MeasureSCID-CT (mood, anxiety, psychosis, substance use)

PHQ-8

GAD-7

C-SSRS Lifetime

C-SSRS Since Last Visit

C-SSRS Last Year

Psychotic symptoms last month

ScreeningX

X

X

X

Study VisitsWhen indicated*

X

X

X

XX

* The SCID was triggered at any study visit by a C-SSRS finding of suicidal ideation or any suicidal behavior

Table 1. Central Rater Assessments

Table 2. Subject Characteristics

Psychiatric AEs Overall study population Age group ( N=56 ) % ( N=925 ) % 48% male 60.5% male 12-14

15-17

18-29

30-44

45-54

2 (3.6)

15 (26.8)

28 (50.0)

9 (16.1)

2 (3.6)

103 (11.1)

294 (31.8)

415 (44.9)

102 (11.0)

11 (1.2)

Psychiatric symptom N (%)Insomnia 23 (41)Anxiety 12 (21)Depression 7 (12.5)Attention deficit/hyperactivity disorder 3 (5)Mood swings 3 (5)Sleep disorder 3 (5)Panic attack 2 (3.5)Restlessness 2 (3.5)Stress 2 (3.5)Adjustment disorder 1 (1.8)Affect lability 1 (1.8)Anger 1 (1.8)Apathy 1 (1.8)Bradyphrenia 1 (1.8)Delusion 1 (1.8)Depressed mood 1 (1.8)Disorientation 1 (1.8)Dysthymic disorder 1 (1.8)Emotional distress 1 (1.8)Hallucination, auditory 1 (1.8)Libido decreased 1 (1.8)Middle insomnia 1 (1.8)Obsessive thoughts 1 (1.8)Paranoia 1 (1.8)Substance abuse 1 (1.8)

Table 3. Subjects with Psychiatric Symptoms ( N=56)

• SCID-CT lifetime or current history of psychotic symptoms

• SCID-CT diagnoses of MDD, manic episode, hypomanic episode or mixed episode, in the past year

• Any reported suicidal behaviora in the past year, OR serious suicidal ideationb in the past year as defined by type 4 or 5 on the C-SSRS

• Phase III, multi-center • Double-blind, randomized, active-control, parallel-group • Evaluate safety and efficacy of CIP-Isotretinoin • Independent Central Raters • Evaluated the lifetime incidence of neuropsychiatric symptoms at screening • Assessed subjects for emergent clinically-significant neuropsychiatric symptoms throughout the trial • 20-week treatment phase and 4-week follow-up phase • Total of 9 subject visits (1 screening visit and 8 in-study visits) • 49 dermatology offices: 38 in the US and 11 in Canada

Inclusion Criteria Exclusion Criteria

• Males and females

• Ages 12-54 years

• Diagnosis by a dermatologist of severe recalcitrant nodular acne

a attempts, interrupted attempts, aborted attempts or other preparatory behaviors b active suicidal ideation with some intent to act, without specific plan or with a specific plan and intent

Williams, JBW1,2; Davis, D1; Popp, D1; Gross, J4; Salvucci, D1; Detke, M1,3

1MedAvante Inc.; 2College of Physicians and Surgeons, Columbia University; 3Indiana University School of Medicine; 4Cipher Pharmaceuticals Inc.

Feasibility of Central Ratings for Mental Health Safety Screening in a Non-Psychiatric Clinical Trial

©2013 MedAvante Inc.

RESEARCH INSTITUTE

INTRODUCTION

Clinical trials in non-CNS indications frequently include assessments of psychopathology to track associated symptoms and safety signals. Non-mental health sites may not be equipped to diagnose exclusionary mental disorders or to evaluate suicidality. Central Ratings have proven feasible for assessment of adult psychiatric diagnoses, symptom severity, and suicidality across CNS disorders. Central Ratings, in which independent remote clinical raters interview subjects live by videoconferencing or telephone, may be used for safety assessments in non-psychiatric trials with sites (e.g., dermatology) that do not employ staff experienced in psychiatric assessment. Centralizing assessments with mental health experts enables immediate clinical follow-up and actionable diagnostic support for investigators. The primary objective was to evaluate the feasibility of using Central Ratings by mental health clinicians in a phase III dermatology clinical trial to compare the efficacy and safety of two pharmacologic treatments for severe recalcitrant nodular acne in adults and adolescents.

STUDY DESIGN

Figure 1. Summary of screening and follow-up assessments conducted by Central Raters (CR). Note: subjects with psychiatric symptoms of mild severity were recommended to refer to a local mental health service provider; subjects with psychiatric symptoms of moderate severity were immediately referred for psychiatric evaluation. No subjects refused to participate because of the Central Ratings telephone interviews.

