Conditions: Neonatal Opioid Withdrawal Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
A Phase II, multicenter, double blind, double dummy, randomized, 2 arms parallel study to evaluate the efficacy, safety and pharmacokinetics of CHF6563 in babies with Neonatal Opioid Withdrawal Syndrome

Detailed description:
This was a randomised, multicentre, double-blind, double-dummy, parallel-group, controlled study of CHF6563 (non-ethanolic buprenorphine) sublingual solution.

For the enrolled subjects, withdrawal signs were assessed using a pre-defined Finnegan Neonatal Abstinence Scoring Tool (FNAST). FNAST assessments were made in neonates who showed signs of withdrawal despite appropriate non-pharmacological care and were recorded every 4 hours (±1 hour). Pharmacological treatment was to be started up to 7 days after birth in neonates who showed signs of neonatal opioid withdrawal syndrome (NOWS), defined as the sum of three consecutive FNAST scores ≥24 or a single score ≥12, and had failed to respond to non-pharmacological care. After FNAST assessment had started, it was continued for at least 24 hours, even if the baby was not randomised.

Sublingual administration of CHF6563 (non-ethanolic buprenorphine) solution (0.075 mg/mL) at a starting dose of 10 μg/kg every 8 hours (q8), using birth weight and oral administration of morphine-matched placebo (sterile water for injection USP), every 4 hours (q4). Thereafter, up-titrations of CHF6563 were possible to a maximum scheduled dose of 90 μg/kg/day. At the discretion of the physician, rescue doses of CHF6563 or morphine could have been given during the treatment to a neonate who had a single score of ≥12. Duration of treatment could last a maximum of 10 weeks. Adverse events (AEs) and serious adverse events (SAEs) were collected starting from the time of informed consent signature or from the neonate's birth (if the informed consent was signed before birth) through treatment and the follow-up period.

The study was terminated for non-safety reasons on 04 February 2022, due to low recruitment rate, after only 7 subjects out of a planned 57 subjects had been randomised. An Independent Safety Monitoring Board (ISMB) was in-place to review the safety profile of CHF6563/morphine treatment; the study was terminated before the ISMB reviewed any data.

Arms:
arm 1: Sublingual dose of CHF6563 and the corresponding oral dose of morphine matched placebo arm 2: Oral dose of morphine and the corresponding sublingual dose of CHF6563 matched placebo.

Interventions: intervention 1: CHF6563 intervention 2: Morphine intervention 3: CHF6563 matched placebo intervention 4: Morphine matched placebo
Intervention descriptions: intervention 1: Sublingual CHF6563 administration at starting dose of 10 µg/kg q8 intervention 2: Oral morphine administration at starting dose of 0.07 mg/kg q4 intervention 3: Sublingual CHF6563 matched placebo administration intervention 4: Oral morphine matched placebo administration

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL
STUDY CODE No.: CLI-06563AA1-02
IND No: 131,339
A Phase II, multicenter, double blind, double dummy, randomized, 2 arms parallel study to 
evaluate the efficacy, safety and pharmacokinetics of CHF6563 in babies with Neonatal Opioid 
Withdrawal Syndrome
Version No.: 6.0
Date: 18 March 2021
The information contained in this document is confidential and will not be disclosed to others without written authorization 
from Chiesi Farmaceutici S.p.A., except to the extent necessary to obtain informed consent from those persons to whom the 
drug may be administered or for discussions with local regulatory authorities, Ethics Committee/Investigational Review 
Boards, or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy
NCT no. NCT04104646


Clinical Study Protocol
Clinical Study Code No.: CLI-06563AA1-02
Version No.: 6.0
IND No.: 131,339
Date: 18 March 2021
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GENERAL INFORMATION
SPONSOR:
Chiesi Farmaceutici S.p.A* 
Via Palermo 26/A
43122 Parma - Italy
+ 39 0521 2791
*also reported as Chiesi throughout 
the text
SPONSOR MEDICAL EXPERT
(Clinical Research Physician)
Largo F. Belloli, 11/A 
43122 Parma (Italy)
Office: 
E-mail: 
Readily available in case of medical 
questions
MONITORING CRO
 
OTHER CENTRAL TECHNICAL 
LABORATORIES
 
 
 
VERSION HISTORY
Version 
Date 
Change History
1.0
04 June 2019
First version
2.0
26 June 2019
Second version - Changing CRP and minor 
formatting changes
3.0
11 July 2019
Third version– changing of volume of PK blood 
collection and minor typo errors
4.0
24 October 2019
Fourth version– changing of phenobarbital, 
packaging, addition of appendix and minor typo 
errors
5.0
28 February 2020
Fifth version -addition of functional unblinding 
description, appendix 3(List of psychotropic drugs), 
intensity of adverse event description and 
correction of minor typo errors 
6.0
 18 March 2021
Sixth version - For detailed list of changes see
Summary of Changes from Protocol v 5.0 to
Protocol v 6.0


Clinical Study Protocol
Clinical Study Code No.: CLI-06563AA1-02
Version No.: 6.0
IND No.: 131,339
Date: 18 March 2021
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PROTOCOL OUTLINE
Study title
A Phase II, multicenter, double blind, double dummy, randomized, 2 arms 
parallel study to evaluate the efficacy, safety and pharmacokinetics of 
CHF6563 in babies with Neonatal Opioid Withdrawal Syndrome
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CHF6563 sublingual solution
Center(s)
Multicenter 
Indication 
Neonatal opioid-withdrawal syndrome (NOWS) with or without other 
concomitant drug withdrawal syndromes
Study design
Randomized, multicenter, double blind, double-dummy, parallel group, 
controlled study
Due to the different lengths of weaning, functional unblinding will be 
possible following the last scheduled dose of CHF6563 up to the end of the 
study.
Study phase
II
Objectives
Primary Objectives
•
To assess the efficacy of sublingual CHF6563 in babies with NOWS 
•
To assess the safety and tolerability of CHF6563 in babies with 
NOWS
Secondary Objectives
•
To investigate the pharmacokinetics of CHF6563 in babies with 
NOWS
•
To assess the use of the adjunctive therapy for NOWS
Treatment duration
up to 10 weeks
Test product 
dose/route/regimen  
CHF6563 
Sublingual administration of CHF6563 solution at concentration of 0.075 
mg/mL
Regimen
CHF6563
Initial dose
10 μg/kg q8
Doses for up-titrations 
15, 20, 25, 30 μg/kg q8
Maximum daily dose
90 μg/kg/day
Maximum # of up-titrations
4
Weaning rate 
-15%
Cessation dose
between 
90-110% 
of 
the 
initial dose
Dosing interval until cessation dose 
(hours)
8
Dose 
interval 
extension 
#1 
at 
cessation dose (hours)
12
Dose 
interval 
extension 
#2 
at 
cessation dose (hours)
24


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Reference product 
dose/route/regimen 
Morphine
Oral administration of a morphine solution at concentration of 0.5 mg/mL
Regimen
Morphine
Initial dose
0.07 mg/kg q4
Doses for up-titrations
0.09, 0.12, 0.16, 0.21 mg/kg
Maximum daily dose
1.25 mg/kg/day
Maximum # of up-titrations
4
Weaning rate
-15%
Cessation dose
< 0.025 mg/kg 
Dosing interval until cessation 
dose (hours)
4
Number of subjects
57
Study population
Babies with neonatal opioid-withdrawal syndrome (NOWS) with or 
without other concomitant drug withdrawal syndromes
Inclusion/exclusion criteria
Inclusion Criteria
Neonates must meet all of the following inclusion criteria to be eligible for 
randomization into the study:
1. Written informed consent obtained by parents/legal representative 
(according to local regulation) prior to or after birth.
2. Birth weight ≥ 3rd centile for gestational age (GA), according to the 
CDC growth chart
3. Gestational age ≥ 36 weeks 
4. Exposure to opioids during the last month before delivery
5. Signs of neonatal opioid withdrawal syndrome requiring treatment, and 
the sum of 3 consecutive Finnegan assessment scores (FNAST) is ≥ 24 
or a single score ≥12  
Exclusion Criteria
The presence of any of the following exclusion criteria will exclude a 
neonate from study randomization:
1. Familial history of prolonged QTC syndrome 
2. Major congenital malformations or evidence of congenital infection
3. Signs of fetal alcohol spectrum disorders 
4. Maternal alcohol abuse, defined as average of 3 or more drinks per 
week in the last 30 days 
5. Medical illness at the time of randomization, including but not 
exclusively:
a.
Neonatal hypoglycaemia requiring intravenous glucose therapy
b.
Neonatal respiratory illness requiring non-invasive or invasive 
respiratory support 
c.
Neonatal 
encephalopathy 
(including 
hypoxic 
ischemic 
encephalopathy or seizures 
d.
Severe hyperbilirubinemia - bilirubin at or above the exchange 
transfusion threshold as defined by the AAP


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e.
Severe elevation of serum aminotransferases (more than twice the 
upper limit of the age appropriate aminotransferases reference 
range of the investigational site).
f.
Proven or suspected early onset neonatal infection which will 
require more than 48 hours treatment with antibiotics
6. Unable to tolerate an oral or sublingual medication
7. Need for medications forbidden in this study protocol
8. Any condition that, in the opinion of the Investigator, would place the 
neonate at undue risk
9. Participation in another clinical trial of any medicinal product, placebo, 
experimental medical device or biological substance conducted under 
the provisions of a protocol on the same therapeutic target. The 
participation in studies involving diagnostic devices or treatments for 
conditions other than NOWS and NAS may be permitted following an 
agreement with the Sponsor. Non-interventional observational studies 
are allowed.
Study plan
Neonates will be assigned in a 2:1 ratio to either CHF6563 or morphine. 
Randomization will be stratified according to the following variables, 
using a dynamic randomization algorithm (i.e. minimization) to balance 
treatment arms with respect to stratification factor levels, while 
maintaining an overall treatment balance: 
•
Feeding status at time of randomization (exclusive formula versus 
[maternal breast milk [including a combination of maternal breast 
milk and formula])
•
Maternal primary opioid use (buprenorphine/methadone/other)
•
Maternal concurrent use of benzodiazepines, antidepressants or 
gabapentin (polypharmacy yes/no)
The minimization method will balance each stratification variable as well 
as the overall treatment balance across the arms in a 2:1 ratio. This method 
achieves a greater level of balance across multiple stratification variables 
compared to a traditional stratified randomization
Following 2 consecutive FNAST with a sum ≥ 12, if all eligibility criteria 
except for Inclusion Criterion #5 are met, then neonates will be pre-
randomized in the IRT system to ensure treatment is available should 
Inclusion Criterion #5 be met (i.e. the sum of 3 consecutive FNAST scores 
≥ 24 or a single score ≥12). 
Treatment period
Pharmacological treatment will start up to 7 days after birth in neonates 
who show signs of NOWS and have failed to respond to non-
pharmacologic care. Withdrawal signs will be assessed using a predefined 
Finnegan Neonatal Abstinence Scoring Tool (FNAST).  If all the 
inclusion/exclusion criteria are met the baby will be randomized in one of 
the following groups:
CHF6563: babies will receive a sublingual dose of CHF6563 at a starting 
dose of 10 μg/kg q8 (using birth weight) and the corresponding oral dose 


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of morphine matched placebo q4.
Morphine: babies will receive an oral dose of morphine at a starting dose 
of 0.07 mg/kg q4 (using birth weight) and the corresponding sublingual 
dose of CHF6563 matched placebo q8.
Signs of withdrawal will be assessed and recorded every 4 hours (±1 hour).
CHF6563 treatment
From initiation through cessation dose, CHF6563 will be administered 
every eight hours (±1 h). In the up-titration phase, dose escalation will 
occur if the sum of the 3 consecutive FNAST scores is ≥ 24 or a single 
score is ≥ 12. No more than one dose escalation can take place each day 
unless a rescue dose is required after which a dose increase will occur. 
During the up-titration phase, doses will increase by 5 ug/kg steps, i.e. after 
the initial 10 ug/kg dose there can be consecutive dose increases to 15, 20, 
25 and 30 ug/kg, if signs of withdrawal persist (i.e. FNAST scores remain ≥ 
24 as the sum of three consecutive scores or a single score is ≥ 12). 
The stabilization phase begins when no further drug treatment escalation is 
required. A stabilization period of 48 hours (without need for further drug 
treatment escalation) is required before weaning of drug treatment can 
begin. 
The initiation of weaning will begin after a 48 hour stabilization period, 
providing the sum of the previous 3 scores is < 18 and no single score is 
≥8: doses will be decreased by 15% once per day. 
If during a 24 hour period, the sum of the previous 3 scores is ≥ 18 or a 
single score is ≥ 8, (even if no dose escalation has been required), weaning 
will not take place, the current dose will continue to be administered. Once 
the sum of the previous 3 scores is < 18 and no single score is ≥ 8, weaning 
can resume.  
No more than one dose reduction is permitted in one calendar day. 
The cessation dose will be around the initial dose, i.e. between 90-110% of 
10 ug/kg.
The maximum dose of 90 μg per kilogram of body weight per day is 
reached after 4 increases in dose.
Morphine treatment 
From initiation through cessation dose, morphine will be administered 
every four hours (±1 h). In the up-titration phase, dose escalation will take 
place if the sum of the 3 consecutive FNAST scores is ≥ 24 or a single 
score is ≥ 12. No more than one dose escalation can take place each day 
unless a rescue dose is required after which a dose increase will occur. 
During the up-titration phase, after the initial 0.07 mg/kg dose the 
consecutive dose increases are 0.09, 0.12, 0.16 and 0.21 mg/kg, if signs of 
withdrawal persist (i.e. FNAST scores remain ≥ 24 as the sum of three 
consecutive scores or a single score is ≥ 12).
The stabilization phase begins when no further drug treatment escalation is 


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required. A stabilization period of 48 hours (without need for further drug 
treatment escalation) is required before weaning of drug treatment can 
begin. 
The initiation of weaning will begin after a 48 hour stabilization period, 
providing the sum of the previous 3 scores is < 18 and no single score is ≥ 
8: doses will be decreased by 15% once per day. 
If during a 24 hour period, the sum of the previous 3 scores is ≥ 18 or a 
single score is ≥ 8, (even if no dose escalation has been required), weaning 
will not take place, the current dose will continue to be administered. Once 
the sum of the previous 3 scores is < 18 and no single score is ≥ 8, weaning 
can resume: doses will continue to be decreased by 15% once per day.  
No more than one dose reduction is permitted in one calendar day. 
The cessation dose is < 0.025 mg/kg q 4 hours.
The maximum dose of 1.25 mg per kilogram per day is reached after 4 
increases in dose.
Additional rescue dose during the escalation phase 
At the discretion of the physician, a rescue dose of CHF6563 or morphine 
may be given during the up-titration phase to a neonate who has a single 
score ≥ 12. A rescue dose should not be administered within 1 hour of the 
previous dose or 1 hour before the next scheduled dose. Rescue dose will 
be the same as the previous dose. A rescue dose must not be given once the 
maximum dose has been reached. The administration of a rescue dose in 
the up-titration period will trigger a dose escalation at the next scheduled 
dose.
Additional rescue dose during the weaning phase
If patient evaluation is consistent with worsening NOWS, at the discretion 
of the physician, a rescue dose of CHF6563 or morphine may be given 
during the weaning phases to a neonate who has a single score ≥ 12. A 
rescue dose should not be administered within 1 hour of the previous dose 
or 1 hour before the next scheduled dose. Rescue dose will be the same as 
the previous dose. The administration of a rescue dose in the weaning 
period will not trigger a dose escalation. If after 24 hours the sum of the 
previous 3 scores is < 18 and no single score is ≥ 8 weaning (i.e. further 
dose reduction) can resume. If after cessation of therapy a rescue dose is 
given, the neonate must be observed for at least 48 hours.
Adjunct phenobarbital therapy 
If in either group, withdrawal as assessed by the FNAST is not controlled at 
the maximum dose of primary therapy (CHF6563 / morphine), 
phenobarbital will be initiated with an oral loading dose of 20 mg/kg, 
followed by a daily oral dose of 5 mg/kg/day. Birth weight will be used for 
the calculation of phenobarbital loading and maintenance dose. Treatment 
with adjunctive phenobarbital will continue for at least two days and 
stabilization should be achieved before weaning of the opioid. Weaning 
will commence with reduction of the primary therapy (CHF6563 / 
morphine) according to the same rules as indicated above. When the 
primary therapy (CHF6563 / morphine) has been weaned to 50% of the 


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maximal dose and the sum of the previous three scores is < 18 and no 
single score is ≥ 8, the phenobarbital dose will be reduced to 2.5 
mg/kg/day. The primary therapy (CHF6563 / morphine) dose will not be 
weaned on the day phenobarbital is weaned. Phenobarbital will be 
discontinued 72 hours after the dose reduction to 2.5 mg/kg/day, provided 
the sum of the previous three scores is < 18 and no single score is ≥ 8, and 
prior to the discontinuation of the primary therapy (CHF6563 / morphine). 
The primary therapy (CHF6563 / morphine) will not be weaned on the day 
when phenobarbital is discontinued. 
Follow up
Following discontinuation of opioid treatment, babies will be observed for 
at least 48 hours during which time scoring of NOWS signs will continue.
Regular follow up will continue during the inpatient admission and 
following discharge from the hospital, to identify those babies who suffer 
recurrence of significant withdrawal. The duration of this follow up will be 
for 6 weeks after the final opioid treatment dose. 
Evidence of recurrence of significant withdrawal will be monitored for all 
babies who remain within the hospital. For babies discharged following the 
required period of inpatient observation (at least 48 hours post last opioid 
dose), daily telephone contact with the primary caregiver (parental/legal 
guardian or foster mother) will continue for the first 7 days and will record 
the infant’s well-being and identify any escalation of withdrawal signs. 
Thereafter weekly telephone contact will continue for the duration of the 
follow up period. 
Significant escalation of withdrawal signs will warrant clinical review and 
assessment for relapse severe enough to require pharmacological treatment 
and readmission.
An additional long-term assessment at 18-months (± 1 months) of age will 
be performed for confirmation of the safety of the test treatment.
Adverse events 
Adverse events (AEs) and serious adverse event (SAEs) will be collected 
starting from the Informed Consent signature or from the neonate’s birth (if 
the Informed consent is signed before birth). Ongoing AEs/SAEs will be 
followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the Investigator.
For neonates who will not be randomized, only SAEs will be collected.
An Independent Safety Monitoring Board (ISMB) will review the safety 
profile of CHF6563 / morphine treatment.
Most relevant allowed 
concomitant treatments
Phenobarbital (only as adjunctive therapy).
Acetaminophen administration for analgesia or treatment of pyrexia should 
not exceed 48 hours, with a maximum daily permitted dose of 60 
mg/kg/day.
During the weaning phase only: sedative and analgesia medications 
(including general and spinal anesthesia, skeletal muscle relaxants, 
benzodiazepines, and short acting opioids) required prior to or during 


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surgical, investigational and imaging procedures.
Any concomitant medication required for the standard care of babies will 
be permitted during the study. 
Wherever possible post-operative analgesia should avoid systemic opioids; 
spinal / epidural analgesia, oral / parenteral acetaminophen and NSAIDS 
are permissible
Most relevant forbidden 
concomitant treatments
Metabolic enzyme-inducing or inhibiting drugs, or drugs known to have a 
well-defined potential for hepatotoxicity should not be taken.
Other drugs which may give additive CNS/respiratory depression if used in 
combination with opioids (benzodiazepines, skeletal muscle relaxant, 
anticholinergics, etc.) unless required prior to or during surgical, 
investigational and imaging procedures undertaken. 
Other drugs or biological substance to be administered under the 
provisions of a protocol on the same therapeutic target. Treatments for 
different conditions than NOWS and NAS may be permitted following an 
agreement with the Sponsor.
Breastfeeding
Breastfeeding is allowed.
Current feeding status (formula or maternal breast milk [including 
combination of maternal breast milk and formula]) will be recorded just 
prior to randomization.
During the study, actual feeding will be collected in terms of 
breastfeeding, formula feeding, mixed feeding, and the proportion of 
feeding which is breast milk for subjects receiving both formula and 
breast milk.
Efficacy variables
(and/or pharmacokinetics 
variables)
Primary endpoint   
Duration of treatment defined as the number of hours from first dose of 
study drug administration until the last dose of study drug.
Secondary endpoints: 
•
Time to first weaning, defined as the number of hours from first dose 
of study drug administration until the first dose reduction
•
Requirement for adjunctive drug therapy (phenobarbital) for signs of 
NOWS (yes/no)
•
Total hours of treatment with adjunctive therapy 
•
Requirement for rescue doses (CHF6563 or morphine) (yes/no)
•
Number of rescue doses administered per neonate 
•
Percentage of total amount of active study drug which is from rescue 
doses per neonate 
•
Length of opioid related hospital stay, defined as number of days 
from day of birth until 48 hours after the final dose of drug treatment 
for NOWS
•
Relapse of NOWS, defined as experiencing recurrence of significant 
signs of withdrawal (yes/no)
•
Incidence of readmissions, defined as readmission to hospital for 
NOWS relapse (yes/no)


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Safety variables
During administration of sublingual CHF6563 or oral morphine:
Number and percentage of babies with peri-dosing adverse events (AEs) 
(i.e., 
mouth 
irritation 
or 
inflammation, 
apnea, 
desaturation, 
brady/tachycardia, cough, immediate swallowing of sublingual drug, 
regurgitation, vomiting occurring after administration)
During the study
•
Hematology and blood chemistry: full blood count (FBC), urea, 
creatinine and electrolytes (sodium, potassium, magnesium calcium, 
phosphorus), glucose, C-reactive protein if collected before 
randomization according to site clinical practice.
•
Adverse events and adverse drug reactions (ADRs) will be collected.
•
Liver enzymes analysis-function testing (AST, ALT) will be 
performed on 3 occasions: after first dose, at stabilization and 48 
hours (±4 h) after the last treatment dose.
•
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen 
saturation (SpO2), body temperature (BT) will be monitored, and data 
collected during the escalation and stabilization phases. 
•
Weight, head circumference 
•
Blood pressure (SBP, MBP, DBP) will be monitored according to 
individual site clinical practice.
End of treatment period (48 hours ±4 h after last dose)
•
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen 
saturation (SpO2), body temperature (BT). Blood pressure (SBP. 
MBP. DBP) if collected according to site clinical practice.
•
General physical and neurological examination.
•
Assessment of growth: head circumference, body weight, length.
•
Further adverse events as well as changes in those already reported.
Pharmacokinetics 
An 
opportunistic 
sampling 
strategy 
combined 
with 
population 
pharmacokinetic modelling will be adopted. Blood sampling for PK will 
occur the day of randomization and then every 5±1 days until the last dose. 
The analysis of this data will follow a population pharmacokinetic 
modelling approach, to be described in a separate analysis plan and report.   
Sample size calculation
Based on the results of similar studies, it was determined that a sample size 
of 51 babies (17 morphine; 34 CHF6563) will provide a power of 80% to 
detect a difference in duration of treatment of 13 days (312 hours,), 
assuming a common standard deviation of 15 days and a two-sided 
significance level of 0.05.  Assuming an early withdrawal rate of 10%, a 
total of 57 babies (19 morphine; 38 CHF6563) will be randomized to 
obtain a minimum of 51 evaluable babies completing the treatment period.
Statistical methods
Primary efficacy analysis:
An ANCOVA model based on log-transformed data will be performed to 
test the treatment effect as duration of treatment (hours). The model 


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will include treatment (CHF6563 and morphine) as a fixed effect, primary 
feeding method (formula / any maternal breast milk), maternal primary 
opioid use (buprenorphine/methadone/other), and concurrent maternal use 
of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]) as covariates. In cases where observed primary feeding method 
during the treatment period (formula / any maternal breast milk) differs 
from the feeding method at time of randomization, the observed primary 
feeding method will be used for analysis. The adjusted ratio of geometric 
means between treatments, its 95% CI and associated p-value will be 
estimated by the model.  Babies who discontinue study medication prior to 
end of the study treatment will be allowed to remain in the study and 
receive standard of care according to clinical practice. Handling of such 
cases will be described in the SAP. Babies who discontinue completely 
(including withdrawal due to treatment longer than 10 weeks) will be 
imputed using the maximum of the observed value (10 weeks for patients 
withdrawn due to treatment longer than 10 weeks) or the value of the 90th 
percentile of duration of any subject completing the study, regardless of 
treatment group.
Secondary efficacy analyses:
In cases where observed primary feeding method during the treatment 
period (formula / any maternal breast milk) differs from the feeding 
method at time of randomization, the observed primary feeding method 
will be used for analysis.
Time to first weaning (hours) An ANCOVA model based on log-
transformed data will be performed to test the treatment effect as time to 
first weaning (hours). The model will include treatment (CHF6563 and 
morphine) as a fixed effect, primary feeding method (formula / any 
maternal 
breast 
milk), 
maternal 
primary 
opioid 
use 
(buprenorphine/methadone/other), and maternal use of benzodiazepines, 
antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. The 
adjusted ratio of geometric means between treatments, its 95% CI and 
associated p-value will be estimated by the model.
Requirement for adjunctive drug therapy (phenobarbital) for signs of 
NOWS (yes/no) during the treatment period will be analyzed using 
logistic regression.  The Odds ratio and corresponding 95% CI and p-
value will be presented, adjusting for primary feeding method (formula / 
any 
maternal 
breast-milk), 
maternal 
primary 
opioid 
use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]).
Total hours of treatment with adjunctive therapy will be analyzed 
using an ANCOVA model. The model will include treatment (CHF6563 
and morphine) as a fixed effect and primary feeding method (formula/any 
maternal 
breast-milk), 
maternal 
primary 
opioid 
use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. 
Babies not requiring adjunctive therapy will be included with a value of 0.


