Table 3

Schedule of trial assessments

Period	Screening	Randomisation	Optimisation (titration)				Maintenance			End of study (EOS)	Taper*	End of taper	Follow-up
Visit	V1	V2	V3†	V4†	V5	V6	V7†	V8	V9	V10/ET		V11	V12†
Day (D)/week (W)		D 1 W1	D3±1 W1	D 5±2 W1	D14±2 W2	D21±2 W3	D28±1 W4	D49±3 W7	D77±3 W11	D105±3 W15	D105−133±3 W15-19	D112−140±3 W16-20	D119−147±3 W17-21
Enrolment
Informed consent	X
Inclusion/exclusion criteria	X	X
Wash-out instructions	X
Demographics	X
Randomisation		X
Interventions
Gabapentin+tramadol placebo
Tramadol+gabapentin placebo
Assessments
Medical/medication history	X
Concomitant/rescue medication	X	X	X	X	X	X	X	X	X	X		X	X
Physical examination	X					X		X	X	X		X
Vital signs	X	X			X	X		X	X	X		X
Weight/height/BMI	X									X
Clinical laboratory test‡	X									X
Serum (s)/urine hCG (u)§	X (s)	X (u)								X (u)		X (u)
ECG	X									X
Blood sampling for pharmacokinetics					X¶	X¶				X¶
Investigator dose assessment			X	X	X	X	X
Pain intensity score (FLACC, FPS-R, NRS-11)	X	X	X	X	X	X	X	X	X	X		X	X
Observational assessment of pain intensity (NRS-11)**	X	X			X	X		X	X	X		X	X**
Self-assessment of pain for children ≥8 years (FPS-R)	X	X	X	X	X	X	X	X	X	X		X	X
Pain charts	X	X								X
Patient diary assessment		X			X	X		X	X	X		X
Global satisfaction with treatment (NRS-11; parent, subject)										X
CGI-S (investigator)		X
CGI-I (investigator)						X				X
PGIC (parent and subject)						X				X
PedsQL		X								X
C-SSRS	X					X				X		X
UMSS (investigator and parent)††			X	X	X	X	X
Assessment of blinding (investigator, parent and subject‡‡)										X
Five-point Facial Hedonic Scale										X
Adverse events collection		X	X	X	X	X	X	X	X	X	X	X	X
R-MOAS		X				X				X
Renal ultrasound scan (only for <3 years of age)	X									X
Investigational product dispensed		X				X		X	X	X
Taper phone call											X
Exploratory assessments (to be performed only if specific consent is provided)
Blood sampling for metabolomics	X									X
Blood sampling for pharmacogenomics	X

*During taper period (if applicable), site staff will contact subjects every week to ensure that they are complying with the taper schedule and to remind subjects to start the next week of dose taper.
†Visits V3, V4, V7 and V12 are phone call visits. V7 will not be performed if the patient has reached optimal dose of IMPs prior to the last visit of the dose optimisation period (V6).
‡Standard clinical haematology and biochemistry, including cystatin-C and serum creatinine.
§If a blood sampling is required for the visit, only a serum beta human chorionic gonadotropin (HCG) test will be performed.
¶PK sampling will be performed according to a sampling matrix at either D14 or D21 or EOS visit. Patient allocation will be defined according to randomisation scheme. In total, four samples will be collected, one before dosing and at three Udifferent time windows postdosing (0–2 hours; 2–4 hours and 4–6 hours). Details of the sampling procedures will be described in the study procedures.
**This assessment will be performed only by parent(s) of children above 3 years of age.
††University Michigan Sedation Scale (UMSS). This scale will assist parents at home to evaluate the level of sedation of their child during the 3-week titration period and the first week of the maintenance period.
‡‡Assessment will be performed by both parent(s) and investigator. Subjects will be asked to guess the treatment arm if at an adequate level of maturity.
BMI, body mass index; C-SSRS, Columbia – Suicide Severity Rating Scale; ET, early termination; FLACC, Face, Legs, Activity, Cry, Consolability; FPS-R, Faces Pain Scale – Revised; IMPs, investigational medicinal products; NRS-11, Numeric Rating Scale; PGIC, Patient /parent Global Impression of Change; PK, pharmacokinetic; R-MOAS, Retrospective-Modified Overt Aggression Scale.