]

Show Outcome Measure 1

2. Secondary:

Changes From Study Period III Baseline (Week 2) to Weeks 3, 4, 6, 8, and 12 in Positive and Negative Syndrome Scale Total Score in Not Early Onset Response-Risperidone and Not Early Onset Response-Olanzapine Patients [ Time Frame: Weeks 2, 3, 4, 6, 8, 12 ]

Show Outcome Measure 2

3. Secondary:

The Number of Participants in the Early Onset (EO) and Not Early Onset-Risperidone (NEO-RIS) Groups Who Show a 20% or Greater Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score [ Time Frame: Week 0 to Week 12 ]

Show Outcome Measure 3

4. Secondary:

The Number of Participants in the Not Early Onset-Risperidone (NEO-RIS) and Not Early Onset-Olanzapine (NEO-OLZ) Groups Who Show a 20% or Greater Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score [ Time Frame: Week 0 to Week 12 ]

Show Outcome Measure 4

5. Secondary:

Number of Participants in the Early Onset and Not Early Onset-Risperidone Groups Who Show a 50% or Greater Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Baseline or Meet 'a Priori' Specified Criteria for Remission [ Time Frame: Week 0 to Week 12 ]

Show Outcome Measure 5

6. Secondary:

Number of Participants in the Not Early Onset-Risperidone and Not Early Onset-Olanzapine Groups Who Show a 50% or Greater Reduction in Positive and Negative Syndrome Scale Total Score From Baseline or Meet 'a Priori' Specified Criteria for Remission [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 6

7. Secondary:

Number of Participants With Psychiatric Hospitalizations in the Early Onset and Not Early Onset-Risperidone Groups [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 7

8. Secondary:

Vital Signs - Mean Change From Baseline to 10 Week Endpoint in Body Mass Index [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 8

9. Secondary:

Number of Participants With Treatment-Emergent Abnormal Fasting Laboratory Analytes Reported in >=2% of All Participants [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 9

10. Secondary:

Mean Change From Baseline to 10 Week Endpoint in Extrapyramidal Symptoms as Measured by the Modified Simpson-Angus Scale [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 10

11. Secondary:

Mean Change From Baseline to 10 Week Endpoint in Extrapyramidal Symptoms as Measured by the Barnes Akathisia Rating Scale - Total Score [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 11

12. Secondary:

Mean Change From Baseline to 10 Week Endpoint in Extrapyramidal Symptoms as Measured by the Abnormal Involuntary Movement Scale (AIMS)- Non-Global Total Score [ Time Frame: Week 2 to Week 12 ]

Show Outcome Measure 12

13. Secondary:

Vital Signs - Mean Change From Baseline to 10 Week Endpoint in Sitting Pulse Rate [ Time Frame: Week 2 and Week 12 ]

Show Outcome Measure 13

14. Secondary:

Vital Signs - Change From Baseline to 10 Week Endpoint in Standing Diastolic Blood Pressure [ Time Frame: Week 2 and Week 12 ]

Show Outcome Measure 14

15. Secondary:

Vital Signs - Change From Baseline to 10 Week Endpoint in Standing Mean Arterial Pressure [ Time Frame: Week 2 and Week 12 ]

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16. Secondary:

Vital Signs - Mean Change From Baseline to 10 Week Endpoint in Standing Pulse Rate [ Time Frame: Week 2 and Week 12 ]

Show Outcome Measure 16

17. Secondary:

Vital Signs - Mean Change From Baseline to 10 Week Endpoint in Standing Systolic Blood Pressure [ Time Frame: Week 2 and Week 12 ]

Show Outcome Measure 17

18. Secondary:

Vital Signs - Mean Change From Baseline to 10 Week Endpoint in Body Weight [ Time Frame: Week 2 and Week 12 ]

Show Outcome Measure 18

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
phone: 1-800-545-5979

No publications provided by Eli Lilly and Company

Publications automatically indexed to this study:

Kinon BJ, Chen L, Ascher-Svanum H, Stauffer VL, Kollack-Walker S, Zhou W, Kapur S, Kane JM. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology. 2010 Jan;35(2):581-90.

Responsible Party:	Chief Medical Officer, Eli Lilly
ClinicalTrials.gov Identifier:	NCT00337662 History of Changes
Obsolete Identifiers:	NCT00373321
Other Study ID Numbers:	10769, F1D-US-HGMN
Study First Received:	June 14, 2006
Results First Received:	December 3, 2008
Last Updated:	February 8, 2010
Health Authority:	United States: Food and Drug Administration