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Requirement for rescue doses of CHF6563 or morphine (yes/no) during 
the treatment period will be analyzed using logistic regression, adjusting 
for primary feeding method (formula/any maternal breast-milk), maternal 
primary opioid use (buprenorphine/methadone/other), and maternal use of 
benzodiazepine, antidepressants or gabapentin (polypharmacy [yes/no]). 
The odds ratio of incidence between treatment groups will be presented 
together with the 95% CI and corresponding p-value.  
The mean number of rescue doses per neonate and the mean 
percentage of total amount of active study drug which is from rescue 
doses will be analyzed using an ANCOVA model. The model will include 
treatment (CHF6563 and morphine) as a fixed effect and primary feeding 
method (formula/any maternal breastmilk), maternal primary opioid use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. 
Babies not requiring rescue dose(s) of active study drug will be included 
with a value of 0.
Length of opioid related hospital stay will be analyzed using an 
ANCOVA model based on log transformed data. The model will include 
treatment (CHF6563 and morphine) as a fixed effect and primary feeding 
method (formula/ any maternal breastmilk), maternal primary opioid use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]) as covariates.
Incidence of relapse of NOWS (yes/no) will be analyzed using logistic 
regression, adjusting for primary feeding method (formula/ any maternal 
breastmilk), 
maternal 
primary 
opioid 
use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]). The odds ratio of 
incidence between treatment groups will be presented together with the 
95% CI and corresponding p-value.  
Incidence of readmissions (yes/no) during the study period will be 
analyzed using logistic regression, adjusting for primary feeding method 
(formula/ any maternal breastmilk), maternal primary opioid use 
(buprenorphine/methadone/other), and maternal use of benzodiazepine, 
antidepressants or gabapentin (polypharmacy [yes/no]). The odds ratio of 
incidence between treatment groups will be presented together with the 
95% CI and corresponding p-value. 
Pharmacokinetics
The relative low number of blood samples per baby, the opportunistic 
sampling strategy and the continuous variation of the administered dose 
prevent the application of standard non-compartmental analysis for the 
characterisation of CHF6563 pharmacokinetics in the neonate population.
Instead, a population pharmacokinetic modelling approach will be applied. 
Separated analysis plan and report will be produced.   


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Safety variables
•
The number and percentage of subjects experiencing Treatment-
emergent adverse events (TEAE), drug-related AE, serious TEAE, 
serious related TEAE, TEAE leading to study discontinuation, TEAE 
leading to death and peri-dosing adverse events, as well as the 
number of events, will be presented by treatment group and overall. 
Each of these groups of adverse events will also be summarized by 
System Organ Class and Preferred Term.
•
Liver-function test parameters and their changes from baseline will 
be summarized using descriptive statistics.
•
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen 
saturation (SpO2), body temperature (BT), blood Pressure (SBP. 
MBP. DBP) will be monitored if collected according to site clinical 
practice. These variables will be presented as descriptive statistics 
only.
•
Head circumference and body weight (and percentile) and its change 
from baseline will be summarized using descriptive statistics.
The following parameters collected at end of treatment will be listed only:
•
Growth parameters: head (and percentile), and length (and percentile) 
•
General physical and neurological examination 
  


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AAP
American Academy of Pediatrics
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification
BT
Body temperature
CDC
Center for Disease and Control
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
DBP
Diastolic Blood pressure
DMPKA
Drug Metabolism and PharmacoKinetics
CBC
Complete blood count
FSFV
First Subject First Visit
FNAST
Finnegan Neonatal Abstinence Scoring Tool
eCRF
Electronic case report form
GA
Gestational age
GCP
Good Clinical Practices
GLP
Good Laboratory Practice
HR
Heart rate
ICH
International Conference on Harmonization
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISMB
Independent Safety Monitoring Board
ITT
Intention to Treat
LSLV
Last Subject Last Visit
MBP
Mean Blood pressure
MedDRA
Medical Dictionary for Regulatory Activities
NAS
Neonatal Abstinence syndrome
NOWS
Neonatal opioid-withdrawal syndrome
NSAIDS
Nonsteroidal anti-inflammatory drugs
PK
Pharmacokinetics
PP
Per-Protocol
RR
Respiratory rate
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood pressure
SmPC
Summary of Product Characteristics
SpO2
Peripheral oxygen saturation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment emergent adverse event


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CONTENT
GENERAL INFORMATION ...........................................................................................................................................2
PROTOCOL OUTLINE ..................................................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...............................................................................................14
CONTENT.................................................................................................................................................................15
1.
INTRODUCTION ..............................................................................................................................................17
1.1 BACKGROUND INFORMATION.........................................................................................................................................17
1.2 STUDY RATIONALE .......................................................................................................................................................18
1.3 RISK/BENEFIT ASSESSMENT............................................................................................................................................19
2.
STUDY OBJECTIVES .........................................................................................................................................20
2.1 PRIMARY OBJECTIVE(S).................................................................................................................................................20
2.2 SECONDARY OBJECTIVE(S).............................................................................................................................................20
3.
STUDY DESIGN................................................................................................................................................20
4.
SUBJECT SELECTION CRITERIA .........................................................................................................................21
4.1 SUBJECT RECRUITMENT ................................................................................................................................................21
4.2 INCLUSION CRITERIA ....................................................................................................................................................22
4.3 EXCLUSION CRITERIA....................................................................................................................................................22
4.4 SUBJECT WITHDRAWAL ................................................................................................................................................23
5.
CONCOMITANT MEDICATIONS........................................................................................................................23
5.1 PERMITTED CONCOMITANT MEDICATIONS........................................................................................................................23
5.2 NON-PERMITTED CONCOMITANT MEDICATIONS ................................................................................................................24
6.
TREATMENT(S)................................................................................................................................................24
6.1 APPEARANCE AND CONTENT..........................................................................................................................................24
6.2 DOSAGE AND ADMINISTRATION .....................................................................................................................................25
6.3 PACKAGING................................................................................................................................................................31
6.4 LABELING...................................................................................................................................................................32
6.5 TREATMENT ALLOCATION..............................................................................................................................................32
6.6 TREATMENT CODE.......................................................................................................................................................33
6.7 TREATMENT COMPLIANCE .............................................................................................................................................33
6.8 DRUG STORAGE ..........................................................................................................................................................33
6.9 DRUG ACCOUNTABILITY................................................................................................................................................34
6.10 PROVISION OF ADDITIONAL CARE ..................................................................................................................................34
7.
STUDY PLAN ...................................................................................................................................................34
7.1 STUDY SCHEDULE ........................................................................................................................................................34
7.2 INVESTIGATIONS..........................................................................................................................................................41
8.
EFFICACY ASSESSMENTS .................................................................................................................................42
8.1 PRIMARY EFFICACY ENDPOINT........................................................................................................................................42
8.2 SECONDARY EFFICACY ENDPOINTS: .................................................................................................................................42
9.
SAFETY ASSESSMENTS ....................................................................................................................................43
10.
ADVERSE EVENT REPORTING ..........................................................................................................................44
10.1 DEFINITIONS.............................................................................................................................................................44


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10.2 EXPECTEDNESS..........................................................................................................................................................45
10.3 INTENSITY OF ADVERSE EVENT .....................................................................................................................................45
10.4 CAUSALITY ASSESSMENT.............................................................................................................................................46
10.5 ACTION TAKEN WITH THE STUDY DRUG DUE TO AN AE ......................................................................................................46
10.6 OTHER ACTIONS TAKEN...............................................................................................................................................46
10.7 OUTCOME ...............................................................................................................................................................46
10.8 RECORDING ADVERSE EVENTS......................................................................................................................................47
10.9 REPORTING SERIOUS ADVERSE EVENTS TO CHIESI ............................................................................................................47
10.10 REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY AUTHORITIES/ETHICS COMMITTEES/IRB..........................................48
10.11 GENERAL NOTES .....................................................................................................................................................48
10.12 INDEPENDENT SAFETY MONITORING BOARD.................................................................................................................48
11.
DATA MANAGEMENT .....................................................................................................................................49
12.
STATISTICAL METHODS...................................................................................................................................49
12.1 SAMPLE SIZE ............................................................................................................................................................49
12.2 POPULATIONS FOR ANALYSIS........................................................................................................................................50
12.3 STATISTICAL ANALYSIS.................................................................................................................................................50
13.
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD APPROVAL...................................................................54
14.
REGULATORY REQUIREMENTS........................................................................................................................54
15.
INFORMED CONSENT......................................................................................................................................54
16.
SOURCE DOCUMENTS/DATA...........................................................................................................................55
16.1 RECORDING OF SOURCE DATA ......................................................................................................................................55
16.2 DIRECT ACCESS TO SOURCE DOCUMENT/DATA.................................................................................................................55
17.
STUDY MONITORING ......................................................................................................................................55
18.
QUALITY ASSURANCE......................................................................................................................................55
19.
INSURANCE AND INDEMNITY..........................................................................................................................55
20.
CONFIDENTIALITY ...........................................................................................................................................56
21.
PREMATURE TERMINATION OF THE STUDY.....................................................................................................56
22.
CLINICAL STUDY REPORT.................................................................................................................................56
23.
RECORD RETENTION .......................................................................................................................................56
24.
PUBLICATION OF RESULTS ..............................................................................................................................56
25.
REFERENCES....................................................................................................................................................57
APPENDIX 1 - APPROVAL OF THE PROTOCOL BY CLINICAL INVESTIGATOR(S)............................................................60
APPENDIX 2 – MATERNAL SCREENING QUESTIONNAIRE ..........................................................................................62
APPENDIX 3 – LIST OF PSYCHOTROPIC DRUGS..........................................................................................................69
APPENDIX 4 – FINNEGAN NEONATAL ABSTINENCE SCORING TOOL (FNAST).............................................................71


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1.
INTRODUCTION
1.1 Background information
Neonatal opioid withdrawal syndrome (NOWS) is a subset of Neonatal abstinence syndrome (NAS) 
and refers to neonatal withdrawal from opioid drugs and can occur in the presence of other drug 
withdrawal syndromes. In the United States, neonatal withdrawal following in-utero opioid 
exposure is typically the result of prolonged maternal use and/or abuse of illicit or prescribed 
opioids during pregnancy. Birth leads to the abrupt cessation of fetal substance exposure and can 
precipitate acute withdrawal symptoms that can result in severe health complications with 
prolonged recovery and longer hospitalization.  Withdrawal can be both severe and intense, with an 
estimated 60% to 80% of exposed neonates requiring pharmacological intervention to control 
symptoms [1][2]. 
While the signs and symptoms of NOWS are similar to those experienced by adults undergoing 
acute opiate withdrawal, they present a higher risk to the neonate due to the babies’ dependence on 
others for all aspects of well-being.
NOWS presenting signs include central nervous system hyperirritability (tremors, jitteriness, 
irritability, hyperactive muscle reflexes, and excessive high-pitched cry), autonomic nervous system 
deregulation and instability (tachypnea, nasal flaring, hyperphagia, temperature instability, 
insomnia, sweating, mottle skin, yawning, and sneezing), and gastrointestinal symptoms (diarrhea, 
vomiting, and poor feeding) [3][4][5]. Seizures are generally rare, although they have been reported 
occurring in 2% to 11% of neonate cases in the early stage of severe opioid withdrawal [6][7], 
especially if medical treatment has been delayed.  A recent large observational cohort study of 
Medicaid babies in 46 US States reported an incidence of seizures was 2.7% among the 1705 
observed cases of NAS [8]. Neonates with NOWS can also experience weight loss or failure to 
thrive, which often results from a combination of poor feeding, vomiting, nausea, and diarrhea [4] 
[5].  If left untreated, some cases of NOWS may even lead to death [5].  Some of the less severe 
signs and symptoms of opiate withdrawal may persist for several months [3].
The onset, duration, and the severity of NOWS are dependent on several factors: the type of opiate 
exposure, maternal-fetal drug transferability, poly-drug exposure, time and duration of opiate 
exposure, placental and fetal drug concentrations, the rate of excretion, spatial representation and 
density of opiate receptors, and gestational age [4][1][9][10].
The management of neonates at risk of this withdrawal syndrome is based on the following [11]:
Identification of neonates at risk, preferably by identification of maternal substance exposure 
during pregnancy; 
Early initiation of non-pharmacological care (this first-line treatment provides a suitable, 
supportive environment for both the mother and baby, which minimizes exposure to stress, and 
encourages breastfeeding where appropriate);
Monitoring for signs of withdrawal;
Pharmacological care, which is instituted when the signs of withdrawal become too severe to be 
managed with non-pharmacological care 
There are no FDA-approved drugs for the treatment of NOWS with or without other concomitant 
drug withdrawal syndromes; however, there is consensus within the neonatology community that 


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opioid replacement should be the first-line pharmacotherapy treatment [3][4][12]. Morphine is the 
most often used opioid for the treatment of neonatal withdrawal following in-utero opioid exposure, 
followed by methadone, with some hospitals using buprenorphine. While morphine is used in 
morethan 80% of NAS cases requiring pharmacological treatment [11], there is no agreed standard 
of care [13] or treatment regimens [1][14] and the optimal pharmacological treatment protocols 
have not been established in large, well-controlled studies.  
Commercially available liquid formulations of morphine and methadone are unsuitable for the 
neonatal population for several reasons.  They contain inappropriately high concentrations of 
opioid, necessitating local compounding of extemporaneous formulations or dilution prior to 
administration within the hospital pharmacy or by neonatal nursing staff, increasing the risk of 
medication errors [15][16][17][18]. Commercially available liquid formulations frequently contain 
alcohol and other preservatives and excipients that are contraindicated or undesirable in the 
neonatal population.  Whilst an alcohol-free morphine solution is available, commercial methadone 
solutions contain alcohol. Therefore, the currently available pharmacological treatments for NOWS 
leave the neonate at risk of medication errors, other hazards related to local compounding of 
extemporaneous formulations, and exposure to alcohol, other preservatives, and excipients that are 
contraindicated or undesirable in the neonatal population.
Buprenorphine has several characteristics that make it an attractive agent in the treatment of 
NOWS.  Buprenorphine is a long acting μ-opioid receptor partial agonist and κ-opioid receptor 
antagonist.  The long half-life and duration of action prevents the rapid change in receptor 
occupancy that can precipitate withdrawal and should allow a simplified dosing regimen to be 
developed.  Sublingual buprenorphine shows a lack of the cardiovascular liability that is associated 
with methadone.  Related to the lack of cardiovascular liability, sublingual buprenorphine possesses 
a well-established safety profile in adults.  Moreover, buprenorphine has the lowest incidence of 
respiratory depression among opioids, which is dose-dependent and has a ceiling effect in relation 
to the long half-life of buprenorphine [19][20][21][22]. 
The CHF6563 development program is intended to develop a neonate-specific formulation of 
buprenorphine. CHF6563 does not contain ethanol, naloxone, or any excipients considered 
contraindicated, unsafe, or inappropriate for use in the neonatal population. CHF6563 is intended to 
control or reduce withdrawal symptoms, decrease duration of treatment, and reduce length of 
hospital stay in neonates diagnosed with NOWS with or without other concomitant drug withdrawal 
syndromes.
1.2 Study rationale
Chiesi is developing CHF6563 (sublingual buprenorphine) for the treatment of NOWS with or 
without other concomitant drug withdrawal syndromes.  
The safety and efficacy of buprenorphine as a treatment for NOWS with or without other 
concomitant drug withdrawal syndromes has been investigated in 5 published studies 
[23][24][25][26][27] using an extemporaneous formulation containing 30% ethanol. Across the 5 
studies, sublingual buprenorphine demonstrated a significant reduction in duration of treatment and 
stay compared to the standard of care (oral morphine or methadone). The extemporaneously 
prepared ethanolic buprenorphine sublingual formulation was generally well tolerated in the target 
population and demonstrated a similar safety profile to oral morphine.  
The CHF6563 development program is focused on finding an appropriate, safe, and efficacious 
buprenorphine formulation, and establishing a buprenorphine-dosing regimen that provides 
effective control of the clinical signs of NOWS when non-pharmacological therapy has failed. The 
PK profile of buprenorphine should enable a dosing regimen to be developed that will increase the 


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interval between doses compared with morphine and simplify the weaning regimen, potentially 
bringing safety and efficacy benefits to the neonate, their families, and healthcare systems. 
This study will evaluate the efficacy and safety of a model-derived CHF6563 dosing regimen as a 
treatment for NOWS with or without other concomitant drug withdrawal syndromes when non-
pharmacological therapy has failed. 
1.3 Risk/benefit assessment
Sublingual buprenorphine shows a lack of the cardiovascular liability that is associated with 
methadone. Related to the lack of cardiovascular liability, sublingual buprenorphine possesses a 
well-established safety profile in adults. Moreover, buprenorphine has the lowest incidence of 
respiratory depression among opioids, which is dose-dependent and has a ceiling effect in relation 
to the long half-life of buprenorphine [19][20][21][22].
Buprenorphine is a long-acting, partial μ-opioid receptor agonist and κ-opioid receptor antagonist. 
Due to its favorable pharmacological characteristics of long half-life and duration of action, 
buprenorphine has been shown to significantly reduce the median duration of treatment and a 
median length of stay when compared to morphine and methadone in both retrospective and in RCT 
study [23][24][25][26][27]. The long half-life and duration of action prevents the rapid change in 
receptor occupancy that can precipitate withdrawal seen with shorter acting opioids (i.e. morphine). 
In contrast to the full μ-opioid agonists (morphine and methadone) commonly used to treat NOWS, 
increasing buprenorphine serum concentration results in a ceiling effect for important opioid 
agonistic side effects, namely respiratory depression (morphine and methadone) or cardiovascular 
liability including QTc interval prolongation (methadone) [19][20][21][22]. In Kraft’s 2017 study, a 
model based analysis demonstrated that at any time during treatment the mean respiratory rate in 
morphine treated infants was lower by 4.4 breaths per minute (95% Cl: 0.7, 8.1; p=0.020) as 
compared to buprenorphine treated infants in the same strata. Although all the respiratory rates 
recorded were within the normal range, these data suggest a possible safer profile for 
buprenorphine. In this same study, 13 adverse events occurred in 7 infants in the buprenorphine 
group and 10 events in 8 infants in the morphine group (P = 0.79 for the no. of events by Fisher’s 
exact test) [28]. Cough, tachycardia, umbilical granuloma, involvement of skin conditions and of 
gastrointestinal conditions have been observed. There were two serious adverse events. One was an 
inguinal hernia repair in the morphine group, and one was a supraglottoplasty associated with the 
Pierre Robin syndrome in the buprenorphine group. There were no elevations in levels of alanine 
aminotransferase or aspartate aminotransferase in any infant.
The results of the available toxicology studies showed that buprenorphine possess less adverse 
reactions over other opioids. Single and repeated dose of buprenorphine significantly decreased 
adverse clinical observations associated with opioid withdrawal. Main acute toxic signs in animals 
associated with buprenorphine treatment were CNS and cardiorespiratory depression. Subchronic 
toxicity studies of buprenorphine in rat, dog and monkey showed decreased body weight, 
inflammatory reaction at the injection site, and clinical biochemistry and hematology parameters 
changes that reflect this inflammatory reaction. No adverse findings were observed during 
histology. Positive findings were noted in few genotoxicity assays and an increased incidence of 
testicular interstitial cell tumors was observed in rats. No effects on fertility and no teratogenic 
effects were noted, although some developmental effects were observed.  During a 4 weeks study in 


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juvenile rats transient increased activity, excessive behaviors and decreased body weight were 
noted[29][30][31][32][33][34][35][36][37].
Considering the safety profile of the treatments, the measures in place to ensure the patients’ safety 
and the expected scientific value, the overall risk/benefit assessment can be considered acceptable 
for the proposed trial.
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and amendments) 
current ICH E6 Good Clinical Practices and all other applicable laws and regulations.
2.
STUDY OBJECTIVES
2.1 Primary Objective(s)

To assess the efficacy of CHF6563 in babies with NOWS 

To assess the safety and tolerability of CHF6563 in babies with NOWS
2.2 Secondary Objective(s)

To investigate the pharmacokinetics of CHF6563 in babies with NOWS

To assess the use of the adjunctive therapy for NOWS
3.
STUDY DESIGN 
This is a randomized, multicenter, double blind, double-dummy, parallel group, controlled study.
Fifty-seven neonates with neonatal opioid-withdrawal syndrome (NOWS) with or without other 
concomitant drug withdrawal syndromes will be randomized to receive CHF6563 or morphine 
treatment. In order to maintain the blind, a double-dummy design will be used so that the subjects 
will receive either CHF6563 and morphine matched placebo, or morphine treatment and CHF6563 
matched placebo.
The weaning period requires a lower number of weaning steps for CHF6563 compared to morphine.  
In order to avoid maintaining babies randomized to CHF6563 in the hospital following completion 
of study drug, only to receive placebo for several days (about 5, depending on the severity of the 
withdrawal), the unblinded pharmacist will advise the clinical staff that the baby has completed 
active study treatment following the last active dose of CHF6563 and babies will be eligible for 
discharge (at least insofar as the clinical trial is concerned) 48 hours after the last active dose. Since 
the cessation dose will not occur at the same weaning step for the 2 treatment arms, it will be 
possible to ascertain the treatment for each baby after the weaning step which corresponds to the 
cessation dose of CHF6563. This is considered a “functional unblinding” since, after this point, it 
will be possible for members of the blinded team to ascertain the treatment arm. 
Prior to the last scheduled dose of CHF6563, all members of the blinded study team will remain 
completely blinded.  Following the last scheduled dose of CHF6563/placebo, members of the 
blinded study team will not have access to the explicit treatment codes, but it will be possible to 
ascertain the treatment arm.  Similarly, data review will occur without access to explicit treatment 
codes, since the explicit treatment codes will be maintained in a confidential manner. The 
randomization list and explicit treatment codes will be disclosed to blinded study team members 
only after the database is locked.  