Remotely administered via telephone by Central Raters:• SCID-CT1

• PHQ-82

• C-SSRS Lifetime3

• C-SSRS Last Year1

• 3 psychosis questions

Subjects indermatology

offices(n=1265)

Remotely administered via telephone by Central Raters:• SCID-CT*1

• PHQ-82

• GAD-74

• C-SSRS Since Last Visit3

• C-SSRS Last Year3

• 3 psychosis questions

Subjects randomized to

clinical trial(n=924)

*SCID-CT was triggered at any study visit by a C-SSRS finding of suicidal ideation or behavior

Screening

Follow-up

Subjects randomized to

clinical trial(n=924)

Subjects experiencedspontaneous neuropsychiatric

Adverse Events(n=56)

See Table 1and Figure 2

No psychiatricsymptomsSCID-CT or PHQ-8 diagnosis

• Psychiatric symptoms of mild (n=33) or moderate (n=17) severity

• No severe psychiatric symptoms reported

PHQ-8*• Scores ranged from 0-21 (M=1.02, SD=1.89)

• Score of zero (n=612)

• Score > 10 (n=8)

C-SSRS• Suicidal ideation (score of 4-5; n=1)

• Self-injurious behavior (n=10)

• Suicidal behavior in the past year (n=5)

Psychiatric reports

Psychiatric reports

C-SSRS - subjects answered “yes” tosuicidal behavior question or receivedscore of 4-5 (n=4)

• Zero had a history of suicidal behavior• Previous history of wishing to be dead (n=2)• AE of depression = study discontinuation (n=1)• Self-injurious behavior (n=1)

PHQ-8• Change in score of > 10 at one visit only (n=9)• Score > 10 on two consecutive visits (n=1)• Within-subject visit-to-visit change (M=0.32, SD=0.70)

GAD-7• Scores stable within each subject• Total scores > 10 at single time points (n=6)• Within-subject visit-to-visit change (M=0.21, SD=0.51)

Psychosis - experienced psychotic episode during study (n=2)• One subject experienced auditory hallucinations when treated with medication• Other subject experienced persecutory delusions and others, as well as depression and paranoia – treated with pharmacology and improved

* a PHQ score > 10 is considered clinically significant2

METHODS

• 29 Central Raters, independent of study sites, conducted mental health evaluations by tele- phone with the subjects in the dermatologists’ offices at baseline and weeks 2, 4, 8, 12, 16, 20 and 24 (Fig. 1).

• Central Raters were well-trained mental health professionals who were calibrated to the same standard at the beginning of the study and regularly calibrated throughout the study.

• A child psychiatrist was contracted to be on call to handle emergent cases by telephone.

• Any psychiatric Adverse Events (AEs) that were considered clinically significant by the investigator were evaluated by a local psychiatrist.

RESULTS

Table 1. Subjects with Psychiatric Symptoms ( N=56)

Figure 2. Subject characteristics for (A) the overall study population (60.5% male), and (B) occurrences of psychiatric Adverse Events (AEs) (48% male).

A. Overall Study Population (n=925) B. Psychiatric AEs (n=56)

Age group (years)

12-14 (n=103)

15-17 (n=294)

18-29 (n=415)

30-44 (n=102)

45-54 (n=11)

11%1% 11%

45%

32%

4% 3%

16%

27%

50%

Age group (years)

12-14 (n=2)

15-17 (n=15)

18-29 (n=28)

30-44 (n=9)

45-54 (n=2)

PSYCHIATRIC SYMPTOMS REPORTED DURING FOLLOW-UP ASSESSMENTS WITH CENTRAL RATERS

• SCID-CT lifetime or current history of psychotic symptoms

• SCID-CT diagnoses of MDD, manic episode, hypomanic episode or mixed episode, in the past year

• Any reported suicidal behaviora in the past year, OR serious suicidal ideationb in the past year as defined by type 4 or 5 on the C-SSRS

• Phase III, multi-center • Double-blind, randomized, active-control, parallel-group • Evaluate safety and efficacy of CIP-Isotretinoin • Independent Central Raters • Evaluated the lifetime incidence of neuropsychiatric symptoms at screening • Assessed subjects for emergent clinically-significant neuropsychiatric symptoms throughout the trial • 20-week treatment phase and 4-week follow-up phase • Total of 9 subject visits (1 screening visit and 8 in-study visits) • 49 dermatology offices: 38 in the US and 11 in Canada

Inclusion Criteria Exclusion Criteria

• Males and females

• Ages 12-54 years

• Diagnosis by a dermatologist of severe recalcitrant nodular acne

a attempts, interrupted attempts, aborted attempts or other preparatory behaviors b active suicidal ideation with some intent to act, without specific plan or with a specific plan and intent

DISCUSSION

This study was conducted to support regulatory approval of a drug product, and supports the integration of Central Ratings by remote mental health experts into non-psychiatric studies. It also established the feasibility and acceptability of routine screening and monitoring of psychopathology and suicidality in a non-psychiatric population. Central Raters effectively identified subjects who did not qualify for entry at the beginning of the study because they had active suicidal ideation with intent and/or plan and significant active or recent mood disorder in the last year, or a lifetime incidence of psychosis. These subjects were excluded from the study and referred for clinical care. Throughout the study, Central Raters identified cases of emergent psychosis and mood disorder symptoms.

References: 1First MB, Williams, JBW, Veroff AE, Bartolic E, Kingery L, Katz R. Improving diagnosis in CNS Clinical Trials: Introducing the SCID-CT. Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, June, 2007. 2Kroenke K, Spitzer RL, Williams JBW. The PHQ-9 - Validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-13. 3Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, Fisher P, Zelazny J, Burke A, Oquendo M, Mann J. Columbia-Suicide Severity Rating Scale (C-SSRS) 2009. See www.cssrs.columbia.edu/. 4Spitzer RL, Kroenke K, Williams JBW, Lowe B. A brief measure for assessing generalized anxiety disorder - The GAD-7. Archives of Internal Medicine. 2006;166(10):1092-97. One or more authors report potential conflicts which are described in the program.

The authors would like to acknowledge the help of Lori M. Price, MS.

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