. 2020 Nov 5;51(8):2959–2972. doi: 10.1007/s10803-020-04709-8

Table 3.

Investigation schedule

	Selection (Screening)	Inclusion (Baseline)	Double-blind 26-week treatment period									Visits to complete in case of IMP discontinuation during the double-blind period BUT not withdrawal from the study
	ASSE	W000	W000 + 48/72 h	W000 + Day 10	W000 + Day 17	W004	W008	W012	W016	W020	W026	W012	W026
Informed consents/assents	X¹
Demography	X
IQ test²	X
DSM-5	X
ADOS-2³	X
ADI-R⁴	X
Selection / Non-selection criteria	X
Inclusion / Non-inclusion criteria		X
Autism diagnostic history	X
Medical / surgical history	X
Previous treatments⁵	X
Concomitant treatments⁵	X	X	X	X	X	X	X	X	X	X	X	X	X
IRS
Patient number	X
Randomization		X
IMP allocation		X				X	X	X	X	X	X
IMP dispensation		X				X	X	X	X	X	X
Oral solution volume adaptation to patient weight if needed		X						X			X
Compliance IMP						X	X	X	X	X	X

	Selection	Inclusion	Double-blind 26-week treatment period									Visits to complete in case of IMP discontinuation during the double-blind period BUT not withdrawal from the study
	ASSE	W000	W000 + 48/72 h	W000 + Day 10	W000 + Day 17 (D017)	W004	W008	W012	W016	W020	W026	W012	W026
Efficacy measurements
CARS2-HF/ CARS2-ST/ CARS2-QPC		X				X		X			X	X	X
CGI-S	X	X						X			X	X	X
CGI-I					X	X	X		X	X
SRS-2		X				X		X			X	X	X
VABS II		X									X
Safety measurements
Suicidality (C-SSRS-C)		X						X			X
Adverse events		X	X	X	X	X	X	X	X	X	X	X	X
PAERS scale		X			X	X	X	X	X	X	X
Laboratory tests (blood and urine)	X							X			X
Blood electrolytes monitoring (K, Na)	X		X	X	X	X	X⁽⁶⁾	X	X⁽⁶⁾	X⁽⁶⁾	X
ECG	X⁽⁷⁾					X⁽⁸⁾	X⁽⁸⁾	X⁽⁸⁾			X⁽⁸⁾
Renal ultrasound	X										X⁽⁸⁾
Sitting and standing blood pressure/heart rate	X	X			X			X			X
Body weight and height	X	X⁽⁹⁾			X⁽⁹⁾	X⁽⁹⁾	X⁽⁹⁾	X	X⁽⁹⁾	X⁽⁹⁾	X
Tanner Stage⁽¹⁰⁾		X									X
Other measurements for inclusion
Urinary drug screening	X
βHCG—Blood Pregnancy test⁽¹¹⁾	X
Pharmacokinetics (blood samples)								X			X
Other measurements
PedsQL		X				X		X			X
WHOQOL-brief		X				X	X	X			X
EQ-5D-3L		X						X			X
Acceptability questionnaire											X

	Open-label 26-week active treatment period									FU	WD Withdrawal visit to be undergone in case of IMP definitive discontinuation or in case of total withdrawal from the study, whatever the period
	W026 + 48/72 h	W026 + Day 10	W026 + Day 17 (D199)	W030	W034	W038	W042	W046	W052	Wend
Concomitant treatments⁽⁵⁾	X	X	X	X	X	X	X	X	X	X	X
IRS
IMP allocation				X	X	X	X	X
IMP definitive discontinuation											X
IMP dispensation				X	X	X	X	X
Oral solution volume adaptation to patient weight						X
Compliance IMP				X	X	X	X	X	X		X
Efficacy measurements
CARS2-HF/ CARS2-ST/CARS2-QPC						X			X	X	X⁽¹²⁾
CGI						X⁽¹³⁾			X	X	X
SRS-2						X			X		X⁽¹²⁾
VABS II									X		X⁽¹²⁾
Safety measurements
Suicidality (C-SSRS-C)						X			X		X
Adverse events	X	X	X	X	X	X	X	X	X	X	X
PAERS scale			X	X	X	X	X	X	X		X
Laboratory tests (blood and urine)						X			X		X
Blood electrolytes monitoring (K, Na)	X	X	X	X	X⁽⁶⁾	X	X⁽⁶⁾	X⁽⁶⁾	X		X
ECG				X⁽⁸⁾	X⁽⁸⁾	X⁽⁸⁾			X⁽⁸⁾		X
Renal ultrasound									X⁽⁸⁾		X
Sitting and standing blood pressure/heart rate			X			X			X		X
Body weight and height			X⁽⁹⁾	X⁽⁹⁾	X⁽⁹⁾	X	X⁽⁹⁾	X⁽⁹⁾	X		X
Tanner Stage⁽¹⁰⁾									X		X
Other measurements
PedsQL				X		X			X		X⁽¹²⁾
WHOQOL-brief				X	X	X			X		X⁽¹²⁾
EQ-5D-3L						X			X		X⁽¹²⁾
Acceptability questionnaire											X

ADI-R Autism Diagnostic Interview Revised, ADOS-2 Autism Diagnostic Observation Schedule-Generic, CARS2-HF Childhood Autism Rating Scale, Second Edition-high-functioning version, CARS2-QPC Childhood Autism Rating Scale, Second Edition-Questionnaire for Parents or Caregivers, CARS2-ST Childhood Autism Rating Scale, Second Edition-standard version, CGI Clinical Global Impression, CGI-I Clinical Global Impression-Improvement Scale, CGI-S Clinical Global Impression-Severity Scale, C-SSRS-C Columbia Suicide Severity Rating Scale Children’s version, D day, DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition, ECG electrocardiogram, EQ-5D-3L EuroQol five-dimension three-level questionnaire, FU follow-up, IMP investigational medicinal product, IRS Interactive response system, PAERS Pediatric Adverse Event Rating Scale, PedsQL Pediatric Quality of Life Inventory, SRS-2 Social Responsiveness Scale Second Edition, VABS II Vineland Adaptive Behavior Scale Second Edition, W week, WD withdrawal, WHOQOL World Health Organization Quality of Life

¹To obtain at the latest at ASSE but before any procedure related to the study

²Only to be performed if retrospective exam is not available in the 12 months prior to ASSE

³Should not be performed if an ADOS-2 evaluation has been done within the 12 months prior to ASSE and is documented in the site

⁴Only to be performed if retrospective ADI-R is not available after the 4 y.o. of the patient

⁵Including non-pharmacological therapies (psychotherapy, social skills training, behavioral interventions, etc.)

⁶Prescribed based on the clinical opinion of nephrologist or investigator

⁷Triplicate ECG only at ASSE

⁸Results of the exam should be available at this visit, prescription to be done at the previous visit

⁹Only body weight

¹⁰For patients aged 7 to 17 years only

¹¹Only for post-pubertal females

¹²Only to be undergone after the last IMP intake by patients discontinuing prematurely from the study after W000 + Day 10

¹³CGI-I only