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Withdrawal signs will be assessed using a predefined Finnegan Neonatal Abstinence Scoring Tool 
(FNAST). FNAST assessments will commence in neonates who show signs of withdrawal despite 
appropriate non-pharmacological care and recorded every 4 hours (±1 hour). Pharmacological 
treatment will start up to 7 days after delivery in neonates who show signs of NOWS (sum of 3 
consecutive FNAST scores ≥24 or a single score ≥12) and have failed to respond to non-
pharmacologic care. After FNAST assessment has started, it should continue for at least 24 hours, 
even in case the baby is not randomized. 
According to a randomization algorithm, neonates will be assigned to one of the two arms: 

Test arm: babies will receive a sublingual dose of CHF6563 at a starting dose of 10 μg/kg 
every 8 hours (±1 h) (using birth weight which should be rounded to the second decimal 
place) and the corresponding oral dose of morphine matched placebo q4.

Reference arm: babies will receive an oral dose of morphine at a starting dose of 0.07 mg/kg 
every 4 hours (±1 h) (using birth weight which should be rounded to the second decimal 
place) and the corresponding sublingual dose of CHF6563 matched placebo q8.
Pharmacological treatment consists of the following phases; initiation, escalation, stabilization, 
weaning and cessation. Assessment of the need for treatment and dose adjustments will be based 
upon clinical signs of withdrawal evaluated using a FNAST and continued until at least 48 hours 
after the last dose of opioid treatment.  A review of the drug dose will take place on a daily basis 
or more frequently during the escalation phase to ensure timely dose adjustment. 
The duration of follow up will be for 6 weeks after the final opioid treatment dose. Evidence of 
recurrence of significant withdrawal will be monitored for all babies who remain within the 
hospital. For babies discharged following the required period of inpatient observation (48 hours 
post last opioid treatment dose), daily telephone contact with the primary caregiver (parental/legal 
guardian or foster mother) will continue for the first 7 days and will record the baby’s wellbeing 
and identify any escalation of withdrawal signs.
Thereafter weekly telephone contact will continue for the duration of the follow up period. The 
first weekly telephone contact will occur 7 days after the last daily phone call.  Significant 
escalation of withdrawal signs will warrant clinical review and assessment for relapse severe 
enough to require pharmacological treatment and readmission.
The end of the trial is defined as the last follow-up at 6 weeks contact of the last subject in the trial.
 
An 18-month (± 1 months) follow-up visit to assess neurodevelopmental and general health status 
and confirmation of the safety of the test treatment will be undertaken by the participating centers. 
This assessment will be evaluated separately from the main part of the study.
4.
SUBJECT SELECTION CRITERIA
4.1 Subject Recruitment
57 neonates with neonatal opioid-withdrawal syndrome (NOWS) with or without other concomitant 
drug withdrawal syndromes will be randomized.  


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4.2 Inclusion Criteria 
Neonates must meet all of the following inclusion criteria to be eligible for randomization into the 
study:
1. Written informed consent obtained by parents/legal representative (according to local 
regulation) prior to or after birth.
2. Birth weight ≥ 3rd centile for gestational age (GA), according to the CDC growth chart
3. Gestational age ≥ 36 weeks 
4. Exposure to opioids during the last month before delivery 
5. Signs of neonatal opioid withdrawal syndrome requiring treatment, and the sum of 3 
consecutive FNAST scores is ≥ 24 or a single score ≥ 12  
4.3 Exclusion Criteria
The presence of any of the following will exclude a subject from study randomization: 
1. Familial history of prolonged QTc syndrome 
2. Major congenital malformations or evidence of congenital infection
3. Signs of fetal alcohol spectrum disorders
4. Maternal alcohol abuse, defined as average of 3 or more drinks per week in the last 30 days 
5. Medical illness at the time of randomization, including but not exclusively:
a) Neonatal hypoglycemia requiring intravenous glucose therapy
b) Neonatal respiratory illness requiring non-invasive or invasive respiratory support 
c)  Neonatal encephalopathy (including hypoxic ischemic encephalopathy or seizures
d) Severe hyperbilirubinemia–bilirubin at or above the exchange transfusion threshold as 
defined by the AAP
e) Severe elevation of serum aminotransferases (more than twice the upper limit of the age 
appropriate aminotransferases reference range of the investigational site).
f)
Proven or suspected early onset neonatal infection which will require more than 
48hours treatment with antibiotics
6. Unable to tolerate an oral or sublingual medication
7. Need for medications forbidden in this study protocol
8. Any condition that, in the opinion of the Investigator, would place the neonate at undue 
risk
9. Participation in another clinical trial of any medicinal product, placebo, experimental 
medical device or biological substance conducted under the provisions of a protocol on the 
same therapeutic target. The participation in studies involving diagnostic devices or 
treatments for conditions other than NOWS and NAS may be permitted following an 
agreement with the Sponsor. Non-interventional observational studies are allowed


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More details on the characteristics of mothers whose babies are allowed to be recruited are 
provided in section 0 and in APPENDIX 2 – Maternal Screening Questionnaire.
4.4 Subject Withdrawal
Babies must be discontinued from the study for any of the following reasons:

An adverse event occurs that, in the opinion of the investigator, makes it unsafe for the 
subject to continue in the study

Additional drug therapy is required when withdrawal signs as assessed by the FNAST are 
not controlled with the maximum dose of the study drug in combination with 
phenobarbital. 

Prolonged requirement for opioid therapy defined as > 10 weeks (> 70 days) i.e. inability 
to wean from opioid therapy. 

The baby is lost to follow-up.

Parents or legal guardian withdraws consent.

The baby’s safety is affected by use of not-permitted concomitant medication.

The baby transfers to another inpatient facility during the phase of administration of 
study drug

The sponsor or the regulatory authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular 
subject. 
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawals of subjects should be avoided.
However, should a baby discontinue study medication, data collection will continue and all efforts 
will be made to complete and report the observations as thoroughly as possible.
In case of withdrawal, the Investigator must fill in the “Study Termination” page in the eCRF, 
reporting the main reason for withdrawal.   
If a baby is withdrawn/drops-out of the study after receiving the test treatment, the subject study 
number and corresponding test treatments should not be reassigned to another subject.
5.
CONCOMITANT MEDICATIONS
5.1 Permitted concomitant Medications
Phenobarbital (as adjunctive therapy only, see section 6.2.2.4)
Acetaminophen administration for analgesia or treatment of pyrexia should not exceed 48 hours, 
with a maximum daily permitted dose of 60 mg/kg/day.
During the weaning phase only: sedative and analgesia medications (including general and spinal 
anaesthesia, skeletal muscle relaxants, benzodiazepines, and short acting opioids) required prior to 
or during surgical, investigational and imaging procedures.


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Any concomitant medication required for the standard care of babies will be permitted during the 
study. 
Investigators are required to record all medications in the eCRF with the exception of the drugs 
listed below, unless these drugs are administered to treat an adverse event: 
Multivitamins or single vitamins, iron, folic acid, calcium and phosphorus, simethicone, cream for 
napkin dermatitis, glycerin suppository, reflux medications, sucrose solution, dextrose gel, oral 
glucose gel, vaccines.
Wherever possible post-operative analgesia should avoid systemic opioids; spinal / epidural 
analgesia, oral / parenteral acetaminophen and NSAIDS are permissible
5.2 Non-permitted concomitant Medications
Metabolic enzyme-inducing or inhibiting drugs, or drugs known to have a well-defined potential 
for hepatotoxicity should not be taken.
Other drugs which may give additive CNS/respiratory depression if used in combination with 
opioids (benzodiazepines, skeletal muscle relaxant, anticholinergics, etc.) unless required prior to 
or during surgical, investigational and imaging procedures undertaken. 
Other drugs or biological substances to be administered under the provisions of a protocol on the 
same therapeutic target. Treatments for different conditions than NOWS and NAS may be 
permitted following an agreement with the Sponsor. However urgent treatment should not be 
withheld or delayed.
6.
TREATMENT(S)
The study medications will be supplied to the clinical site under the responsibility of the Sponsor, 
who will also provide the Pharmacist/Investigator with appropriate certificates of analytical 
conformity.
6.1 Appearance and Content
CHF6563, Chiesi liquid preparation 0.075 mg/mL for sublingual administration (Test 
treatment & rescue medication)

Active ingredient: Buprenorphine

Excipients: Citric buffer pH 6, Hydroxyethylcellulose 

Presentation: transparent solution  
CHF6563 matched placebo, Chiesi liquid preparation, for sublingual administration  

Excipients: Citric buffer pH 6, Hydroxyethylcellulose 

Presentation: transparent solution 
Morphine sulfate injection USP 0.5 mg/mL to be used for oral administration (Reference 
treatment & rescue medication) 

Active ingredient: morphine sulfate pentahydrate


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
Excipients: water for injection USP, sodium chloride. May contain HCl/or NaoH for pH 
adjustment. 
Morphine matched placebo: Sterile water for injection to be used for oral administration
Sterile water for injection USP is a sterile, nonpyrogenic preparation of water for injection 
which contains no bacteriostatic, antimicrobial agent or added buffer and is supplied only in 20 mL
single-dose containers. 
Phenobarbital oral solution USP 20 mg/5mL (adjunctive therapy) 

Active ingredient: phenobarbital  

Excipients: alcohol, FD&C Red no.40, flavors, glycerin, sucrose, water

Presentation: red-orange clear solution 
6.2 Dosage and Administration 
6.2.1 Selection of doses in the study
Based on the results of the NCT01452789 study [26], a pharmacokinetic/pharmacodynamic 
(PK/PD) model has been created and published [29][38][38]. 
The PK/PD model allowed a number of observations to be made regarding buprenorphine in 
NOWS:

Efficacy of time to stabilization is driven primarily by buprenorphine exposure, implying 
that most of the variability in dose response has a PK basis.

Exposure is driven primarily by changes in clearance, with no clearly identified covariates 
that can predict PK variability.

There were no identifiable changes in respiratory rate associated with buprenorphine 
exposure.
Since in NCT01452789 there was no evidence of decline in respiratory rate in infants treated with 
higher doses of buprenorphine compared to lower doses, a higher initial dose may allow therapeutic 
buprenorphine concentrations to be reached more quickly, ultimately leading to shorter lengths of 
treatment and hospital stay. This hypothesis has been tested by exploring in silico a variety of 
dosing-related factors: initial buprenorphine doses (from 0.1 to 15 µg/kg), up titration rates (25%, 
33% and 50%), maximum buprenorphine doses (up to 25 µg/kg) and weaning rates (10%, 15% and 
25%).
Simulations results showed that the best combinations of dosing factors are the following:

Initial dose: 8 µg/kg

Uptitration rate: 33%

Maximum dose: 25 µg/kg

Weaning rate: 15%
Results of this pharmacometric approach refer to the ethanolic formulation used in NCT01452789. 
To account for the difference in absorption showed by CHF6563, doses derived by the PK/PD 
modelling were increased by a 20% factor. This CHF6563-adjusted regimen has been further 
adapted and simplified to avoid calculation errors, by imposing up-titration steps based on a fixed 5 
µg/kg rise rather than a percentage-based rate. 


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6.2.2 Dosage
All doses of CHF6563, morphine, respective matched placebos and phenobarbital are adjusted 
according to the birth weight which should be rounded to the second decimal place. 
6.2.2.1 Test treatment dosage
Starting dose
The starting dose for CHF6563 is 10 μg/kg (30 μg/kg/day).
Frequency of administration
CHF6563 will be administered every 8 hours (±1 h), together with oral morphine matched placebo. 
Oral morphine matched placebo will be administered also every 4 hours (±1 h), to match the 
morphine administration schedule. 
There is a ± 1hour interval around each nominal time point to account for sleeping and feeding 
schedule. 
If dosing occurs at a time different from the specified nominal time (± 1 hour), the next dose will be 
scheduled to take place 8 hours following the actual dose administration.
Lost doses: if a baby spits or vomits soon after administration, the administration will not be 
repeated to avoid potential overmedication. 
Dose escalation
In the up-titration phase, dose escalation will occur if the sum of 3 consecutive FNAST scores is ≥ 
24 OR a single score is ≥ 12 OR a rescue dose was administered. 

No more than one dose escalation can take place each day unless a rescue dose is required. 

During the up-titration phase, doses will increase by 5 ug/kg steps, i.e. after the initial 10 
ug/kg dose there can be consecutive dose increases to 15, 20, 25 and 30 ug/kg, if signs of 
withdrawal persist. 

The maximum dose (90 ug/kg/day) is therefore reached, if needed, after 4 up-titration steps. 
Stabilization 
The stabilization phase is defined as the period of treatment when no further drug treatment 
escalation is required. A stabilization period of 48 hours (without need for further drug treatment 
escalation) is required before weaning of drug treatment can begin.
Weaning
The initiation of weaning will begin after a 48 hour stabilization period, providing the sum of the 
previous 3 FNAST scores is < 18 and no single score is ≥ 8. 

Doses will be decreased by 15% once per day providing the sum of the previous 3 scores is 
< 18 and no single score is ≥ 8. 

If during a 24 hour period the sum of the previous 3 scores is ≥ 18 or a single score is ≥ 8, 
(even if no dose escalation has been required), weaning will not take place, the current dose 
will continue to be administered. 

If the sum of the previous three scores is ≥ 28 and at the discretion of the treating physician, 
the standing dose may revert to the previous dose or dose interval at which signs were 
controlled.

Once the sum of the previous 3 scores is < 18 and no single score is ≥ 8, weaning can 
resume, and doses will continue to be decreased by 15% once per day.  


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
No more than one dose reduction is permitted in one calendar day.      
Dose cessation
The cessation dose will be around the initial dose, (i.e. between 90-110% of the 10 ug/kg initial 
dose). Once this is reached, the dosing frequency is decreased from q8 to q12 hours for 24 hours, 
followed by a further decrease in dosing frequency from q12 to q24 hours prior to stopping.
Following cessation of dosing, babies will be observed in an inpatient setting for at least 48 hours, 
during which time scoring of NOWS signs will continue.
6.2.2.2 Reference treatment dosage 
Starting dose
The starting dose for morphine is 0.07 mg/kg (0.42 mg/kg/day).
Frequency of administration
Morphine will be administered every 4 hours (±1 h) together with sublingual CHF6563 matched 
placebo. Sublingual CHF6563 matched placebo will be administered every 8 hours (±1 h), to match 
the CHF6563 administration schedule. 
There is a ±1 hour interval around each nominal time point to account for sleeping and feeding 
schedule. If dosing occurs at a time different from the specified nominal time (±1 hour), the next 
dose will be scheduled to take place 4 hours following the actual dose administration.
Lost doses: if a baby spits or vomits soon after administration, the administration will not be 
repeated to avoid potential over medication. 
Dose escalation
In the up-titration phase, dose escalation will occur if the sum of the 3 consecutive FNAST scores is 
≥ 24 OR a single score is ≥ 12 OR a rescue dose was administered. 

No more than one dose escalation can take place each day unless a rescue dose is required. 

During the up-titration phase, after the initial 0.07 mg/kg dose there can be consecutive dose 
increases to 0.09, 0.12, 0.16 and 0.21 mg/kg, if signs of withdrawal persist. 

The maximum dose (1.25 mg/kg/day) is therefore reached, if needed, after 4 up-titration 
steps.
Stabilization 
The stabilization phase is defined as the period of treatment when no further drug treatment 
escalation is required. A stabilization period of 48 hours (without need for further drug treatment 
escalation) is required before weaning of drug treatment can begin.
Weaning
The initiation of weaning will begin after a 48 hour stabilization period, providing the sum of the 
previous 3 scores is < 18 and no single score is ≥ 8. 

Doses will be decreased by 15% once per day providing the sum of the previous 3 scores is 
< 18 and no single score is ≥ 8. 

If during a 24 hour period, the sum of the previous 3 scores is ≥ 18 or a single score is ≥ 8, 
(even if no dose escalation has been required), weaning will not take place, the current dose 
will continue to be administered. 


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
If the sum of the previous three scores is ≥ 28 and at the discretion of the treating physician, 
the standing dose may revert to the previous dose or dose interval at which signs were 
controlled.

Once the sum of the previous 3 scores is < 18 and no single score is ≥ 8, weaning can 
resume, and doses will continue to be decreased by 15% once per day.  

No more than one dose reduction is permitted in one calendar day.      
Dose cessation
The cessation dose will be < 0.025 mg/kg q4 hours. 
Following cessation of dosing, babies will be observed in an inpatient setting for at least 48 hours, 
during which time scoring of NOWS signs will continue.
6.2.2.3 Rescue dose (CHF6563 0,075 mg/mL or morphine 0.5 mg/mL)
If, between scheduled doses, a baby has a single score ≥ 12, a rescue dose of CHF6563 or morphine 
may be administered at the discretion of the treating physician.  

The rescue dose will be the same as the previous dose. 

A rescue dose must be given at least 1 hour after the previous dose and 1 hour before the 
next scheduled dose. 

The rescue dose must not be given once the maximum dose has been reached. 

The administration of a rescue dose in the up-titration period will trigger a dose escalation at 
the next schedule dose. 

The administration of a rescue dose in the weaning period will not trigger a dose escalation. 

If after cessation of therapy a rescue dose is given, the baby must be observed for 48 hours. 
To maintain the blinding, both active drug as well as placebo will be administered at the same time.
Chiesi Farmaceutici S.p.A. will supply the rescue medication. Rescue medication will be packed for 
the trial as the test treatment (CHF6563/its matched placebo) and the reference treatment 
(morphine/its matched placebo).
6.2.2.4 Adjunctive therapy (phenobarbital USP 20 mg/mL )
If in either group, withdrawal as assessed by the FNAST is not controlled at the maximum dose of 
primary therapy (CHF6563 / morphine), phenobarbital will be initiated with an oral loading dose of 
20 mg/kg, followed by a daily oral dose of 5 mg/kg/day. 
Birth weight will be used for the calculation of phenobarbital loading and maintenance dose.

Treatment with adjunctive phenobarbital will continue for at least two days and stabilization 
should be achieved before weaning of the opioid. Weaning will commence with reduction of 
the primary therapy (CHF6563 / morphine) according to the same rules as indicated above 
in the CHF6563 and in the morphine treatment section.

When the primary therapy (CHF6563 / morphine) has been weaned to 50% of the maximal 
dose and the sum of the previous three scores is <18 and no single score is ≥ 8, the 
phenobarbital dose will be reduced to 2.5 mg/kg/day.  

The primary therapy (CHF6563 / morphine) dose will not be weaned on the day 
phenobarbital is weaned. 


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
Phenobarbital will be discontinued 72 hours after the dose reduction to 2.5 mg/kg/day, 
provided the sum of the previous three scores is < 18 and no single score is ≥ 8, and prior to 
the discontinuation of the primary therapy (CHF6563 / morphine). 

