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January 16, 2015, revised 25.08.2015, according to needed adjustments discovered during analysis

Quetiapine versus aripiprazole in children and adolescents with psychosis - protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial

Statistical analysis plan.

Trial registration: ClinicalTrials.gov NCT01119014

Table 1

Definition of outcomes for the analysis of the TEA randomized clinical trial. Based on the researchhypotheses, the TEA trialhas a single primary outcome and four key secondary outcomes. The additional secondary outcomes are statistically handled as explorative outcomes.

AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BMI = Body MassIndex; CGI = Clinical Global Impression (-I = Improvement -S = Severity -E = Efficacy); CRF=Case Report Forms; GAPD = Global Assessment of Psychosocial Disability; K-SADS-PL = Kiddie-SADS-Present and LifetimeVersion; PANSS = Positive and Negative Syndrome Scale; UKU = ‘Udvalget for Kliniske Undersøgelser’ Side Effect Rating Scale. Laboratory tests: Blood tests (fasting): triglycerides; total cholesterol; high-density and low-density lipoproteins; glucose; insulin; prolactin; creatinphosphokinase;haemoglobin; leukocyte cell and differential count; thrombocyte cell count; sodium; potassium; creatinine; aspartate amino transferase; alkaline phosphatases; thyroid stimulating hormone; ECG: Standard leads.