The primary therapy (CHF6563 / morphine) will not be weaned on the day when 
phenobarbital is discontinued. 
Lost doses: if a baby spits or vomits soon after administration, the administration will not be 
repeated in order to avoid potential over medication. A replacement dose of study medication may 
be considered at the discretion of the treating physician in consultation with the site Principal 
Investigator.
Chiesi Farmaceutici S.p.A. will supply the adjunctive therapy.
6.2.2.5 Randomized Treatment period:
 Test treatment: CHF6563 arm 
CHF6563 0.075 mg/mL sublingual administration every 8 hours
Morphine matched placebo, oral administration every 4 hours
The maximum CHF6563 dose is 90 μg per kilogram of (birth) body weight per day.
Reference treatment: morphine arm 
Morphine solution 0.5 mg/mL oral administration every 4 hours 
CHF6563 matched placebo, sublingual administration every 8 hours
The maximum morphine dose is 1.25 mg per kilogram of (birth) body weight per day.
6.2.3 Administration
The study medication will be prepared for each individual baby by the pharmacist within the 
hospital’s pharmacy department. The procedure for the preparation of the syringe is reported in the 
leaflet of both CHF6563 and its matched placebo and morphine and its matched placebo. CHF6563 
or CHF6563 matched placebo will be administered sublingually and will be differentiated from oral 
study medication morphine / morphine placebo using oral syringes with marks differently colored. 
Each baby will be administered with: 

CHF6563 or CHF6563 matched placebo 
o
A number of clear transparent 1 mL 
oral sterile syringes of 1 mL with color 
1 marks, calculated on the basis of birth weight and FNAST score containing 
CHF6563 or CHF6563 matched placebo, prepared by the pharmacist at the 
hospital’s pharmacy.
Each syringe will be filled with CHF6563 or CHF6563 matched placebo up to the 1 mL 
marking.
or

Morphine or morphine matched placebo 


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o
A number of clear transparent 1 mL 
 oral sterile syringe with color 2 marks, 
calculated on the basis of birth weight and FNAST score containing morphine 
solution at the concentration of 0.5 mg/mL or water INJ (morphine matched 
placebo), prepared by the pharmacist at the hospital’s pharmacy.
Each syringe will be filled with morphine solution (concentration of 0.5 mg/mL) or 
morphine matched placebo (water INJ) up to the 1 mL marking.
Following preparation, the filled syringes will be dispensed to the neonatal service and stored as per 
hospital standard operational procedures for opioid medication. For investigational drug specific 
storage information and in-use storage condition please refer to the leaflet. Immediately prior to 
administration and according to the hospital standard operational procedures for opioid 
administration, members of the clinical staff will together prepare the correct dose of CHF6563 or 
CHF6563 matched placebo (color 1 mark syringes) AND morphine or morphine matched placebo 
(color 2 mark syringes) by adjusting the volume within the syringes. The correct dose is based on 
birth weight (which should be rounded to the second decimal place), FNAST and treatment regime. 
Information on how to calculate and administer the dose are reported in the leaflet of both CHF6563 
and its matched placebo and morphine and its matched placebo.
Administration of the sublingual medication (CHF6563 or CHF6563 matched placebo) should 
always precede the oral medication (morphine or morphine matched placebo).
In accordance with the hospital standard operational procedures for opioid administration the 
clinical staff will administer the study drugs to the neonate following the correct administration 
practices for an oral and a sublingual drug.
In order to ensure the blinding between the two study drugs, one of which is administered by the 
sublingual route and the other orally, the trial has double dummy design, so a baby randomized to 
receive CHF6563 will also receive morphine matched placebo (water for injection) and a baby 
randomized to receive morphine will also receive CHF6563 placebo.
The two-different colored marks of the oral syringes will reduce the chances of the pharmacist 
preparing the incorrect study medication / placebo syringes, avoid a mismatch between the two 
solutions available: CHF6563/matched placebo and morphine/matched placebo when the volume of 
drug in the prefilled syringe is adjusted to the correct dose, and will allow the clinical staff to 
distinguish and administer the correct drug via the oral or sublingually route.
The frequency of administration is 8 hours for test treatment and of 4 hours for reference treatment, 
therefore the matched placebo of morphine will be administered every 4 hours in the CHF6563 arm 
and the matched placebo of CHF6563 will be administered every 8 hours in the comparator arm.
To allow for alteration in sleeping and feeding schedules, each dose of drug can be administered ± 1 
hour around nominal time point for that dose. 
Administration of CHF6563 or CHF6563 placebo will be as follows: the nurse will hold the 
neonate’s head at approximately 45 degrees, gently move the tongue to the side and administer the 
drug under the tongue. The use of a pacifier to reduce swallowing of drug is permitted. If the 
volume of the drug is > 0.5 mL, the drug will be administered in two (or more) aliquots of no more 
than 0.5 mL, separated by 2 minutes.


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If in either group, withdrawal as assessed by the FNAST is not controlled at the maximum dose of 
primary therapy (CHF6563 / morphine), phenobarbital will be initiated with a loading dose of 20 
mg/kg, followed by a daily oral dose of 5 mg/kg/day. Birth weight will be used for the calculation 
of phenobarbital loading and maintenance dose (see section 6.2.2.4). 
6.3 Packaging 
All investigational medicinal product will be prepared according to the Good Manufacturing 
Practices (GMP) as required by the current Good Clinical Practices (GCP). Chiesi Farmaceutici 
S.p.A. will supply the study drug for the treatment period.
After randomization, at starting dose, at each step of up-titration and of weaning and in case the 
rescue dose is needed, for each baby, the pharmacist will be provided with the kits according to the 
randomization arm. The pharmacist will prepare the study medication in the pharmacy prior to the 
administration. The administration will be performed by the clinical staff at the bed side. 
Dispensing and administration will be done according to the package instruction leaflets and 
hospital standard operational procedures for opioid administration. 
A package leaflet will be included in each kit with study medications in local language.
If the syringe drops on the floor during the filling procedure a new kit shall be used. In case the vial 
content has not been contaminated, it can still be used, the user needs to take a new syringe from the 
back up syringes kit provided for the study.
6.3.1 CHF6563 or CHF6563 matched placebo kit:
One labelled vial containing 2 mL of CHF6563 or matched placebo co-packed with one labelled 
pouch containing 
- Oral syringe 1 mL, transparent, with color 1 marks, in a 
labelled holder.
Primary packaging: labelled vial containing 2 mL of CHF6563 or matched placebo plus one 
labelled pouch containing 
- Oral syringe 1 mL transparent with color 1 
marks.
Secondary packaging: labelled box containing one vial of 2 mL of CHF6563 or matched placebo 
plus one 
- Oral syringe 1 mL transparent with color 1 marks plus the 
instruction for use.
6.3.2  Morphine kit
A labelled box containing one labelled commercial vial of 10 mL of morphine sulfate injection 
solution 0.5 mg/mL. 
Primary packaging: one labelled vial of 10 mL.
Secondary packaging: one labelled box containing a 10 mL vial of morphine sulphate injection 
0.5 mg/mL plus the instruction for use.
6.3.3 Morphine matched placebo (water for injection) kit
A labelled box containing one labelled commercial vial of 20 mL of water for injection. 


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Primary packaging: one labelled vial of 20 mL.
Secondary packaging: one labelled box containing a 20 mL vial of water for injection plus the 
instruction for use 
6.3.4 Syringes kit
Two separate labelled boxes containing respectively a set of 
- Oral syringe 1 
mL transparent, with color 1 marks for CHF6563/matched placebo administration and a set of 
- Oral syringe 1 mL transparent with color 2 marks for morphine/Water For 
Injection USP administration.
Primary packaging: one labelled pouch containing each one 
- Oral syringe 1 
mL transparent syringe
Secondary packaging: one labelled box containing labelled 
- Oral syringes 1 
mL transparent syringes.
The syringe kit containing the set of 
- Oral syringes 1 mL transparent, with 
color 1 marks is a back up kit, in case the syringe drops on the floor.
The syringe kit containing the set of 
- Oral syringe 1 mL transparent, with 
color 2 marks is NOT a backup kit, but it must be used for every preparation of 
morphine/matched placebo.
6.3.5 Adjunctive therapy kit 
A 473 mL labelled commercial bottle of phenobarbital oral solution 20 mg/mL.
      Primary packaging: labelled plastic bottle of 473 mL. Instruction for use secured to the bottle 
with a rubber band. 
      Secondary packaging: not present. 
6.4 Labeling 
All labeling will be in local language and according to local law and regulatory requirements and 
will be compliant with 21 CFR 312.6 “Labelling of an Investigational New Drug”, for US trials. 
6.5 Treatment allocation
Babies will be assigned in a 2:1 ratio to either CHF6563 or morphine. Randomization will be 
stratified according to the following variables, using a dynamic randomization algorithm (i.e. 
minimization) to balance treatment arms with respect to stratification factor levels, while 
maintaining an overall treatment balance: 

Neonate’s feeding status at time of randomization (formula/ any maternal breast- milk 
[including combination of breast milk and formula]) 

Maternal primary opioid use (buprenorphine/methadone/other)

Maternal concurrent use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]); please refer to APPENDIX 3 – List of PSYCHOTROPIC DRUGS for the list of 
drugs to be checked. 


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The minimization method is planned in order to maximize the balance of each stratification variable 
as well as the overall treatment balance across arms in a 2:1 ratio, considering the planned sample 
size [37]. This method achieves a greater level of balance across multiple stratification variables 
compared to a traditional stratified randomization
Babies will be centrally assigned to one of the two treatment arms on randomization through an IRT 
system (Interactive Response Technology, combination of voice and web response system and also 
referred as IVRS/IWRS).
Following 2 consecutive FNAST with a sum ≥ 12, if all eligibility criteria except for Inclusion 
Criterion #5 are met, then babies will be pre-randomized in the IRT system to ensure treatment is 
available should Inclusion Criterion #5 be met (i.e. the sum of 3 consecutive FNAST scores ≥ 24 or 
a single score ≥12).
The IRT will allocate the patient to a certain treatment group using biased coin application of the 
Pocock and Simon minimization algorithm [37], and assign the study medication kit number 
corresponding to the babies’ treatment group. IRT specifications will be fully described in a specific 
document. The IRT will also generate a confirmation after every IRT transaction is performed.
The patient will be identified by a unique number of six digits: the investigational site number will 
be the first three digits and the following three digits will be the progressive numbering of the 
patient within each site (e.g. 101001, 101002 etc.).
6.6 Treatment Code
The kit list will be provided to the labeling facility. Neither the kit list, nor any randomization list   
will be available to subjects, investigators, monitors or employees of the center involved in the 
management of the trial before unblinding of the data, unless in case of emergency. Pharmacists 
will be unblinded.
The Sponsor’s clinical team will also be blinded during the study as they will not have direct access 
to the randomization list. Of note, it will be possible following the last scheduled dose of 
CHF6563/placebo to ascertain the treatment for each subject. However, the randomization list and 
explicit treatment codes will not be available to the blinded team until after the database is locked.  
In case of emergency, unblinding of the treatment code will be done through IRT. The treatment 
group will be disclosed, and confirmation will follow (by fax and/or notification email). The IRT 
will be designed to send a confirmation (by fax and/or notification email) to the site for every 
transaction performed by the Investigators. The Investigator will be provided with credentials for 
randomization purposes and separate credentials to unblind the study treatment in case of 
emergency situation, where he/she considers essential to know what treatment the patient was 
taking. The IRT will promptly notify the Sponsor and the Clinical Monitor whenever a treatment 
code is unblinded. 
Users from Chiesi Global Pharmacovigilance will have their own credentials to unblind babies in 
case of SUSARs to be reported to the competent Regulatory Authorities and Ethic Committees/IRB. 
6.7 Treatment compliance
Not applicable.
6.8 Drug Storage 
The Pharmacist/Investigator will be responsible for the safe storage of all medications assigned to 
this study, in a secure place with restricted access, and maintained within the appropriate ranges of 


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temperature. For investigational drug specific storage information and in-use storage condition 
please refer to the leaflet. In addition, the hospital’s standard operational procedures for the storage, 
handling and administration of opioids will be followed.
CHF6563 and its matched placebo vials must be stored between 2°- 8° C (36° to 46°F) 
protected from light. Once withdrawn from the vial, the solution must be stored in the syringe 
below 25°C (77°F) and protected from the light. 
Morphine sulphate IV solution 0.5 mg/mL vials must be stored at controlled room 
temperature, protected from light at 20° to 25°C (68° to 77°F). Once withdrawn from the vial, 
the solution must be stored in the syringe below 25°C (77°F) and protected from the light.
Water for injection 20 mL must be stored at 20° to 25°C (68° to 77°F). Once withdrawn from 
the vial, the solution must be stored in the syringe below 25°C (77°F).
Phenobarbital oral solution must be stored at 20° to 25°C (68° to 77°F) protected from light.
6.9 Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the management of 
all the study medications to be used for the study. Study medications should be stored in a locked, 
secure storage facility with access limited to those individuals authorized to dispense the study 
medications and according to the hospital’s standard operational procedures for the storage, 
handling of opioids.
An inventory will be maintained by the Investigator or pharmacist (or other designated individual), 
to include a signed account of all the study medication(s) received, dispensed and returned to the 
pharmacist by each Investigator/nurse during the trial. 
At the conclusion or termination of the study, the Investigator or the pharmacist shall conduct and 
document a final drug supply inventory. An explanation will be given for any discrepancies.
All the study medications supplied, used or unused, will be returned to Chiesi or to the designated 
CRO under Sponsor’s responsibility or destroyed directly at the site (hospital pharmacist). In this 
case, a destruction certificate must be completed by the investigational center and filed both at site 
and at Sponsor. Return and destruction will not occur until authorized by Chiesi.
6.10 Provision of additional care
Not applicable
7.
STUDY PLAN
7.1 Study Schedule
The mothers of potential infants will be identified through the outpatient maternity, treatment 
clinics or upon admission to hospital. All babies for whom consent has been obtained will have 
NOWS graded according to FNAST. Pharmacological treatment will start up to 7 days after 
delivery in neonates who have persisting signs of NOWS despite the implementation of appropriate 
non-pharmacologic care. If all the inclusion/exclusion criteria are met the baby will be eligible for 
the randomization.  
Following 2 consecutive FNAST with a sum ≥ 12, if all eligibility criteria except for Inclusion 
Criterion #5 are met, then neonates will be pre-randomized in the IRT system to ensure treatment is 
available should Inclusion Criterion #5 be met (i.e. the sum of 3 consecutive FNAST scores ≥ 24 or 
a single score ≥12). If eligibility is confirmed, the randomization will be confirmed in the IRT 
system and the baby will be treated.  


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The study will be conducted as follows for each baby:
A pre-screening visit with the mother to explain the study and obtain the informed consent to 
participate in the study, and to confirm the use of opioid in the last month of pregnancy. This 
visit will be carried out during the last month of pregnancy or after delivery. The maternal 
screening questionnaire will also be completed. 
A screening visit on the neonates who show sign of NOWS. The visit will be carried out up to 7 
days after delivery.
A randomization visit to verify the eligibility of the neonate for inclusion in the study and to 
assign the neonates to a treatment and provide the first treatment administration.
Treatment period: from randomization, up to 48 hours after the last dose. The treatment period 
can last up to 10 weeks (70 days) from the first treatment dose.
Regular follow up will continue both before and after discharge from hospital to identify those 
babies who suffer recurrence of significant withdrawal. The duration of follow up will be for 6 
weeks after the final opioid treatment dose. Evidence of recurrence of significant withdrawal will 
be monitored for all babies who remain within the hospital. For babies discharged following 
the required period of in-patient observation (48 hours post last opioid treatment dose), 
daily telephone contact with the primary caregiver (parental/legal guardian or foster 
mother) will continue for the first 7 days and will record the infant’s wellbeing and identify 
any escalation of withdrawal signs. Thereafter weekly telephone contact will continue for the 
duration of the follow up period. 
A 18-months (± 1 months) follow-up visit for a further long-term assessment and confirmation of 
the safety of the test treatment. 
The 
study 
plan 
and 
scheduled 
tests 
are 
summarized 
in 
the 
following 
table:


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Treatment Period
End of 
treatment 
Follow Up
Pre-
screening
(Mother)
Screening
(neonates)
Randomization
up to stabilization
Weaning up to end
 of treatment
48h±4 h  
after last 
dose
Up to 6 
weeks
18 months
Informed consent forms1,2
2
Questionnaire 

Maternal urine toxicology 
data (optional)

Baby toxicology data 
(optional)

Inclusion and exclusion 
criteria 

3
Gestational Age, sex and 
race/ ethnicity

Weight





Length



Head circumference



Randomization

Vital signs4




NOWS scores5




Escalation of withdrawal 
signs

hematology and blood 
chemistry (data recorded)

Liver Function6
(x2)

PK CHF65637


Medical history

Concomitant 
medications/procedures 





Drug administration 


Cognitive and behavioral 
development


Feeding status




Adverse Events assessment8





General well-being

Health status

Environmental / social factors

Assessments of the mother / 
primary carer using 
standardized questionnaires

1.Maternal urine toxicology data collection requires the mother to sign a separated Informed Consent form.
2.Informed Consent Form for the baby: this is required prior to screening and can be obtained at several time points i.e. during the last 
month of pregnancy, following birth, or when the baby shows signs of NOWS.
3.Inclusion and exclusion criteria will be checked at randomization.
4.Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), Body Temperature (BT). From randomization 
up to the stabilization they will be collected at the same time of the NOWS score, except for BT which will be collected at least once 
per day. Blood pressure (DBP; MBP; SBP) will be recorded if collected according to site clinical practice. From weaning until the 
end of the treatment they will be collected once a day at the time of NOWS score. Cardiorespiratory monitoring using continuous 3-
lead ECG and pulse oximetry should be performed during treatment (starting before the first dose of study drug and continuing up to 
the initial stage of the weaning phase).
5.NOWS scores: FNAST will be used to assess withdrawal signs every 4 hours (±1 hour). After FNAST assessment has started, it should 
continue for at least 24 hours, even in case the baby is not randomized.
6.Liver function: Liver-function testing (AST, ALT) will be performed on 3 occasions: after the first dose, at stabilization and 48 (±4 h) 
hours after the last treatment dose
7.Blood sampling for PK will occur on the day of randomization and then every 5±1 days until the last dose. The first blood sampling on 
randomization day might be taken after the first dose; in each subsequent other occasion sampling should occur after one of the 
morning doses and be timed to fit in with the following sampling windows; one blood sample should be taken in the 0-2h post-dose 
time window, one in the 2-4h post-dose time window and one in the 4-8h post-dose time window. 
8.Non-serious AEs will not be collected for screening failure. 


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7.1.1 Pre-screening visit
A pre-screening visit will be carried out in order to identify mothers with history of opioid use in the last 
month of pregnancy, obtain information on additional drugs or substance use during the pregnancy and 
exclude a family history of prolonged QTc syndrome (this should include questions on unexplained sudden 
death in otherwise healthy individuals). Use of opioid could be licit or illicit. Mothers who have been using 
other substances and/or are on prescribed medications can take part in this study.
The mother will be asked to undertake the following:

Prior to birth (if possible) or following birth, or when the baby shows signs of NOWS: 
a) written informed consent for the completion of the maternal screening questionnaire
b) written informed consent for access to the maternal electronic medical record to collect 
demographic information
c) written informed consent for access to maternal urine toxicology data collected during 
pregnancy and labor (optional within the consent) 

Written informed consent for the baby to enter the treatment phase can be obtained at this visit. 
This should be signed by the parent /legal representative, following full explanation of the study by 
the investigator. The investigator or his/her designee should provide them ample time and 
opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. 
Once their written informed consent has been obtained (either prior to or after birth), inclusion and 
exclusion criteria will be evaluated, and neonate’s eligibility assessed.
The investigator or his/her designee will complete the maternal screening questionnaire in discussion with 
the mother (refer to APPENDIX 2 – Maternal Screening Questionnaire)
7.1.2 Screening Visit
After delivery, a screening visit will be carried out up to 7 days after birth to identify neonates with signs of 
NOWS who may be eligible for the study. 
The following information will be collected:
NOWS score: FNAST will be used to assess withdrawal signs every 4 hours (±1 hour)
Gestational age, sex
Race/ ethnicity
Birth weight, head circumference, birth length (or length captured during Screening) 
Baby toxicology data, if available (optional)
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), body 
temperature (BT). Blood pressure (DBP; MBP; SBP) will be recorded if collected according to site 
clinical practice  
Hematology and blood chemistry data: the results of investigations performed prior to randomization 
will be recorded; these can include complete blood count (CBC), urea, creatinine and electrolytes 
(sodium, potassium, magnesium calcium, phosphorus), glucose, C-reactive protein, if collected before 
randomization according to clinical practice 
Medical history 


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AEs and concomitant medication/procedures to be checked and recorded. Non-serious AEs will not be 
collected for screening failure.
After FNAST assessment has started, it should continue for at least 24 hours, even in case the baby is not 
randomized.
7.1.3 From randomization to stabilization 
Once the baby’s eligibility to take part in the study is confirmed, the Investigator will randomize the baby to 
the assigned treatment by using the IRT system. Pharmacological treatment will start up to 7 days after 
delivery in neonates who show signs of NOWS and have failed to respond to non-pharmacologic care. 
All neonates enrolled in the study should receive routine cardiorespiratory monitoring using continuous 3-lead 
ECG and pulse oximetry This should commence before the first dose of study drug (CHF6563 or morphine) is 
administered and continue throughout the dose-escalation phase, stabilization phase and the initial stage of the 
weaning phase. During the later stages of weaning, the continuous ECG monitoring may be discontinued at the 
investigator’s discretion, to allow nonpharmacological care strategies to be maximized. 
If an abnormal rhythm is detected by the continuous 3-lead ECG, the neonate should be evaluated with a 12-lead 
ECG and dosing interrupted. If a pediatric cardiologist confirms a QTc interval of ≥500 ms on a 12-lead ECG, 
the study treatment should be discontinued. 
The following procedures will take place only at randomization:
Inclusion/ exclusion criteria
Randomization: neonates with a GA ≥36 weeks and the sum of 3 consecutive FNAST assessment 
scores ≥ 24 or a single score ≥12 will be assigned in a 2:1 ratio to either CHF6563 or morphine. 
Treatment doses will be calculated according to birth weight which should be rounded to the second 
decimal place.
The following procedures will take place from randomization to stabilization:
NOWS score: FNAST will be used to assess withdrawal signs. Signs of withdrawal will be assessed 
and recorded every 4 hours (±1 hour) 
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), and body 
temperature (BT) will be collected at the same time of the NOWS score, except for BT which will be 
collected at least once per day. Blood pressure (DBP; MBP; SBP) will be recorded if collected 
according to site clinical practice. Routine cardiorespiratory monitoring will be performed using 
continuous 3-lead ECG and pulse oximetry.
Body weight – all body weights recorded as part of standard of care will be collected (minimum 
requirement - once a week)
Treatment administration: treatment doses will be calculated according to birth weight (which should 
be rounded to the second decimal place) and the NOWS score which will be assessed and recorded 
every 4 hours.
Feeding status: breastfeeding, formula feeding, mixed feeding, and the proportion of maternal 
breastmilk intake during this period of time i.e. randomization to stabilization will be recorded.  
Liver function test (AST, ALT): will be performed after first dose and following treatment 
stabilization prior to the first weaning dose and recorded.
Blood sampling for CHF6563 pharmacokinetics will be performed.
Further concomitant medications/procedures and adverse events as well as changes in those already 
reported will be recorded. 


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7.1.4 From weaning to the end of treatment 
The following procedures will take place:
NOWS score: signs of withdrawal will be assessed and recorded every 4 hours (±1 hour) using 
FNAST
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), body 
temperature (BT) will be collected at the same time of the NOWS score but only once a day. Blood 
pressure (DBP; MBP; SBP) will be recorded if collected according to site clinical practice. 
Cardiorespiratory monitoring will be continued during the initial stage of weaning and can be 
discontinued at the investigator’s discretion during later stage.    
Body weight – all body weights recorded as part of standard of care with be collected (minimum 
requirement - once a week).
Treatment administration: treatment doses will be calculated according to birth weight (which should 
be rounded to the second decimal place) and the NOWS score which will be assessed and recorded 
every 4 hours.
Feeding status: breastfeeding, formula feeding, mixed feeding, and the proportion of maternal 
breastmilk intake during this period of time i.e. weaning to end of treatment will be recorded.
Blood sampling for CHF6563 pharmacokinetics will be performed.
Further concomitant medications/procedures and adverse events as well as changes in those already 
reported will be recorded.
7.1.5 End of treatment period Visit (48 hours ±4 h after the last dose) 
The following procedures will take place:
NOWS score
Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), body 
temperature (BT), will be collected; blood pressure (DBP; MBP; SBP) will be recorded if collected 
according to site clinical practice 
Head circumference, and body weight and length 
General physical and neurological examination 
Liver function test (AST, ALT) will be performed and recorded 
Feeding status: breastfeeding, formula feeding, mixed feeding, and the proportion of maternal 
breastmilk intake during this period of time i.e. end of treatment to discharge will be recorded. 
Further concomitant medications and adverse events as well as changes in those already reported.
7.1.6 Functional unblinding
The weaning period requires a lower number of weaning steps for CHF6563 compared to morphine.  In 
order to avoid maintaining babies randomized to CHF6563 in the hospital following completion of study 
drug, only to receive placebo for several days (about 5, depending on the severity of the withdrawal), the 
unblinded pharmacist will advise the clinical staff that the baby has completed active study treatment 
following the last active dose of CHF6563 and babies will be eligible for discharge (at least insofar as the 
clinical trial is concerned) 48 hours after the last active dose. Since the cessation dose will not occur at the 
same weaning step for the 2 treatment arms, it will be possible to ascertain the treatment for each baby after 
the weaning step which corresponds to the cessation dose of CHF6563. This is considered a “functional 


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unblinding” since, after this point, it will be possible for members of the blinded team to ascertain the 
treatment arm. 
Prior to the last scheduled dose of CHF6563, all members of the blinded study team will remain completely 
blinded.  Following the last scheduled dose of CHF6563/placebo, members of the blinded study team will 
not have access to the explicit treatment codes, but it will be possible to ascertain the treatment arm.  
Similarly, data review will occur without access to explicit treatment codes, since the explicit treatment 
codes will be maintained in a confidential manner. The randomization list and explicit treatment codes will 
be disclosed to blinded study team members only after the database is locked.  
7.1.7 Follow-up
Regular follow up will continue both before and after discharge from the hospital to identify those babies 
who suffer recurrence of significant withdrawal. 
During the first 7 days after the initial 48 hours observation period following the last dose:
a) If the baby has already been discharged from the hospital, daily telephone contact with the 
primary caregiver (parental/legal guardian or foster mother). The following information will 
be recorded:

General well-being 

Escalation of withdrawal signs 

Feeding status: breastfeeding, formula feeding or mixed feeding 

Further concomitant medications and adverse events as well as changes in those 
already reported.
b) If the baby stays in the hospital, the following information will be recorded:

General well-being 

Escalation of withdrawal signs

Feeding status: breastfeeding, formula feeding, mixed feeding, and the proportion of 
maternal breastmilk intake during this period of time i.e. first 7 days. 

Further concomitant medications and adverse events as well as changes in those 
already reported.
From 10 days and until 6 weeks after the last treatment dose, weekly telephone contact with the 
primary care will continue. The following information will be recorded:

General wellbeing 

Escalation of withdrawal signs

Feeding status: breastfeeding, formula feeding or mixed feeding 

Further concomitant medications and adverse events as well as changes in those 
already reported.
7.1.8 Follow-up: 18 months (±1 months)
A further clinical assessment at 18 months (±1 months) will be performed by a multidisciplinary team at 
the participating study centers to assess the general wellbeing, growth and long-term neurodevelopmental 
assessment and growth parameters.  
The clinical assessment will collect information on the following domains:


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
Health status (general medical history and physical examination, including growth parameters, 
medical illness, developmental issues, medications and hospital admission)

Environmental / social factors (foster care, domestic violence exposure, substance use / 
treatment)

Cognitive and behavioral development (Bayley Scales of Infant Development – all 5 domains)

Assessments of the mother / primary carer using standardized questionnaires (e.g. Brief 
Symptom Inventory (BSI), Quick Inventory of Depressive Symptomatology (QIDS), Parenting 
Stress Index (PSI), Child Behavior Checklist (CBCL))
This 18-month clinical assessment will be analyzed and evaluated separately from the initial part of the 
study and be object of an addendum to the initial core clinical study report. Individual assessments will be 
described in more detail in an additional document. 
7.2 Investigations
7.2.1 NOWS score
FNAST (refer to APPENDIX 4 – Finnegan Neonatal Abstinence Scoring Tool (FNAST)) will be used to 
assess the severity of NOWS. 
Details on FNAST, training package and site validation will be provided in a separate report document. 
7.2.2 Feeding Status 
Feeding status will be collected daily from the electronic patient record. (Formula /breast milk or a mixed 
feeding and proportion of maternal breast milk intake).
7.2.3 Toxicological collection 
It will only be performed in those hospitals where this is common clinical practice, according to site 
procedures. 
7.2.4 Vital signs
At screening and from the randomization until the end of the treatment, heart rate (HR), respiratory rate 
(RR), peripheral oxygen saturation (SpO2), body Temperature (BT) will be collected. Blood pressure (DBP; 
MBP; SBP) will be recorded if collected according site clinical practice.
From randomization up to the stabilization they will be collected at the same time of the NOWS score, 
except for BT which will be collected at least once per day. 
From weaning until the end of the treatment they will be collected once a day at the time of NOWS score. 
Cardiorespiratory monitoring using continuous 3-lead ECG and pulse oximetry should be performed during 
treatment (starting before the first dose of study drug and continuing up to the initial stage of the weaning 
phase).
7.2.5 Hematology/blood chemistry and liver function
The results of investigations - if performed according to site clinical practice - prior to randomization will be 
recorded; these can include full blood count (FBC), urea, creatinine and electrolytes (sodium, potassium, 
magnesium, calcium, phosphorus), glucose, C-reactive protein. 
Liver-function test analysis (aspartate aminotransferase [AST], alanine aminotransferase [ALT]),) will be 
performed on 3 occasions: after the first dose, at stabilization and 48 hours (±4 h) after the last treatment 
dose. 


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7.2.6 Pharmacokinetics 
Blood sampling for PK will occur the day of randomization and then every 5±1 day until the last dose. The 
first blood sampling should be taken after the first dose. Subsequent sampling should occur after the 
morning dose and be timed to fit in with the following sampling windows: one blood sample should be taken 
in the 0-2 h post-dose time window, one in the 2-4 h post-dose time window and one in the 4-8 h post-dose 
time window. 
If possible, in order to minimize discomfort for the babies, PK samples should be collected simultaneously 
to routine blood sample collection. 
Twenty μl aliquot of blood will be spotted onto DMPK-A cards and allowed to dry at room temperature on 
an open non-absorbent surface for at least two hours (at least three spots per sample). Cards will be then 
stored at room temperature in a sealed plastic bag containing desiccant until shipment to the central 
Laboratory for determination of CHF6563.
Around 300-360 μl will be collected every 5±1 day until end of last dose.
 is allocated as reference laboratory in charge for the study bioanalysis. 
CHF6563 blood concentrations will be determined using validated HPLC-MS/MS methods.
The laboratory analysis will be carried out following Good Laboratory Practice (GLP) regulations of the 
OECD. The analytical procedure will be described in a separate analytical study plan.
7.2.7 Neurological and behavioral assessment
Neurological and behavioral assessment will be performed at the end of treatment period and at 18 months. 
At the end of treatment period (48h ±4 h after last dose), general physical and neurological examination 
will be performed.
At 18 months, cognitive and behavioral development will be assessed using the Bayley Scales of Infant 
Development– all 5 domains. Moreover, standardized questionnaires will be administered to the 
mother/primary carer (e.g. Brief Symptom Inventory (BSI), Child Behavior Checklist (CBCL)).
8.
EFFICACY ASSESSMENTS
8.1 Primary Efficacy endpoint
Duration of treatment defined as the number of hours from first dose of study drug administration until the 
last dose of study drug.
8.2 Secondary Efficacy endpoints: 

Time to first weaning, defined as the number of hours from first dose of study drug administration 
until the first dose reduction

Requirement for adjunctive drug therapy (phenobarbital) for signs of NOWS

Total hours of treatment with adjunctive therapy 

Requirement for rescue doses (CHF6563 or morphine) 

Number of rescue doses administered per neonate

Percentage of total amount of active study drug which is from rescue doses

Length of opioid related hospital stay, defined as number of days from day of birth until 48 hours 
after the final dose of drug treatment for NOWS

Relapse of NOWS, defined as experiencing recurrence of significant signs of withdrawal 

Incidence of readmissions, defined as readmission to hospital for NOWS relapse


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9.
SAFETY ASSESSMENTS
During administration of sublingual CHF6563 or oral morphine:

Number and percentage of babies with peri-dosing adverse events (AEs) (i.e., mouth irritation or 
inflammation, apnoea, desaturation, brady/tachycardia, cough, immediate swallowing of sublingual 
drug, regurgitation, vomiting occurring after administration)
During the study
From the randomization to the end of the treatment the following information will be collected and 
presented using summary statistics:

Adverse events and adverse drug reactions (ADRs).

Liver enzymes analysis-function testing (AST, ALT,) will be performed on 3 occasions: after the 
first dose, at stabilization and 48 hours (±4 h) after the last treatment dose.

Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), body 
temperature (BT) will be monitored, and data collected during the escalation and stabilization 
phases.

Body Weight and head circumference 

Hematology and blood chemistry: full blood count (FBC), urea, creatinine and electrolytes (sodium, 
potassium, magnesium calcium, phosphorus), glucose, C-reactive protein if collected before 
randomization according to site clinical practice.

Blood pressure (SBP, MBP, DBP) will be monitored according to individual site clinical practice
End of the treatment period
After 48 hours (±4 h) from the last dose the following will be recorded and presented using summary 
statistics:

Vital signs: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2), body 
temperature (BT). Blood pressure (SBP. MBP. DBP) if collected according to site clinical practice

Neurological and behavioral assessment

Body weight, length and head circumference 

All the Adverse Events, and adverse drug reactions, and concomitant medications as well as changes 
in those already reported.
End of 6 week Follow up 

Signs of / escalation of withdrawal 

All the Adverse Events, and adverse drug reactions, and concomitant medications as well as changes 
in those already reported.
Follow up to 18 months

Health status (general medical history and physical examination, including growth parameters, 
medical illness, developmental issues, medications and hospital admission)

Environmental / social factors (foster care, domestic violence exposure, substance use / treatment)

Cognitive and behavioral development (Bayley Scales of Infant Development - all 5 domains)

Assessments of the mother / primary carer using standardized questionnaires (e.g. Brief Symptom 
Inventory (BSI), Quick Inventory of Depressive Symptomatology (QIDS), Parenting Stress Index 
(PSI), Child Behavior Checklist (CBCL))


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10.
ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment”. 
An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
An Adverse Drug Reaction is an “untoward and unintended response to an investigational medicinal 
product related to any dose administered”.
All adverse events judged by either the reporting Investigator or the Sponsor as having a reasonable causal 
relationship to a medicinal product qualify as adverse reactions. The expression “reasonable causal 
relationship” means to convey in general that there are facts (evidence) or arguments meant to suggest a 
causal relationship.
The definition covers also medication errors and uses outside what is foreseen in the protocol, including 
misuse and abuse of the product.
A Serious Adverse Event (SAE)/Serious Adverse Drug Reaction is any untoward medical occurrence or 
effect that at any dose falls in one or more of the following categories:
-
Results in death
Death is not an adverse event but an outcome. It is the cause of death that should be regarded as the adverse 
event. The only exception to this rule is “sudden death” where no cause has been established; in this latter 
instance, “sudden death” should be regarded as the adverse event and “fatal” as its reason for being serious.
-
Is life-threatening
Life-threatening refers to an event in which the subject was at risk of death at the time of the event (e.g., 
aplastic anaemia, acute renal failure, and anaphylaxis). The term does not refer to an event which 
hypothetically might have caused death if it were more severe.
-
Requires hospitalisation or prolongation of existing hospitalisation
Hospitalization refers to a situation whereby an AE is associated with unplanned formal overnight admission 
into hospital, usually for purpose of investigating and/or treating the AE. Hospitalization for the treatment of 
a medical condition that occurs on an “elective” or “scheduled” basis or for a pre-existing condition that did 
not worsen during the study should not necessarily be regarded as a AE. Complications that occur during the 
hospitalisation are AEs. If a complication prolongs hospitalisation, the event is an SAE. Emergency room 
visits that do not result in a formal admission into hospital should be evaluated for one of the other 
seriousness criteria (e.g., life-threatening; persistent or significant disability or incapacity; medically 
significant).
-
Results in persistent or significant disability or incapacity.
The term significant disability should be viewed as any situation whereby an AE has a clinically important 
effect on the subject’s physical or psychological well-being to the extent that the subject is unable to 
function normally.
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Is a congenital anomaly or birth defect
-
Is a medically significant adverse event
This criterion allows for any situations in which important adverse events/reactions that are not immediately 
life-threatening or do not result in death or hospitalisation may jeopardise the subject’s health or may require 
intervention to prevent one of the above outcomes.


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Examples of such events are: intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug 
dependency or drug abuse.
Medical and scientific judgment should be exercised in deciding whether an event is serious because 
medically significant.
Any suspected transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction.
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event or adverse drug 
reaction that does not meet the criteria listed above for a serious adverse event/serious adverse drug reaction.
10.2 Expectedness
An expected adverse reaction is an adverse reaction, the nature or severity of which is consistent with the 
applicable reference safety information (Investigator’s Brochure for CHF6563 and USPI for Morphine), 
otherwise it is considered unexpected. 
Reports which add significant information on specificity or severity of a known, already documented serious 
adverse drug reaction constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator’s Brochure would be considered as “unexpected”. Examples of such events are: 
(a) acute renal failure as a labelled ADR with a subsequent new report of interstitial nephritis and (b) 
hepatitis with a first report of fulminant hepatitis.
In the event an exacerbation is interpreted as due to lack of efficacy, it should not be classified as drug 
related.
10.3 Intensity of Adverse Event
The investigator is asked to assess the intensity of all the adverse events and to report them in the eCRF.
The intensity (severity) of a specific event is defined as mild, moderate, or severe; the event itself, however, 
may be of relatively minor medical significance. This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a threat to a participant's 
functioning.  Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.
Each Adverse Event must be rated on a 3-point scale of increasing intensity:
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only; no change in 
baseline age-appropriate behavior (e.g. oral feeding behavior, voluntary movements and activity). The 
event does not lead to either modification of test treatment dosage or establishment of a correcting 
treatment.
Moderate: resulting in minor changes of baseline age appropriate behavior; requiring minor changes 
in baseline care or monitoring (e.g. oxygenation, ventilation, tissue perfusion, metabolic stability and 
organ functioning). The event leads to a diminution of dosage of the test treatment, or a temporary 
interruption of its administration or to the establishment of a correcting treatment.
Severe: resulting in major changes of baseline age-appropriate behavior; requiring major change in 
baseline care or monitoring; requiring major change in baseline care or monitoring (e.g. brief, local, 
non-invasive or symptomatic treatments). The event causes severe discomfort and it may be of such 
severity to cause the definitive interruption of test treatment.
For the classification of AEs intensity, the ‘’Development of a neonatal adverse event severity scale through 
a Delphi consensus approach’’ article released on September 19, 2019 may be used as a guidance.


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Since the above-mentioned guidance is based on a 5-grade table, the following conversion will be 
performed:
AEs grade 1 Mild
AEs grade 2  Moderate
AEs grade 3, 4 and 5 Severe
In order to guarantee objectivity and consistency in the evaluation of AEs (including classification of 
intensity), the proposed guidance should be followed in alignment with best medical practice. Moreover, 
clinical abnormalities and other assessments will be reported as AEs if are judged by the Investigator as 
being clinically significant. 
10.4 Causality Assessment
The following “binary” decision choice will be used by the Investigator to describe the causality assessment:
Reasonable possibility of a relatedness
No reasonable possibility of relatedness
The expression “reasonable possibility of relatedness” is meant to convey, in general, that there are facts 
(evidence) or arguments meant to suggest a causal relationship.
The Investigator will be asked to consider the following before reaching a decision on causality assessment:
Time relationship between study drug intake and event’s onset;
De-challenge (did the event abate after stopping drug?);
Re-challenge (did the event reappear after reintroduction?);
Medical history;
Study treatment(s);
Mechanism of action of the study drug;
Class effects;
Other treatments-concomitant or previous;
Withdrawal of study treatment(s);
Lack of efficacy/worsening of existing condition;
Erroneous treatment with study medication (or concomitant);
Protocol related process.
10.5 Action taken with the study drug due to an AE
Dose not changed
Drug permanently withdrawn
Drug temporarily interrupted
Unknown
Not applicable
10.6  Other actions taken
Specific therapy/Medication
Concomitant Procedure
N/A
10.7 Outcome
Each Adverse Event must be rated by choosing among:


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Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered with sequelae/resolved with sequelae
Fatal
Unknown
10.8 Recording Adverse Events
All Adverse Events occurring during the course of the study must be documented in the Adverse Event page 
of the electronic Case Report Form (eCRF). Moreover, if the Adverse Event is serious, the Serious Adverse 
Event Form must also be completed. 
It is responsibility of the Investigator to collect all adverse events (both serious and non-serious).  Signs of 
NOWS (the condition under study) are efficacy endpoints in this study. Since detailed information on these 
events will be collected on the relevant page (refer to APPENDIX 4 – Finnegan Neonatal Abstinence 
Scoring Tool (FNAST)), these events therefore do not require to be reported as AEs unless their occurrence, 
severity or unresponsiveness to treatment (both study arms) is considered by the investigator unusual or 
abnormal or suggest another clinical diagnosis or pathology.
Additionally, those events should be reported as SAEs if they fulfill the definition of an SAE as in section 
10.1
All AEs, regardless of seriousness, severity or presumed causality must be recorded in the subject’s medical 
records and in the CRF. AEs that occur in subjects who have screen failed and are not entered into the CRF 
will be captured on the AE Reporting Log in the Investigator Site File. All SAEs occurring in subjects who 
have screen failed will be reported from informed consent and recorded in eCRF.
 