Outcomes / Scale/item / Definition / Variable type / Variable value / Baseline
assess-ment / Week 2assess-ment / Week 4assess-ment / Week 12assess-ment
Hypothesis driven outcomes
1 / Primary
Benefit
Psychopathology
Positive symptoms / PANSS
positive / Sum of scores item P1-P7,
rating=1-7,
range=7-49 / Continuous / Mean / x / x / x / x
2 / Key secondary
Harms
Akathisia / BARS
global item / Definition: A score of at least 2 on the global item, rating=0-5
(adjusting for akathisia at baseline ) / Binary (Y/N) / Frequency / x / x / x / x
3 / Key secondary
Harms
Sedation or asthenia / UKU
Item 1.2,1.3 / Definition:(A score of at least 1on item 1.2 (asthenia/lassitude/increased fatigability) AND rated possible or probable on “related to study drug”)OR (a score of at least 1 on item 1.3(sleepiness/sedation) AND rated possible or probable on “related to study drug”) / Binary (Y/N) / Frequency / x / x / x / x
4 / Key secondary
Harms
Weight change / Weight / Weight, kg / Continuous / Mean / x / x / x / x
5 / Key secondary
Harms
Metabolic effects / HOMA-IR /
6.0 is the conversion factor between mU/l and pmol/l; FPG=fasting plasma glucose, FPI= fasting plasma insulin / Continuous / Mean / x / - / x / x
Additional secondary outcomes
6 / Benefit
Psychopathology
Negative symptoms / PANSS
negative / Sum of scores item N1-N7,
rating=1-7,
range=7-49 / Continuous / Mean / x / x / x / x
7 / Benefit
Psychopathology
General symptoms / PANSS
general / Sum of scores item G1-G16,
rating=1-7,
range=16-102 / Continuous / Mean / x / x / x / x
8 / Benefit
Psychopathology
Total symptoms / PANSS
total / Sum of scores all 30 PANSS items, rating=1-7,
range=30-210 / Continuous / Mean / x / x / x / x
Outcomes / Scale/item / Definition / Variable type / Variable value / Baseline
assess-ment / Week2
assess-ment / Week4
assess-ment / Week 12
assess-ment
9 / Benefit
Psychopathology
Depressive symptoms / PANSS Depressive factor. / Sum of scores item G2+G3+G6 (anxiety, guilt feelings, depression), rating=1-7,
range=3-21 / Continuous / Mean / x / x / x / X
10 / Benefit
Response rate / N response at week 12 / Definition: PANSS total reduction of at least 30% AND a CGI-I score of 1 (very much improved) or 2 (much improved) / Binary (Y/N) / Frequency / x
11 / Benefit
Remission rate / N cross-sectional remission at week 12 / Definition:
PANSS </= 3 (“mild”) on all following:
P1 delusions
P2 conceptual disorganisation
P3 hallucinatory behavior
N1 blunted affect
N4 social withdrawal
N6 lack of spontaneity
G5 mannerism/posturing
G9 unusual thought contents / Binary (Y/N) / Frequency / x
12 / Benefit
Psychopathology
Global severity / CGI-severity / Score on Lickert scale rating 1-7 (1=normal, not at all ill; 2=Borderline mentally ill; 3=Mildly ill; 4= Moderately ill; 5=Markedly ill; 6=Severely ill; 7=Among the most extremely ill patients) / Continuous / Mean / x / x / x / X
13 / Benefit
Psychopathology
Global Improvement / CGI-improvement / Score on Lickert scale rating (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse) / Continuous / Mean / - / x / x / x
14 / Benefit
Psychosocial disability / GAPD / Scores on GAPD
Rating 0 (ideal) to 8 (severe disability) / Continuous / Mean / x / x / x / x
15 / Benefit/Harm
Psychopathology
Suicidality / Suicidality
K-SADS-PL
Specific items / Sum of scores on K-SADS suicidality items (items 1-4) / Continuous / Mean / x / x / x / x
Outcomes / Scale/item / Definition / Variable type / Variable value / Baseline
assess-ment / Week 2
assess-ment / Week 4
assess-ment / Week 12
assess-ment
16 / Harm
Number of AE, AR, SAE, SAR, or SUSAR and types. / Number of events and number of persons with an event.
And event type / Type iscategorized in four groups on UKU: Psychic, neurologic, autonomic, or other
Definitions:
AE: items that score at least 1 (mild) on UKU AND improbable (not related to study drug) at week 2,4,12 + items noted in the section of CRF called unintended events and rated 0 (not serious) and 0 (not related).
AR:items that score at least 1 (mild) on UKU AND possible or probable (related to study drug) at week 2,4,12 + items noted in the section of CRF called unintended events and rated 0 (not serious) and 1 (related).
SAE:Based on the section of CRF calledunintended events and rated 1 (serious) and 0 (not related).
SARBased on the section of CRF called unintended events and rated 1 (serious) and 1 (related).
SUSARBased on the section of CRF called unintended events and rated 1 (serious) and 1 (related) and 1 (unexpected). / Binary (Y/N) / Frequency
N events
N
participants with events / x / x / x / X
17 / Harm
Cardiologic
QTc interval / ECG
QTc interval / Change in length of QTc interval (msec) from baseline / Continuous / Mean / x / - / x / x
18 / Harm
Abnormal QTc interval / ECG
QTc interval / Definition:
a)QTc>450 msec, OR
b) QTc prolonged with >60 msec since baseline / Binary (Y/N) / Frequency / x / - / x / x
19 / Harm
Metabolic, BMI / BMI / weight (kg) / height (m)2 / Continuous / Mean / x / x / x / X
Outcomes / Scale/item / Definition / Variable type / Variable value / Baseline
assess-ment / Week 2
assess-ment / Week 4
assess-ment / Week 12
assess-ment
20 / Harm
Metabolic
Weight gainers / Weight / Definition: Subjects who gain >/= 7 % weight from baseline to week 12 / Binary (Y/N) / Frequency / X
21 / Harm
Metabolic parameters / Laboratory tests / Concentration in plasma at baseline, week 4 and 12: glucose, cholesterol, LDL, HDL, triglyceride / Continuous / Mean / x / - / x / x
22 / Harm
Prolactin / Laboratory tests / Concentration in plasma at baseline, week 4 and 12: prolactin / Continuous / Mean / x / - / x / x
23 / Harm
Abnormal laboratory test unspecified / Laboratory tests / Definition: Frequency of abnormal laboratory values and types (deviation from reference intervals) / Binary (Y/N) / frequency / x / - / x / X
24 / Harm
Neuromotor
Extrapyramidal symptoms / SAS / Total score on 10 SAS items,
Ratings 0-4
Range 0-40. / Continuous / mean / x / x / x / X
25 / Harm
Neuromotor
Involuntary movements / AIMS / Definition:
Dyskinesia: A score ≥ 2 on one AIMS item (1-7)at any time from week0-12. / Binary (Y/N) / Frequency / X
26 / Harm
neuromotor Antiparkinson medication use / Information on concomitant medication / Definition: Participants who received drugs with the indication to ameliorate neuromotor side effects. / Binary (Y/N) / Frequency / x / x / x / X
27 / Discontinuations / N of participants who discontinue participation in trial before week 12 / Binary (Y/N) / Frequency / x / x / x / x