The investigator should carefully check inclusion and exclusion criteria because some of these morbidities 
may not allow the neonate to be randomized.
Clinically significant abnormalities detected at Screening visit not due to a pre-existing condition or 
clinically significant changes at the following visits in the medical opinion of the investigator must be 
reported as adverse events in the eCRF, taking into consideration the above assessment.
A diagnosis, if known, or clinical signs and symptoms if diagnosis is unknown, rather than the clinically 
significant abnormal laboratory finding, should be reported on AE eCRF page. If no diagnosis is known and 
clinical signs and symptoms are not present, then the abnormal finding should be recorded.
For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as completely and 
practically as possible their nature and/or causality until resolution of all queries, clinical recovery is 
complete, laboratory results have returned to normal, stable condition is reached or until the subject is lost to 
follow-up. Follow-up may therefore continue after the subject has left the study. In this case, the follow-up 
will continue with no timelines for related SAEs, while for unrelated SAEs the type and extent of follow-up 
undertaken will be determined for each individual case and will depend upon the nature (e.g. events with 
poor prognosis or which do not resolve), severity and medical significance of the event. 
10.9 Reporting Serious Adverse Events to Chiesi
The Investigator must report all Serious Adverse Events to the 
 Safety Contact listed below within 24 
hours of awareness. The information must be sent by providing the completed paper Serious Adverse Event 


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form. At a later date, the 
 Safety Contact will report all information to Chiesi Global 
Pharmacovigilance, the Clinical Project Manager and the Clinical Research Physician. 
Name and Title
Telepho
ne no.
Mobile 
no.
Fax no.
E-mail
Associate Safety Project Manager
 Safety Contact
 
 
 
  
 
Global Pharmacovigilance Operation
Specialist 
Chiesi Farmaceutici S.p.A. Parma 
(Italy)
 
-
Reporting of SAEs from the investigator site is from the time of subject’s signature of informed 
consent and until the subject’s study participation ends. After this date, even if no active monitoring of 
subjects is required, only related SAEs occurring to a subject should be reported if the investigator 
becomes aware of them. 
Up to the closure of the site, SAE reports should be reported to the 
 Safety Contact. New 
related serious adverse events occurring after the site is closed should be reported directly to the Chiesi 
Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB
The Sponsor or 
 will report adverse events to the regulatory authorities in compliance with the 
timelines and standards of reporting according to local regulations (Guidance for industry and Investigators-
Safety Reporting Requirements for INDs and BA/BE studies, December 2012). All suspected unexpected 
serious adverse reactions (SUSARs), which occur with the investigational medicinal product or marketed 
active comparator, within or outside the concerned clinical trial, will be reported by the Sponsor or
 
to regulatory authorities, as required, as well as to the Investigators and Central IRB, if applicable, by 
MedWatch/CIOMS form. The Investigator (or Sponsor/CRO where required) must inform the IRB per 
Sponsor instruction upon receipt of the SUSAR notification. An IND and/or NDA Safety Report will be 
submitted to regulatory authorities unblinded. Participating Investigators and IRB will receive a blinded IND 
Safety Report, unless otherwise specified. Regarding regulations in force for Pharmacovigilance, the 
Investigator must fulfill his/her obligation according to the law in force in his country. 
10.11 General Notes
In case of death, a comprehensive narrative report of the case should be prepared by the Investigator 
and sent to the 
 Safety Contact by fax together with the Serious Adverse Event form, retaining a 
copy on site.
If an autopsy is performed, copy of autopsy report should be actively sought by the Investigator and 
sent to the
 Safety Contact as soon as available, retaining a copy on site.
All source documents provided by the Investigator or site staff to the 
 Safety Contact must be 
carefully checked for respect of confidentiality. All personal patient’s data must be redacted.
10.12 Independent Safety Monitoring Board
An Independent Safety Monitoring Board (ISMB) will be established to ensure the safety of study subjects 
on an on-going basis. The involvement of independent expert advisors will provide an unbiased evaluation 


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of the overall safety in the study, with particular regard to the incidence of major adverse outcomes (i.e. 
Serious Adverse Events) during and following study treatment administration.
Independent Clinicians (2 or 3) and one independent Biostatistician will compose the ISMB.
The Sponsor (and other study personnel) may be involved in some blinded parts of the ISMB meetings.
All ISMB members will keep as confidential all information and data deriving from the ISMB activity, 
without disclosing them to others.
The ISMB will have periodical face-to-face or telephone meetings, as appropriate, and meeting minutes will 
be issued after each meeting.
The complete ISMB guidelines including details regarding the members, duties and responsibilities, work 
and communication processes, frequency of meetings will be established by the ISMB members during the 
first meeting and reported in a separate charter.
11.
DATA MANAGEMENT
An electronic CRF (eCRF) will be filled-in by the Investigator and/or his/her representative designee. 
Front-end edit checks will run at the time of data collection and back-end edit checks will be used by the 
Data Manager to check for discrepancies and to ensure consistency and completeness of the data. 
Subject questionnaires will be collected on paper and data will be entered at the site into the eCRF.
Medical history, adverse events and concomitant procedures will be coded using the MedDRA dictionary; 
medications will be coded using the WHO Drug dictionary and Anatomical Therapeutic Chemical 
classification (ATC). Access to electronic systems used for data collection will be granted to the study 
personnel only after appropriate training.
After the completion of data collection and cleaning, one or more data review meetings will be held to 
determine the occurrence of any protocol violation and to define the subject populations for the analysis. 
Although it will be possible to derive the treatment arm for patients who have reached or surpassed the end 
of the weaning phase, the explicit treatment codes will not be disclosed to the blinded team who are 
reviewing the data.  All data review will occur without explicit access to treatment codes.  Once the database 
has been declared to be complete and accurate, it will be locked, the randomization codes will be opened, 
and the planned statistical analysis will be performed.  Of note, the randomization list will remain 
confidential from the blinded study team until after database lock, even for patients who are functionally 
unblinded.   
If the database is unlocked after the initial lock, the process must be carefully controlled and documented; 
updates to the study data must be authorized by Chiesi.
At the study conclusion, a complete copy of the study data will be created for archival purposes at Chiesi. 
The investigators will receive copies of the patient data for retention at the investigational sites.
The 18-months (± 1 month) follow up data will be recorded in a separate database.
12.
STATISTICAL METHODS
12.1  Sample Size
On the basis of the results of similar studies, it was determined that a sample size of 51 babies in (17 
randomized to morphine and 34 randomized to CHF6563) will provide a power of 80% to detect a 
difference in duration of treatment of 13 days (312 hours), assuming a common standard deviation of 15 
days and a two-sided significance level of 0.05.  Assuming an early withdrawal rate of 10%, a total of 57 
neonates will be randomized in order to reach a total of 51 evaluable babies completing the treatment period.
Based on an assumed screening failure rate of 80%. It is anticipated that approximately 285 mothers should 
be pre-screened to achieve 57 randomized babies.


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12.2 Populations for analysis
Enrolled Population:  all subjects for whom informed consent was signed.  
Randomized Population:  all randomized subjects.
Intention-to-Treat population (ITT): all randomized subjects who receive at least one dose of the 
study treatment and with at least one available evaluation of efficacy after the baseline.
Per-protocol population (PP): all subjects from the ITT population without any major protocol 
deviations (i.e., wrong inclusions, non-permitted medications). Exact definition of major protocol 
deviations will be discussed by the study team during the review of the data and described in the Data 
Review Report.
Safety population: all randomized subjects who receive at least one dose of study treatment.
-
The primary analysis population for efficacy will be the ITT. Analysis on the primary variable(s) 
will be repeated in the PP population 
-
The Safety population will be used in the analysis of all safety variables.
-
In case of deviation between as-randomised treatment and treatment actually received, the 
treatment actually received will be used in the safety analyses (i.e. an as-treated analysis will be 
performed).
12.3 Statistical analysis
A detailed statistical analysis plan will be described in the Statistical Analysis Plan. The plan might be 
reviewed and updated as a result of the blind review of the data and will be finalized before breaking the 
blind. 
12.3.1 Descriptive Statistics 
General descriptive statistics for numeric variables will include the n (number of observed values), the 
mean, the standard deviation, the median, the minimum, and the maximum values. For categorical variables, 
the number and percent of subjects with a specific level of the variable will be presented.
12.3.2 Missing data
Babies for whom the parent/legal guardian wishes to discontinue treatment with study medication will be 
encouraged (via the parent/guardian) to remain in the study for collection of safety and efficacy data until 
the patient is discharged from the hospital or consent is otherwise withdrawn.  These babies will receive 
standard of care according to clinical practice but will continue to contribute to study assessments.  Handling 
of such cases will be described in the SAP. 
Primary Efficacy Variable:  Duration of treatment for babies who discontinue from the study prior to end 
of study treatment for any reason, including withdrawal due to treatment longer than 10 weeks, will be 
imputed using for the primary efficacy analysis.  The imputed value will be the maximum of:
the actual value for duration of treatment for the neonate (10 weeks for patients withdrawn due to 
treatment longer than 10 weeks) or 
the 90th percentile value for duration of treatment of all neonates, regardless of treatment group.  
Further details on dealing with missing data, along with the handling of possible outliers, will be described 
in the Statistical Analysis Plan (SAP). Other critical missing data, if any, will be discussed during the review 
of the data. Decisions will be fully documented in the Data Review Report.
12.3.3 Patient demographics and baseline characteristics
Demographics and baseline variables will be summarized by treatment arm using descriptive statistics for 
the ITT population.
The following variables will be presented: gestational age, sex, race/ ethnicity, head circumference and 
percentile, weight and percentile, medical history, concomitant diseases, FNAST scores, primary feeding 


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method, feeding type at randomization, duration of breastfeeding, maternal smoking, alcohol consumption, 
primary opioid and use of other licit and illicit drugs, prior medications (baby), and vital signs (neonate).
Summary statistics of demographic and baseline characteristics will be presented for the Safety Population 
(if different from the ITT population) and the PP.
12.3.4 Primary efficacy variable
The primary efficacy variable is the duration of treatment defined as the number of hours from start of the 
treatment until the last dose of study drug.
An ANCOVA model based on log-transformed data will be performed to test the treatment effect as 
duration of treatment (hours). 
The model will include treatment (CHF6563 and morphine) as a fixed effect and covariates for primary 
feeding method (formula/ any maternal breast- milk), Maternal primary opioid use (buprenorphine/ 
methadone / other), and maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]). In cases where observed primary feeding method during the treatment period (formula / any 
maternal breast milk) differs from the feeding method at time of randomization, the observed primary 
feeding method will be used for analysis. The adjusted geometric mean in each treatment group, the adjusted 
ratio of geometric means between treatments, together with its 95% CI and associated p-value will be 
estimated by the model.  
Missing data handling for the primary efficacy analysis is described in Section12.3.2.
Sensitivity analyses will be performed as described in the SAP.
12.3.5 Secondary efficacy variables
In cases where observed primary feeding method during the treatment period (formula / any maternal breast 
milk) differs from the feeding method at time of randomization, the observed primary feeding method will 
be used for analysis.
Time to first weaning  
Time to first weaning is defined as the number of hours from start of the treatment until the first dose 
reduction.  
An ANCOVA model based on log-transformed data will be performed to test the treatment effect as time to 
first weaning (hours). 
The model will include treatment (CHF6563 and morphine) as a fixed effect and covariates for primary 
feeding method (formula/ any maternal breast- milk), Maternal primary opioid use (buprenorphine/ 
methadone / other), and maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]). The adjusted geometric mean in each treatment group, the adjusted ratio of geometric means 
between treatments, together with its 95% CI and associated p-value will be estimated by the model.  
Requirement for adjunctive drug therapy (phenobarbital) for signs of NOWS
Only adjunctive drug therapy during the treatment period will be considered.  Odds ratios and corresponding 
95% CIs will be presented, based on logistic regression, adjusting for primary feeding method (formula / any 
maternal breast milk), maternal primary opioid use (buprenorphine /methadone / other), and maternal use of 
benzodiazepines, antidepressants or gabapentin (polypharmacy [yes/no]).   
Total hours of treatment with adjunctive therapy (phenobarbital)
Total hours of treatment with adjunctive therapy is defined as the sum of time on each occasion when 
adjunctive therapy is required (since babies may require adjunctive therapy on separate occasions).  For each 


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occasion requiring adjunctive therapy, the time of treatment is defined as the time of first dose until the last 
dose.
Total hours of treatment with adjunctive therapy will be analysed using an ANCOVA model. The model 
will include treatment (CHF6563 and morphine) as a fixed effect and primary feeding method (formula/any 
maternal breast- milk), maternal primary opioid use (buprenorphine/ methadone/ other), and maternal use of 
benzodiazepines, antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. Babies not requiring 
adjunctive therapy will be included as 0 hours.
Requirement for rescue doses (CHF6563 or morphine) 
Only rescue doses during the treatment period will be considered.  Odds ratios and corresponding 95% CIs 
will be presented, based on logistic regression, adjusting for primary feeding method (formula / any 
maternal breast milk), maternal primary opioid use (buprenorphine /methadone / other), and maternal use of 
benzodiazepines, antidepressants or gabapentin (polypharmacy [yes/no]).   
Number of rescue doses administered 
Number of rescue doses administered will be analyzed using an ANCOVA model. The model will include 
treatment (CHF6563 and morphine) as a fixed effect and primary feeding method (formula / any maternal 
breast milk), maternal primary opioid use (buprenorphine / methadone / other), and maternal use of 
benzodiazepines, antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. Babies not requiring 
rescue dose(s) will be included with a value of 0.
Percentage of total amount of active study drug which is from rescue doses
The percentage of total amount of active study drug which is from rescue doses will be analyzed using an 
ANCOVA model. The model will include treatment (CHF6563 and morphine) as a fixed effect and primary 
feeding method (formula / any maternal breast milk), maternal primary opioid use (buprenorphine / 
methadone / other), and maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]) as covariates. Babies not requiring rescue dose(s) of active study drug will be included with a 
value of 0.
Length of opioid related hospital stay
Length of opioid related hospital stay is defined as number of days from day of birth until 48 hours after the 
final dose of drug treatment for NOWS.  
Length of opioid related hospital stay (days) will be analyzed using an ANCOVA model based on log-
transformed data. will be performed to test the treatment effect as length of opioid-related hospital stay 
(days). 
The model will include treatment (CHF6563 and morphine) as a fixed effect and primary feeding method 
(formula / any maternal breast milk), maternal primary opioid use (buprenorphine / methadone / other), and 
maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy [yes/no]) as covariates. The 
adjusted mean in each treatment group, the adjusted ratio of geometric means between treatments, its 95% 
CIs and associated p-value will be estimated by the model.  
Incidence of relapse of NOWS, defined as experiencing recurrence of significant signs of withdrawal 
Odds ratios and corresponding 95% CIs will be presented, based on logistic regression, adjusting for 
primary feeding method (formula/ any maternal breast milk), maternal primary opioid use (buprenorphine 
/methadone / other), and maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]).   The odds ratio of incidence between treatment groups will be presented together with the 95% CI and 
corresponding p-value.  
Incidence of readmissions, defined as readmission to hospital for NOWS relapse
Odds ratios and corresponding 95% CIs will be presented, based on logistic regression, adjusting for 
primary feeding method (formula/any maternal breast milk), maternal primary opioid use (buprenorphine 


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/methadone / other), and maternal use of benzodiazepines, antidepressants or gabapentin (polypharmacy 
[yes/no]).   The odds ratio of incidence between treatment groups will be presented together with the 95% CI 
and corresponding p-value.  
12.3.6 Pharmacokinetic variables
The relative low number of blood samples per baby, the opportunistic sampling strategy and the continuous 
variation of the administered dose prevent the application of standard non-compartmental analysis for the 
characterization of CHF6563 pharmacokinetics in the neonate population.
Instead, a population pharmacokinetic modelling approach will be applied. A separate analysis plan and 
report will be produced.   
12.3.7 Safety variables
Adverse Events
Safety analysis will be based on Safety population. All adverse events starting on or after the time of first 
study drug intake will be classified as treatment emergent adverse event (TEAE). Any adverse events started 
after the informed consent signature and before the time of first study drug intake will be classified as pre-
treatment adverse events.
The number of babies who experienced at least one TEAE, drug-related TEAE, serious TEAE, serious 
related TEAE, TEAE leading to study discontinuation, TEAE leading to death, and peri-dosing TEAEs will 
be summarized by treatment arm. Summaries will be presented overall (number and percentage of babies 
having at least one event, total number of events) and by system organ class and preferred term (number and 
percentage of babies having at least one occurrence of that event). 
All adverse events will be listed.
Pre-treatment adverse event will be listed only.
The peri-dosing AEs are defined as adverse events occurring during or shortly after administration of 
study treatment, i.e. within 10 minutes from the start of study drug administration. 
Vital signs
Vital signs will be summarized at each planned time point by means of descriptive statistics. At each 
timepoint when vital signs are collected, mean, min, max and standard deviation of the observed values and 
change from baseline will be presented, in addition to being listed.
Laboratory data
Sites will use local labs to obtain liver enzymes analysis-function testing. When consistent with site clinical 
practice, sites will use local labs to collect hematology and blood chemistry. The laboratory values and the 
change from baseline for continuous laboratory parameters will be summarized by descriptive statistics at 
each planned time point. All laboratory data will be listed with abnormal values flagged.
Head circumference (and percentile) and body weight (and percentile) 
Head circumference (and percentile) and body weight (and percentile) and their corresponding changes from 
baseline will be summarized using descriptive statistics at each planned time point.  
Additional Safety Variables
The following parameters collected only at the end of the treatment period will be listed only:
-
Neurological and behavioral assessment
Analysis of safety variables collected at the 18-month follow up visit will be described in the SAP.
12.3.8 Interim analysis
A blinded sample size re-assessment (BSSR) will be performed when approximately 23-28 babies (40-50% 
of the planned sample size) have completed the treatment period.  At this time, the overall variance based on 


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all completed patients (without knowledge or consideration of treatment arm) will be evaluated and the 
sample size may be increased if the variability is higher than anticipated beyond a certain threshold.  
The BSSR may be adjusted for an assumed minimum effect size.  The minimum effect size assumed for 
BSSR may be lower than the effect size assumed for the sample size calculation in order to avoid 
underestimation of the within-group variance.  The BSSR will be restricted such that the sample size may be 
unchanged or increased, but not reduced, as a result of the BSSR.
The methodology planned for this BSSR has been shown to generally control type 1 error (Kieser and 
Friede, 2003).  Therefore, no adjustment will be made to the end-of-study analysis, considering an alpha of 
0.05.  
13.
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD APPROVAL 
The study proposal will be submitted to the Institutional Review Board in accordance with the local 
requirements. 
The IRB shall give its opinion in writing clearly identifying the study number, study title and informed 
consent form approved, before the clinical trial commences.
A copy of all communications with the IRB will be provided to the Sponsor.  
The Investigator should provide written reports to the IRB annually or more frequently if requested on any 
changes significantly affecting the conduct of the trial and/or increasing risk to the subjects (according to the 
requirements of each country).
14.
 REGULATORY REQUIREMENTS
The study will be notified to the Health Authorities (or authorized by) according to the legal requirements in 
each participating country.  
Selection of the subjects will not start before the approval of the Institutional Review Board has been 
obtained and the study notified to Health Authorities (or authorized by).
15.
INFORMED CONSENT 
Informed consent must be written in a language understandable to the mothers/parent/legal guardians. It is 
the responsibility of the Investigator to obtain written consent from each mother/parent/legal guardian prior 
to any study related procedures taking place, by using the latest IRB approved version of the document. 
Adequate time shall be given to the mother/parents of each neonate or from the neonate’s legal 
representative to enquiry ask the PI about for any clarification needed and to consider his or her decision to 
participate to the trial. 
If the parent and his/her legal representative are unable to read, the informed consent will be obtained in the 
presence of an impartial witness, e.g., a person independent of the study who will read the informed consent 
form and the written information for the neonate.
Consent must be documented by the parents/legal representative’s dated signature. The signature confirms 
that the consent is based on information that has been understood. Moreover, the Investigator must sign and 
date the informed consent form.
Each signed informed consent must be kept on file by the Investigator. One copy must be given to the 
neonate’s parents/legal representative.


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16.
SOURCE DOCUMENTS/DATA
16.1 Recording of source data
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data.  
Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents. 
16.2 Direct access to source document/data
The Investigators or designated must permit trial-related monitoring, audits, Ethics Committee/Institutional 
Review Board review or regulatory inspection, providing direct access to source data/documents.
17.
STUDY MONITORING
Monitoring will be performed by 
 who has been designated by Chiesi.
It is understood that the monitor(s) will contact and visit the Investigator/center before the study, regularly 
throughout the study and after the study had been completed, and that they will be permitted to inspect the 
various study records: case reports form, Investigator study file and source data, (source data is any data that 
is recorded elsewhere to the case report forms), provide independent that neonate confidentiality is 
respected.
The purposes of these visits are:
to assess the progress of the study;
to review the compliance with the study protocol;
to discuss any emergent problem;
to validate the contents of the CRFs against the source documents;
to assess the status of drug storage, dispensing and retrieval.
Prior to each monitoring visit, the Investigator or staff will record all data generated since the last visit 
on the case report forms. The Investigator and/or study staff will be expected to be available for at 
least a portion of the monitoring visit to answer questions and to provide any missing information.
It is possible that the Investigator site may be audited by Sponsor personnel or regulatory national 
and/or international regulatory agencies during and after the study has been completed.
18.
QUALITY ASSURANCE
The R&D Quality Assurance Department of Chiesi may perform an audit at any time according to the 
Sponsor’s Standard Operating Procedures, in order to verify whether the study is being conducted in 
agreement with Good Clinical Practices and the protocol. 
19.
INSURANCE AND INDEMNITY 
Chiesi holds and will maintain an adequate insurance policy covering damages arising out of Chiesi’s 
sponsored clinical research studies.
Chiesi will indemnify the Investigator and hold him/her harmless for claims for damages arising out of the 
investigation, in excess of those covered by his/her own professional liability insurance, providing that the 


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drug was administered under his/her or deputy’s supervision and in strict accordance with accepted medical 
practice and with the study protocol.
The Investigator must notify Chiesi immediately upon notice of any claims or lawsuits. 
20.
CONFIDENTIALITY
All study documents are provided by the Sponsor in confidence to the Investigator and his/her appointed 
staff. None of this material may be disclosed to any party not directly involved in the study without written 
permission from Chiesi.
The Investigator must assure the subject’s anonymity will be maintained. The Investigator will keep a 
separate list with at least the initials, the subject’s study numbers, names, and (optional) addresses and 
telephone numbers. The Investigator will maintain this for the longest period of time allowed by his/her own 
institution and, in any case, until further communication from Chiesi.
21.
PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. Should this be 
necessary, the procedures for an early termination or temporary halt will be arranged after consultation by 
all involved parties.
The Sponsor should submit a written notification to the Regulatory Authority concerned and Ethics 
Committee/Institutional Review Board providing the justification of premature ending or of the temporary 
halt.
22.
CLINICAL STUDY REPORT
At the end of the trial a summary of the clinical study report will be provided to all Ethics 
Committees/Institutional Review Boards, to the Competent Authority of the EU Member State or the US 
concerned and to Investigators.
23.
RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an orderly manner 
by the Investigator in a secure study file. 
Regulations require that essential documents must be retained for at least two years after the final marketing 
approval in an ICH region or until two years have elapsed since the formal interruption of the clinical 
development of the product under study. It is the responsibility of the Sponsor to inform the Investigator of 
when these documents can be destroyed. The Investigator must contact Chiesi before destroying any trial-
related documentation. In addition, all subjects’ medical records and other source documentation will be 
kept for the maximum time permitted by the institution.
24.
PUBLICATION OF RESULTS
Chiesi is entitled to publish and/or present any results of this study at scientific meetings, and to submit the 
clinical trial data to national and international Regulatory Authorities. Chiesi furthermore reserves the right 
to use such data for industrial purposes. In the absence of a Study Steering Committee, Investigators will 
inform Chiesi before using the results of the study for publication or presentation and agree to provide the 
Sponsor with a copy of the proposed presentation. Data from individual study sites must not be published 
separately. Negative as well as positive results should be published or otherwise made publicly available 
according to the relevant regulatory requirements.


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Version No.: 6.0 
IND No.: 131,339
Date: 18 March 2021
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25.
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[1] Kraft, Walter K.; Stover, Megan W.; Davis, Jonathan M. Neonatal abstinence syndrome: Pharmacologic 
strategies for the mother and infant Seminars in Perinatology 40.3 (Apr 1, 2016): 203-212
[2] Tolia VN, Patrick SW, Bennett MM, et al. Increasing incidence of the neonatal abstinence syndrome in 
U.S. neonatal ICUs. N Engl J Med. 2015;372(22): 2118– 2126
[3] Hudak ML, Tan RC. The Committee on Drugs and the Committee on Fetus and Newborn. Neonatal 
Drug Withdrawal. Pediatrics. 2012;129; e540
[4] Kocheriakota P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2): e547-561
[5] Sutter MB, Leeman L., Hisi A. neonatal opiod withdrawal syndrome. Obset Gynecol Clin north Am. 
2014; 41(2):317-34
[6] Herlinger RA, Kandall SR, Vaugham HG Jr Neonatal seizure associated with narcotic  eithdrawal, J. 
Pediatric. 1977;91 (4):638-41-
[7] Doberczak TM, Kandall SR, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. 
J Pediatr 1991; 118: 933-7
[8] Desai, R.J., Hernandez-Diaz, S., Bateman, B.T. & Huybrechts, K.F. Increase in prescription opioid use 
during pregnancy among Medicaid-enrolled women. Obstet. Gynecol. 123, 997–1002 (2014)
[9] Nanovskaya TN, Nekhayeva IA, Hankins GD, et al. Transfert of methadone across the dually perfused 
preterm human placental lobule. Am J obsetGynecol.2008; 198 (1):126.e 1-4.
[10]Szeto HH. Kinetics of drug transfer to the fetus. Clin. Obstet Gynecol.1993;36(2): 246-54
[11]Patrick SW, Schumacher RE, Horbar JD, et al. Improving Care for Neonatal Abstinence Syndrome. 
Pediatrics. 2016;137(5):e20153835
[12]Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic 
management. J Opioid Manag 2009;5(1):47–55
[13]Delvin LA, Davis JM. Apractical approch to neonatal opiate withdrawal syndrome. Am J.  Perinatol. 
2018 Mar,35 (4):324-330.
[14]Mian P, Tibboel D, Wildschut ED, Van der Anker JN, Allegaert K. Morphine treatment forn Neonatal 
Abstinence Syndrome: huge dosing variability underscores the need for a better clinical study design. 
Minerva Pediatr.2017 Mar 3.
[15]Sauberan J., Rossi S, Kim JH. Stability of diluite oral morphine solution for neonatal abstinence 
syndrome. J. Addict Med.2013;7(2):113-5
[16]Colombini N., Elias R, Busuttil M, et al. Hospital morphine preparation for abstinecesyndrome 
innewborns exposed to buprenorphine or methadone. Pharm World Sci.2008;30(3):227-34


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Version No.: 6.0 
IND No.: 131,339
Date: 18 March 2021
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[17]Provenza N, Calpena AC,Mallandrich M, et al. Design of pediatric oral formulation with a low 
proportion of methadone or phenobarbital for a treatment of neonatal abstinence syndrome. Pharm Dev 
Technol.2016,21(6):755-62
[18]Snijders J, van Linger RA, Klip H, et al. Specialty-based, voluntaru incident reporting in neonatal 
intensive care: description of 4846 incident reports. Arch Dis Child Fetal Neonatal Ed. 2009;94:F210-
F215
[19]Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. 
Clin Pharmacokinet. 2005;44(7):661-80.
[20]Walsh SL, Preston KL, Stitzer ML, et al. Clinical Pharmacology of buprenorphine: ceiling effects at 
high doses. Clin Pharmacol Ther. 1994; 55:569-80.
[21]Ohtani M. Basic pharmacology of buprenorphine. Eur J Pain Suppl. 2007;1:69-73.
[22]Heel RC, Brodgern RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological 
properties and therapeutic efficacy. Drugs. 1979;17(2):81-110
[23]Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS, Moody DE, Kaltenbach K, 
Ehrlich ME. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized 
trial. Pediatrics. 2008, Sep;122(3): e601-60
[24]Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of 
sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction. 2011 
Mar;106(3):574-80
[25]Kraft W, Adeniyi-Jones S, Chervoneva I, et al. Buprenorphine for the Treatment of the Neonatal 
Abstinence Syndrome.  N. Engl J. Med. 2017, 376
[26]Hall ES, Isemann BT, Wexelblatt SL, et al. A cohort comparison of buprenorphine versus methadone 
treatment for neonatal abstinence syndrome. J Pediatr. 2016; 170:39-44.
[27]Hall ES (b), McAllister JM, Wexelblatt SL. Developmental Disorders and Medical Complications 
Among Infants with Subclinical Intrauterine Opioid Exposures. Popul Health Manag. 2018 Jun 12. doi: 
10.1089/pop.2018.0016.
[28]Kraft W, Adeniyi-Jones S, Chervoneva I, et al. Buprenorphine for the Treatment of the Neonatal 
Abstinence Syndrome.  N. Engl J. Med. 2017, 376
[29]Moore JN, Gastonguay MR, Ng CM, et al. The Pharmacokinetics and Pharmacodynamics of 
Buprenorphine in Neonatal Abstinence Syndrome. Clin Pharmacol Ther. 2018 Jun;103(6):1029-1037.
[30]Pocock, S. J., & Simon, R. (1975).  Sequential Treatment Assignment with Balancing for Prognostic 
Factors in the Controlled Clinical Trial.  Biometrics, 31(1), 103-115.
[31]Buprenex NDA 18-401. Validation of an analytical method for the determination of Buprenorphine and 
Norbuprenorphine in rat and dog plasma by LC-MS/MS.  
[32]Charles River report n. 37601. Harmacokinetic analysis of eneterohepatic circulation of Buprenorphine 
and its active metabolite, Norbuprenorphine, in rats.  November 2016.


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Version No.: 6.0 
IND No.: 131,339
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[33]M Ohtani et al.; Drug Metabolism and Disposition; 1994; 22 (1); 2-7. biliary excretion, metabolism and 
enterohepatic circulation of buprenorphine.  D Brewster et al. Xenobiotica; 1981; 11 (3); 189-196,
[34]R. B. Pontani et al. Disposition in the rat of buprenorphine administered parenterally and as a 
subcutaneous implant.  Xenobiotica; 1985; 15 (4); 287-297.
[35]Charles River study n. 498064. A pharmacokinetic study of Buprenorphine by subcutaneous injection in 
juvenile rats March 2017.
[36]Pharmacokinetics of Buprenorphine following intravenous and oral transmucosal administration in 
dogs. L. A. Abbo et al.  Veterinary Therapeutics; 2008; 9 (2); 83-93.
[37]Han, B., Enas, N. H. and McEntegart, D., Randomization by minimization for unbalanced treatment 
allocation, Statistics in Medicine, 28, 27:3329-3346, 20
[38]Zane NR, Kraft WK, Zuppa AF, Gastonguay MR. Clinical Trial Dose Optimization of Buprenorphine 
for Neonatal Abstinence Syndrome Using an Adaptive Monte Carlo Simulation. Oral presentation at 
American College of Pharmacometrics meeting, San Diego, CA,  October 2018


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APPENDIX 1 - Approval of the protocol by clinical investigator(s)


Clinical Study Protocol – Appendix 1
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A Phase II, multicenter, double blind, double dummy, randomized, 2 arms parallel study to 
evaluate the efficacy, safety and pharmacokinetics of CHF6563 in babies with Neonatal 
Opioid Withdrawal Syndrome
Product: CHF6563
Pharmaceutical Form: sublingual
Approval of Clinical Study Protocol by the Investigator: 
I have carefully read this protocol and I agree that it contains all the necessary information 
required to conduct the study and I agree to conduct it as described.
I understand that this trial will not be initiated without Ethics Committee/Institutional Review 
Board approvals and that the administrative requirements of the governing body of the 
institution will be fully complied with.
Written informed consent will be obtained from the mother/parents/legal guardians and 
appropriately documented, prior to their enrolment in the study. 
The undersigned agrees that the trial will be carried out in conformity with the Declaration of 
Helsinki (as applicable, with attention being drawn to Section concerning freely given 
consent), ICH E6 Good Clinical Practices and with all the other local laws and regulations 
relevant to the use of new and approved therapeutic agents in subjects.
Investigator’s Name:  ____________________,MD
Centre No. : 
__________________________
Signature
     Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy


Clinical Study Protocol – Appendix 2
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APPENDIX 2 – Maternal Screening Questionnaire


Clinical Study Protocol - Appendix 2
Clinical Study Code No.: CLI-06563AA1-02
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F
A Phase 2, Multicenter, Double-blind, Double-dummy, Randomized Study to Evaluate the 
Efficacy, Safety and Pharmacokinetics of CHF6563 in Neonates with Neonatal Opioid 
Withdrawal Syndrome
Maternal Screening Questionnaire
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol - Appendix 2
Clinical Study Code No.: CLI-06563AA1-02
Version No.:6.0
IND No.: 131,339
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F
 
A Phase 2, Multicenter, Double-blind, Double-dummy, Randomized Study to Evaluate 
the Efficacy, Safety and Pharmacokinetics of CHF6563 in Neonates with Neonatal 
Opioid Withdrawal Syndrome
Maternal Screening Questionnaire
  Name: 
Age 
 Number of Weeks Pregnant 
 
 
 
 
 
 
 
 


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Clinical Study Protocol - Appendix 2
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Clinical Study Protocol - Appendix 2
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Date: 18 March 2021
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Clinical Study Protocol - Appendix 2
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Date: 18 March 2021
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Clinical Study Protocol – Appendix 3
Clinical Study Code: CLI-06563AA1-02
Version No.:6.0 
IND No.: 131,339
Date: 18 March 2021
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APPENDIX 3 – List of PSYCHOTROPIC DRUGS


Clinical Study Protocol - Appendix 3
Clinical Study Code No.: CLI-06563AA1-02
Version No.: 6.0
IND No.: 131,339
Date: 18 March 2021
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The following drugs have been associated to increased relative risk of neonatal withdrawal 
among women who were co-exposed to opioids (Huybrechts et al, Risk of neonatal drug 
withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort 
study. BMJ 2017 Aug 2;358:j3326). This table is to be used for the identification of 
stratification criterion #3 (Maternal concurrent use of benzodiazepines, antidepressants or 
gabapentin (polypharmacy [yes/no]), see 6.5 Treatment allocation).
Antidepressants
Selective serotonin reuptake inhibitors
citalopram, 
escitalopram. 
fluoxetine, 
fluvoxamine, paroxetine, sertraline
Serotonin 
and 
norepinephrine 
reuptake 
inhibitors
duloxetine, 
venlafaxine, 
desvenlafaxine, 
levomilnacipran
Tricyclic antidepressant
amitriptyline, 
amoxapine, 
clomipramine, 
desipramine, doxepin, imipramine, maprotiline, 
nortriptyline, protriptyline, trimipramine
others
isocarboxazid, 
phenelzine, 
tranylcypromine, 
bupropion, mirtazapine, nefazodone, trazodone, 
vilazodone, vortioxetine
Benzodiazepines
Long-acting
chlordiazepoxide, 
clobazam, 
clorazepate, 
diazepam, flurazepam, quazepam
Short-acting
alprazolam, midazolam, triazolam, clonazepam, 
estazolam, lorazepam, oxazepam, temazepam
Gabapentin


Clinical Study Protocol – Appendix 4
Clinical Study Code: CLI-06563AA1-02
Version No.:6.0 
IND No.: 131,339
Date: 18 March 2021
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APPENDIX 4 – Finnegan Neonatal Abstinence Scoring Tool 
(FNAST)


Clinical Study Protocol – Appendix 4
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References: 
D’Apolito K (a), Finnegan L. Assessing Signs & Symptoms of Neonatal Abstinence Using the Finnegan Scoring 
Tool: An Inter-Observer Reliability Program Instructional Manual. 2nd ed. Nashville, TN: NeoAdvances, LLC; 
2010a. https://neoadvances.com/ Accessed 30 June 2018
D’Apolito K (b), Finnegan, L. Assessing Signs & Symptoms of Neonatal Abstinence Using the Finnegan 
Scoring Tool: An Inter-Observer Reliability Program [DVD]. Nashville, TN. NeoAdvances, LLC; 2010. 
https://neoadvances.com/ Accessed 30 June 2018.
Hudak ML, Tan RC, Committee On Drugs, Committee On Fetus And Newborn, American Academy of 
Pediatrics. Neonatal drug withdrawal. Pediatrics. 2012 Feb;129(2):e540-60.

SAP_001.pdf: 
P a ge 1 of 4 4 
S T A TI S TI C A L A N A L Y SI S P L A N  
A P h ase II, m ultice nter, d o u ble bli n d, d o u ble d u m m y, r a n d o mize d, 
2 ar ms p ar allel st u d y t o e v al u ate t he effic ac y, s afet y a n d 
p h ar m ac o ki netics of C H F 6 5 6 3 i n b a bies wit h Ne o n at al O pi oi d 
Wit h dr a w al S y n dr o me  
Pr ot oc ol:  C LI -0 6 5 6 3 A A 1 -0 2
: 
 
De vel o p m e nt p h ase:  II 
S p o ns or:  C hiesi Far mace utici S. p. A.  
A n al ysis p ur p ose:  Fi nal a nal ysis  
S A P versi o n n u m ber:  Fi nal  2. 0  
S A P versi o n d ate:  0 7 J UL 2 0 2 2  
N C T n o. N C T 0 4 1 0 4 6 4 6


Page 2 of 44 
PROTOCOL HISTORY 
Protocol: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the changes on the statistical 
analysis 
Final 1.0 
04JUN2019 
NAP 
Final 2.0 
26JUN2019 
NAP 
Final 3.0 
11JUL2019 
NAP 
Final 4.0 
24OCT2019 
NAP 
Final 5.0 
28FEB2020 
NAP 
Final 6.0 
18MAR2021 
Sample size decreased from 99 to 57 
subjects. 
Cardiorespiratory monitoring using 
continuous 3-lead ECG and pulse oximetry 
will be performed during treatment (starting 
before the first dose of study drug and 
continuing up to the initial stage of the 
weaning phase). 
Protocol amendments: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the amendment on the 
statistical analysis 
NAP 
This statistical analysis plan (SAP) only considers the last version of the protocol, and 
of the protocol amendments, as listed above. 


P a ge 3 of 4 4 
LI S T O F A B B R E VI A TI O N S  
A Da M  
a nal ysis data m o del  
A D R  
a d verse dr u g reacti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne tra ns a mi nase 
A S T  
as partate tr a nsa mi nase  
B L( O) Q  
bel o w t he li mit of q ua ntificati o n  
CI  
c o nfi de nce i nter val  
C R F  
case r e p ort f or m  
D B P  
diast olic bl o o d press ure  
D R M  
data re vie w meeti n g  
D R R  
data re vie w re p ort  
D Y  
relati ve da y 
E N R  
e nr olle d set  
F N A S T  
Fi n ne ga n N e o natal A bsti ne nce Sc ori n g T o ol  
H R  
heart r ate  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
N A P  
n ot a p plica ble  
N O W S  
ne o nate o pi oi d -wit h dra w al s y n dr o me  
P K  
p har mac o ki netic  
R N D  
ra n d o mize d set 
S A P  
statistical a nal ysis pla n 
S A F  
safet y set 
S B P  
s yst olic bl o o d press ure 
S D  
sta n dar d de viati o n 
S D T M  
st u d y data ta b ulati o n m o del 
S E  
sta n dar d err or 
 
 
S O P  
sta n dar d o per ati n g pr oce d ure 
S T A T  
statistics 
T E A E  
treat me nt-e mer ge nt a d v erse e ve nt  
T L F  
ta bles, listi n gs a n d fi g ures 


P a ge 4 of 4 4 
V S  
vital si g ns  
W H O  
W orl d Healt h Or ga nizati o n  
WI  
w or k i nstr ucti o n  


P a ge 5 of 4 4 
D E FI NI TI O N O F T E R M S  
case r e p ort f or m 
( C R F) 
A pri nte d, o ptical, or el ectr o nic d oc u me nt desi g ne d t o rec or d 
pr ot oc ol re q uire d i nf or m ati o n t o be re p orte d t o t h e s p o ns or f or eac h 
trial s u bject. 
dis pla y  
A nal ysis ta ble, fi g ure or listi n g  
p hase 
I nter val of ti me i n t he pla n ne d c o n d uct of a st u d y ass ociate d wit h a 
s pecific p ur p os e: f or e x a m ple, scree ni n g, treat me nt, f oll o w -u p.  
r o u n d half a w a y 
fr o m zer o tie-
brea ki n g r ule 
C o n ve nti o n t o r o u n d val ues e n di n g wit h 5 t o t he nearest di git 
a wa y fr o m zer o. T he r o u n d half a wa y fr o m zer o is i m ple me nte d 
i n t he S A S®  R O U N D f u ncti o n.  
E xa m ples:  
D at a b ase v al ue 
R o u n de d v al ue  
- 1. 3 5
- 1. 4
- 1. 2 5
- 1. 3
1. 2 5
1. 3
1. 3 5
1. 4
si g nifica nt di git 
All di gits of a n u m ber use d t o e x press it t o t he re q uire d de gree of 
acc ur ac y, starti n g fr o m t he first n o n -zer o di git. 
st u d y dr u g 
P har mace utical f or m of a n acti ve i n gre die nt or place b o, bei n g teste d 
or use d as a refere n ce i n a cli nical st u d y.  


Page 6 of 44 
TABLE OF CONTENTS 
Protocol history ............................................................................................................ 2 
List of abbreviations .................................................................................................... 3 
Definition of terms ....................................................................................................... 5 
Table of contents .......................................................................................................... 6 
1.
Introduction ......................................................................................................... 9 
1.1 
Study objectives............................................................................................... 9 
1.2 
Estimand for primary analysis ......................................................................... 9 
1.3 
Study design .................................................................................................. 10 
1.4 
Expected sample size ..................................................................................... 11 
1.5 
Randomization and blinding.......................................................................... 12 
1.6 
Interim analysis ............................................................................................. 12 
1.7 
Software ......................................................................................................... 12 
1.8 
Validation model ........................................................................................... 12 
2.
Efficacy and pharmacokinetic analyses ........................................................... 14 
2.1 
Primary efficacy endpoint ............................................................................. 14 
2.1.1 
Derivation rules ............................................................................... 14 
2.1.2 
Presentation of results ..................................................................... 14 
2.2 
Secondary efficacy endpoints ........................................................................ 14 
2.2.1 
Available data .................................................................................. 15 
2.2.2 
Derivation rules ............................................................................... 15 
2.2.3 
Inferential statistics ......................................................................... 15 
2.2.4 
Presentation of results ..................................................................... 15 
2.3 
Pharmacokinetics ........................................................................................... 16 
2.3.1 
Available data .................................................................................. 16 
2.3.2 
Presentation of results ..................................................................... 16 
3.
Safety analyses ................................................................................................... 17 
3.1 
Adverse events............................................................................................... 17 
3.1.1 
Available data .................................................................................. 17 
3.1.2 
Derivation rules ............................................................................... 17 
3.1.3 
Presentation of results ..................................................................... 18 
3.2 
Clinical laboratory evaluation ....................................................................... 19 
3.2.1 
Available data .................................................................................. 19 
3.2.2 
Derivation rules ............................................................................... 19 
3.2.3 
Presentation of results ..................................................................... 19 


Page 7 of 44 
3.3 
Vital signs ...................................................................................................... 20 
3.3.1 
Available data .................................................................................. 20 
3.3.2 
Derivation rules ............................................................................... 20 
3.3.3 
Presentation of results ..................................................................... 20 
3.4 
Escalation of opioid withdrawal .................................................................... 21 
3.4.1 
Available data .................................................................................. 21 
3.4.2 
Presentation of results ..................................................................... 21 
3.5 
Physical examinations ................................................................................... 21 
3.6 
Neurological and behavioral assessment ....................................................... 21 
4.
General characteristics analyses ...................................................................... 22 
4.1 
Subject disposition......................................................................................... 22 
4.2 
Protocol deviations and eligibility ................................................................. 22 
4.3 
Demographic and other baseline characteristics ........................................... 23 
4.3.1 
Available data .................................................................................. 23 
4.3.2 
Derivation rules ............................................................................... 23 
4.3.3 
Presentation of results ..................................................................... 23 
4.4 
Medical history and concomitant diseases .................................................... 24 
4.4.1 
Available data .................................................................................. 24 
4.4.2 
Derivation rules ............................................................................... 24 
4.4.3 
Presentation of results ..................................................................... 24 
4.5 
Procedures and Medications .......................................................................... 24 
4.5.1 
Available data .................................................................................. 24 
4.5.2 
Derivation rules ............................................................................... 25 
4.5.3 
Presentation of results ..................................................................... 25 
4.6 
Exposure to study drug .................................................................................. 26 
4.6.1 
Available data .................................................................................. 26 
4.6.2 
Presentation of results ..................................................................... 26 
5.
General methodology......................................................................................... 27 
5.1 
Analysis sets .................................................................................................. 27 
5.1.1 
Analysis sets .................................................................................... 27 
5.1.2 
As planned versus as actual analysis ............................................... 27 
5.2 
Phases and time points................................................................................... 27 
5.2.1 
Phases .............................................................................................. 27 
5.2.2 
Baseline and change from baseline ................................................. 28 
5.2.3 
Relative day ..................................................................................... 29 


Page 8 of 44 
5.2.4 
Analysis visits ................................................................................. 29 
5.3 
Imputation and rounding rules ....................................................................... 30 
5.3.1 
Missing values ................................................................................. 30 
5.3.2 
Values below or above a threshold ................................................. 30 
5.3.3 
Rounding of derived variables ........................................................ 30 
5.3.4 
Outliers ............................................................................................ 30 
5.4 
Presentation of results.................................................................................... 31 
5.4.1 
Calculation of descriptive statistics and percentages ...................... 31 
5.4.2 
Presentation of treatments ............................................................... 31 
5.4.3 
Ordering in tables and listings ......................................................... 31 
5.4.4 
Raw SAS output .............................................................................. 31 
6.
Changes to the planned analysis ....................................................................... 32 
6.1 
Changes to the planned analysis .................................................................... 32 
6.2 
Changes in the conduct of the Study ............................................................. 32 
6.3 
Changes to the final statistical analysis plan ................................................. 32 
7.
References ........................................................................................................... 36 
8.
List of tables and listings ................................................................................... 37 
8.1 
Tables ............................................................................................................ 37 
8.2 
Listings .......................................................................................................... 40 
9.
Appendices ......................................................................................................... 44 
9.1 
Schedule of assessments ................................................................................ 44 


P a ge 9 of 4 4 
1.
I N T R O D U C TI O N
T his S A P descri bes t he fi nal statistical a nal ysis t o be perf or me d f or t h e C LI -
0 6 5 6 3 A A 1- 0 2 (
) st u d y. 
T his S A P c o vers t he effi cac y, p h ar mac o ki n etic ( P K), safet y  a n d ge n eral 
c haracteristics parts of t he statistical a nal ysis . It s pecifies t he a nal ysis dis pla ys t o be 
prese nte d  a n d descri bes t he met h o ds a n d pr oce d ures i n a m ore el a b orate d wa y t ha n i n 
t he statistical met h o ds secti o n of t he pr ot oc ol. 
T he statistical a nal ysis will p r ocess a n d pres e nt t he res ults f oll o wi n g t he I nter nati o nal 
C o u ncil f or Har m o nizati o n  of Tec h nical Re q uire me nts f or P har mace uticals f or 
H u ma n Use (I C H) sta n dar ds, i n partic ular t he I C H-E 3,  I C H- E 6 a n d I C H-E 9 
g ui deli nes. 
1. 1  
S T U D Y O B J E C TI V E S  
T he pri mar y o bjecti ves of t his st u d y are: 
•
T o assess t he efficac y of C H F 6 5 6 3 i n ba bies wit h N O W S
•
T o assess t he saf et y a n d t olera bilit y of C H F 6 5 6 3 i n ba bies wit h N O W S
T he sec o n d ar y o bjecti ves of t his st u d y are: 
•
T o i n vesti gate t he p har m ac o ki netics of C H F 6 5 6 3 i n ba bies wit h N O W S
•
T o assess t he use of t h e a dj u ncti ve t hera p y f or N O W S
1. 2  
E S TI M A N D F O R P RI M A R Y A N A L Y SI S  
•
Treat me nt: C H F 6 5 6 3
•
P o p ulati o n: ne o nates wit h N O W S meeti n g eli gi bilit y criteria
•
Va ria ble of i nterest: d urati o n of treat me nt f or N O W S
•
S u m mar y meas ure:  mea n, 9 5 % CI
•
I ntercurre nt e v e nt ha n dli n g
o
Disc o nti n uati o n fr o m st u d y d uri n g t he treat me nt p eri o d f or a n y
reas o n.  T hes e ar e t he o nl y f oreseea ble missi n g dat a. E ver y eff ort is
ma de t o mi ni mize t hese wit h dra wals, b ut it ca n b e a ntici pate d t hat
s o me missi n g data d ue t o wit h dra wal of c o nse nt or I n v esti gat or’s
decisi o n  ma y be u na v oi d a ble i n t his patie nt p o p ulati o n. T hese cases
will be i m p ute d as a n e xtre mel y ne gati ve v al ue (s ee secti o n 5. 3. 1 ).
o
All ot her i nterc urre nt e v e nts are treate d as if t he y di d n ot ha p pe n
(treat me nt p olic y strate g y).  T his i ncl u des, b ut n ot li mite d t o:
- 
t he use of a d diti o nal or alter nati ve t hera pies
-
wr o n g treat me nt recei ve d
-
wr o n g d ose r ecei v e d
-
resc ue d os es n ot as f ores een b y pr ot oc ol
- 
a dj u ncti ve t hera p y n ot as f oresee n b y pr ot oc ol


 
 
 
 
P a ge 1 0 of 4 4 
 
1. 3  
S T U D Y D E SI G N  
T his is a ra n d o mize d, m ultice nter, d o u ble bli n d, d o u ble- d u m m y, parallel gr o u p, 
c o ntr olle d st u d y. 
Fift y -se v e n ne o nates wit h ne o natal o pi oi d- wit h dra wal s y n dr o me ( N O W S) wit h or 
wit h o ut ot her c o nc o mita nt dr u g wit h dra wal s y n dr o mes will be ra n d o mize d t o recei ve 
C H F 6 5 6 3 or m or p hi ne tr eat me nt. I n or d er t o mai ntai n t he bli n d, a d o u ble- d u m m y 
desi g n will be use d s o t hat t he s u bjects will recei ve eit her C H F 6 5 6 3 a n d m or p hi ne 
matc he d place b o, or m or p hi ne treat me nt a n d C H F 6 5 6 3 matc he d place b o. D ue t o t he 
differe nt le n gt hs of wea ni n g, f u ncti o nal u n bli n di n g will be p ossi ble f oll o wi n g t he last 
sc he d ule d d ose of C H F 6 5 6 3 u p t o t he e n d of t he st u d y. 
Acc or di n g t o a ra n d o mizati o n al g orit h m, ne o nates will be assi g ne d t o o ne of t he t w o 
ar ms: 
•  Test ar m: ba bies will recei ve a s u bli n g ual d ose of C H F 6 5 6 3 at a starti n g 
d ose of 1 0 μ g/ k g e ver y 8 h o urs ( ± 1 h) ( usi n g birt h wei g ht w hic h s h o ul d 
be r o u n de d t o t he sec o n d deci mal place ) a n d t he c orres p o n di n g oral d os e 
of m or p hi ne matc he d pl ace b o q 4. 
•  Refere n ce ar m: ba bies will recei ve a n oral d ose of m or p hi ne at a starti n g 
d ose of 0. 0 7 m g/ k g e ver y 4 h o urs ( ± 1 h) ( usi n g birt h wei g ht w hic h 
s h o ul d be r o u n de d t o t he sec o n d deci mal place) a n d t he c orres p o n di n g 
s u bli n g ual d ose of C H F 6 5 6 3 matc he d place b o q 8. 
T he m ot hers of p ote ntial i nfa nts will be i de ntifie d t hr o u g h t he o ut patie nt mater nit y, 
treat me nt cli nics or u p o n a d missi o n t o h os pital. All ba bies f or w h o m c o ns e nt has 
bee n o btai ne d will ha v e N O W S gra d e d acc or di n g t o Fi n ne ga n N e o natal A bsti ne nce 
Sc ori n g T o ol F N A S T  (see pr ot oc ol f or d etails o n F N A S T). 
P har mac ol o gical tr eat me nt will start u p t o 7 da ys after d eli ver y a n d c o nsists of t he 
f oll o wi n g p hases: i nitiati o n, escalati o n, sta bilizati o n, wea ni n g a n d cessati o n. 
Assess me nt of t he nee d f or treat me nt a n d d os e a dj ust me nts will be base d u p o n 
cli nical si g ns of wit h dra wal e val uat e d usi n g a F N A S T a n d c o nti n ue d u ntil at least 4 8 
h o urs after t h e last d ose of o pi oi d treat me nt. A re vie w of t he dr u g d os e will ta ke 
place o n a d ail y basis or m ore fre q u e ntl y d uri n g t he escal ati o n p hase t o e ns ure 
ti mel y d ose a dj ust me nt.  
T he d urati o n of f oll o w u p will be f or 6 wee ks after t he fi nal o pi oi d treat me nt d ose. 
E vi de nce of re c urre n ce of si g nifica nt wit h dra w al will be m o nit ore d f or all ba bies 
w h o re mai n wit hi n t he h os pital. F or ba bies disc h ar ge d f oll o wi n g t he re q uire d peri o d 
of i n patie nt o bser vati o n ( 4 8 h o urs p ost last o pi oi d treat me nt d ose), d ail y tele p h o ne 
c o ntact wit h t he pr i mar y care gi v er ( p are nt al/le gal g uar dia n or f ost er m ot her) will 
c o nti n ue f or t he first 7 da ys a n d will rec or d t he b a b y’s well bei n g a n d i de ntif y a n y 
escalati o n of wit h dr a wal si g ns. 
T hereafter wee kl y tele p h o ne c o ntact will c o nti n ue f or t he d urati o n of t h e f oll o w u p 
peri o d. T he first w ee kl y t ele p h o ne c o nt act will occ ur 7 da ys after t he last dail y 
p h o ne call. Si g nifica nt es calati o n of wit h dra wal si g ns will warra nt cli nical re vie w 
a n d assess me nt f or rela ps e se ver e e n o u g h t o re q uire p har mac ol o gical treat me nt a n d 
rea d missi o n. 
T he e n d of t he tri al is  defi ne d as  t he last f oll o w-u p at 6 wee ks c o ntact of t he last 
s u bject i n t he trial. 


Page 11 of 44 
The study will be conducted as follows for each baby: 
•
A pre-screening visit with the mother to explain the study and obtain the
informed consent to participate in the study, and to confirm the use of
opioid in the last month of pregnancy. This visit will be carried out
during the last month of pregnancy or after delivery. The maternal
screening questionnaire will also be completed.
•
A screening visit on the neonates who show sign of NOWS. The visit
will be carried out up to 7 days after delivery.
•
A randomization visit to verify the eligibility of the neonate for
inclusion in the study and to assign the neonates to a treatment and
provide the first treatment administration.
•
Treatment period: from randomization, up to 48 hours after the last
dose. The treatment period can last up to 10 weeks (70 days) from the
first treatment dose.
•
Regular follow up will continue both before and after discharge from
hospital to identify those babies who suffer recurrence of significant
withdrawal. The duration of follow up will be for 6 weeks after the final
opioid treatment dose. Evidence of recurrence of significant withdrawal
will be monitored for all babies who remain within the hospital. For
babies discharged following the required period of in-patient
observation (48 hours post last opioid treatment dose), daily telephone
contact with the primary caregiver (parental/legal guardian or foster
mother) will continue for the first 7 days and will record the infant’s
wellbeing and identify any escalation of withdrawal signs. Thereafter
weekly telephone contact will continue for the duration of the follow up
period.
An 18-month (± 1 months) follow-up visit to assess neurodevelopmental and general 
health status and confirmation of the safety of the test treatment will be undertaken by 
the participating centers. This assessment will be evaluated separately from the main 
part of the study and will therefore not be described in this SAP. Since the study was 
early terminated the 18-month follow-up will not be conducted. 
The schedule of assessments is in appendix 9.1. 
1.4 
EXPECTED SAMPLE SIZE 
On the basis of the results of similar studies, it was determined that a sample size of 
51 babies in (17 randomized to morphine and 34 randomized to CHF6563) will 
provide a power of 80% to detect a difference in duration of treatment of 13 days 
(312 hours), assuming a common standard deviation of 15 days and a two-sided 
significance level of 0.05. Assuming an early withdrawal rate of 10%, a total of 57 
neonates will be randomized in order to reach a total of 51 evaluable babies 
completing the treatment period. 
Based on an assumed screening failure rate of 80% it is anticipated that 
approximately 285 mothers should be pre-screened to achieve 57 randomized babies. 


Page 12 of 44 
1.5 
RANDOMIZATION AND BLINDING 
Babies will be assigned in a 2:1 ratio to either CHF6563 or morphine. Randomization 
will be stratified according to the following variables, using a dynamic randomization 
algorithm (i.e. minimization) to balance treatment arms with respect to stratification 
factor levels, while maintaining an overall treatment balance:  
•
Neonate’s feeding status at time of randomization (formula/any
maternal breast- milk [including combination of breast milk and
formula])
•
Maternal primary opioid use (buprenorphine/methadone/other)
•
Maternal concurrent use of benzodiazepines, antidepressants, or
gabapentin (polypharmacy [yes/no]);
The minimization method is planned in order to maximize the balance of each 
stratification variable as well as the overall treatment balance across arms in a 2:1 
ratio, considering the planned sample size. This method achieves a greater level of 
balance across multiple stratification variables compared to a traditional stratified 
randomization 
Babies will be centrally assigned to one of the two treatment arms on randomization 
through an IRT system (Interactive Response Technology, combination of voice and 
web response system and also referred as IVRS/IWRS). 
Following 2 consecutive FNAST with a sum ≥ 12, if all eligibility criteria except for 
Inclusion Criterion #5 are met, then babies will be pre-randomized in the IRT system 
to ensure treatment is available should Inclusion Criterion #5 be met (i.e. the sum of 3 
consecutive FNAST scores ≥ 24 or a single score ≥12). 
The IRT will allocate the patient to a certain treatment group using biased coin 
application of the Pocock and Simon minimization algorithm and assign the study 
medication kit number corresponding to the babies’ treatment group. IRT 
specifications will be fully described in a specific document. The IRT will also 
generate a confirmation after every IRT transaction is performed. 
The patient will be identified by a unique number of six digits: the investigational site 
number will be the first three digits and the following three digits will be the 
progressive numbering of the patient within each site (e.g. 101001, 101002 etc.). 
1.6 
INTERIM ANALYSIS 
No interim analyses are foreseen. 
1.7 
SOFTWARE 
SAS version 9.4 or later will be used for programming. 
1.8 
VALIDATION MODEL 
 – Clinical Research statistics (STAT) standard 
operating procedures (SOPs) and work instructions (WIs) as effective at the project 
start will be followed throughout the project, provided the applicable regulatory 
requirements are still met. 


P a ge 1 3 of 4 4 
T he  a nal ysis ta bles /listi n gs will be vali date d acc or di n g t o m o del B (re vie w b y a n 
i n de pe n de nt pers o n; see 
). 
I n a d diti o n, t he vali dati o n pr ocess f oll o we d f or t his st u d y is s u mmarize d  i n t he Q C 
pla n. 


P a ge 1 4 of 4 4 
2.
E F FI C A C Y  A N D P H A R M A C O KI N E TI C
A N A L Y S E S
2. 1  
P RI M A R Y E F FI C A C Y E N D P OI N T  
Acc or di n g t o t he pr ot o c ol, t he pri mar y efficac y e n d p oi nt of t his st u d y is: 
•
D urati o n of treat me nt defi ne d as t he n u m ber of h o urs fr o m first d ose of
st u d y dr u g a d mi nistrati o n u ntil t he last d ose of st u d y dr u g.
2. 1. 1  
Deri v ati o n r ules  
D urati o n of treat me nt ( h o urs) = dat e/ti me of last st u d y dr u g a d mi nistrati o n – 
date/ti me of first st u d y dr u g a d mi nistrati o n  
2. 1. 2  
Prese nt ati o n of res ults  
All data rele v a nt t o t he pri mar y efficac y e n d p oi nt will be liste d.  
2. 2  
S E C O N D A R Y E F FI C A C Y E N D P OI N T S  
Acc or di n g t o t he pr ot o c ol, t he sec o n dar y effi cac y e n d p oi nts of t his st u d y are: 
•
Ti me t o first wea ni n g, defi ne d as t he n u m ber of h o urs fr o m first d ose of
st u d y dr u g a d mi nistrati o n u ntil t he first d ose re du cti o n
•
Re q uire me nt f or a dj u ncti ve dr u g t hera p y ( p he n o b ar bital) f or si g ns of
N O W S
•
T otal h o urs of treat me nt wit h a dj u ncti ve t hera p y
•
Re q uire me nt f or r esc u e d oses ( C H F 6 5 6 3 or m or p hi ne)
•
N u m ber of r esc ue d os es a d mi nistere d per n e o nate
•
Perce nta g e of t otal a m o u nt of acti ve st u d y dr u g w hic h is fr o m resc u e
d oses
•
Le n gt h of o pi oi d relate d h os pital sta y, defi ne d as n u m ber of da ys fr o m
da y of birt h u ntil 4 8 h o urs after t he fi nal d ose of dr u g treat me nt f or
N O W S
•
Rela pse of N O W S, defi n e d as e x perie nci n g rec urre nce of si g nif ica nt
si g ns of wit h dra wal
•
I n ci de nce of r ea d missi o ns, defi ne d as rea d missi o n t o h os pital f or
N O W S rela ps e


Page 15 of 44 
2.2.1 
Available data 
The following parameters are collected per study visit or on the study termination 
form: 
•
Date/time of first dose reduction of study drug (SUPPDS.QVAL when
SUPPDS.QNAM is ‘FDREDDTC’)
•
Requirement for adjunctive drug therapy (phenobarbital): yes/no
(SUPPSV.QVAL when SUPPSV.QNAM is ‘PHENOBAR’)
Note: Only adjunctive drug therapy during the treatment period will be
considered.
•
Requirement for rescue doses: yes/no (SUPPSV.QVAL when
SUPPSV.QNAM is ‘RESCUEDO’)
Note: only rescue doses during the treatment phase will be considered.
•
Escalation of opioid withdrawal: yes/no (FA.FASTRESC = ‘Y’ when
FA.FAOBJ is ‘ESCALATION OF OPIOID WITHDRAWAL’ and
FA.FATESTCD is ‘EVIDENCE’)
•
Readmission to hospital: yes/no (FA.FASTRESC = ‘Y’ when
FA.FAOBJ is ‘ESCALATION OF OPIOID WITHDRAWAL’ and
FA.FATESTCD is ‘READHOSP’)
2.2.2 
Derivation rules 
•
Time to first weaning (hours) = date/time of first dose reduction –
date/time of first study drug administration
Note: missing data will not be imputed.
•
Number of rescue doses administered = sum of rescue dose
administrations (SUPPEC.QVAL = ‘Y’ when SUPPEC.QNAM is
‘RESCUEDO’)
Note: 0 for subjects not requiring rescue doses.
2.2.3 
Inferential statistics 
No inferential statistics will be performed. 
2.2.4 
Presentation of results 
All data relevant to the following primary and secondary efficacy endpoints will be 
listed: 
•
Duration of treatment
•
Time to first weaning
•
Requirement for adjunctive drug therapy
•
Number of rescue doses
•
Relapse of NOWS


Page 16 of 44 
2.3 
PHARMACOKINETICS 
2.3.1 
Available data 
Blood samples will be collected for the determination of CHF6563 at the time points 
indicated in the schedule of assessments (see section 9.1). 
2.3.2 
Presentation of results 
Individual CHF6563 blood concentrations and actual blood sampling times from drug 
administration for PK assessments will be listed. 


P a ge 1 7 of 4 4 
3.
S A F E T Y A N A L Y S E S
3. 1  
A D V E R S E E V E N T S  
3. 1. 1  
A v ail a ble d at a  
A d verse e ve nts ( A Es ) ar e c o de d i nt o s yste m or ga n classes a n d preferre d ter ms usi n g 
t he me dical dicti o nar y f or re g ulat or y acti vities ( M e d D R A). F or eac h A E, st art a n d 
st o p date(ti me)s ar e c ollecte d as well as s e verit y, a seri o us ness fla g, treat me nt-
relate d ness, acti o n ta ke n t o war ds t he st u d y dr u g a n d o utc o me. 
3. 1. 2  
Deri v ati o n r ules  
Pre -treat me nt A Es ar e defi ne d as  A Es starti n g bet wee n dat e(ti me) of i nf or me d 
c o nse nt a n d t he dat e(ti me) of first st u d y dr u g a d mi nistrati o n – 1 mi n ute. 
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A E) are d efi ne d as  A Es st arti n g o n or after 
first a d mi nistrati o n  of a n y st u d y dr u g. 
Peri - d osi n g T E A Es ar e d efi ne d as A Es  i n cl u de d i n t he list bel o w occ urri n g d uri n g or 
s h ortl y after st u d y dr u g a d mi nistrati o n, i.e. wit hi n 1 0 mi n utes fr o m t he start of st u d y 
dr u g a d mi nistrati o n: 
•
m o ut h irritati o n or i nfla m mati o n,
•
a p nea, d esat urati o n,
•
bra d y/tac h ycar dia,
•
c o u g h,
•
i m me diate s wall o wi n g of s u bli n g ual dr u g,
•
re g ur gitati o n,
•
v o miti n g occ urri n g after a d mi nistrati o n.
N ote: t he list of preferre d ter ms t o be selecte d as p eri- d osi n g T E A Es
will be fi nalize d pri or t o data base l oc k a n d d oc u m e nte d i n t he D R R. F or
A Es start  dates  wit h missi n g ti me i nf or mati o n w here n o ot her d ata base
i nf or mati o n i n dicates t hat A E starte d o utsi de t he p eri- d osi n g i nter val,
t he w orst-cas e pri nci ple will be a p plie d a n d t hese A Es will be
c o nsi dere d as peri - d osi n g.
P ost- treat me nt A Es ar e d efi ne d as A Es st arti n g o n or after t h e start of t he f oll o w- u p 
p hase.  
Base d o n t heir start date(ti me), A Es will be all ocate d t o t he p hase d uri n g w hic h t he y 
starte d. P hases are defi ne d i n secti o n 5. 2. 1 . I n case t he A E start date(ti me) is 
i nc o m plete or missi n g  a n d t he A E c o ul d c o nse q u e ntl y be all ocate d t o m ore t ha n o ne 
p hase , a w orst-cas e all ocati o n will be d o ne as detaile d bel o w: 
•
Treat me nt p has e vs. n o n- treat me nt p hase: A E will be all ocate d t o t he
treat me nt p hase u nl ess t he a vaila ble p arts of t he A E st o p date(ti me)
pr o vi de e vi de nce f or all ocati n g t o t he n o n- treat me nt p hase.
A fatal A E is defi ne d as a n A E wit h o utc o me ‘fat al’. 
A n A E f or w hi c h t he st u d y dr u g was disc o nti n ue d is defi ne d as a n A E wit h acti o n 
ta ke n ‘ dr u g wit h dr a w n ’. 


Page 18 of 44 
AE onset and duration will be calculated as follows when start and stop dates are 
fully known: 
•
AE onset day (vs. first administration) =
o
AE start date < date of first administration: AE start date – date of first
administration
o
AE start date ≥ date of first administration: AE start date – date of first
administration + 1 day
•
AE duration (rounded as detailed in section 5.3.3) =
o
In minutes: AE end date/time – AE start date/time + 1 minute
o
In hours: AE end date/time – AE start date/time + 1 hour
o
In days:
-
AE end date – AE start date + 1 day
-
study discontinuation date – AE start date + 1 day (when the AE
start date is fully known but the AE is not resolved at the end of the
study)
In this case the duration will be presented as “>x days”.
Note: If AE duration is less than 1 hour, the duration will be presented in 
minutes. If the AE duration is 1 hour or more, but less than 1 day, it will be 
presented in hours. If AE duration is 1 day or more, it will be presented in 
days. 
3.1.3 
Presentation of results 
Tables will present TEAEs and post-treatment AEs only. Pre-treatment AEs will only 
be listed. 
An overview table will show the number and percentage of subjects with at least one 
event and the number of events by treatment for the following: 
•
TEAEs
•
Serious TEAEs
•
Non-serious TEAEs
•
ADRs
•
Serious ADRs
•
Severe TEAEs
•
TEAEs leading to study drug discontinuation
•
TEAEs leading to death
•
Peri-dosing TEAEs
•
ADRs leading to study drug discontinuation
•
ADRs leading to death
•
Peri-dosing ADRs
•
Post-treatment AEs
All AEs, including pre-treatment events and all coding information will be listed. 
AEs started after date of last study medication intake will be flagged. Blank system 
organ classes and preferred terms, if any will be shown as ‘Not Available’. 


P a ge 1 9 of 4 4 
3. 2  
C LI NI C A L L A B O R A T O R Y E V A L U A TI O N  
3. 2. 1  
A v ail a ble d at a  
Per pr ot oc ol, t he f oll o wi n g la b orat or y para meters are e x p ecte d: 
•
Bi oc he mistr y: p otassi u m, s o di u m, ma g nesi u m, p h os p h or us, C- reacti ve
pr otei n, urea nitr o g e n, calci u m, creati ni ne, gl uc os e, bilir u bi n (t otal
ser u m bilir u bi n), bilir u bi n ( direct or c o nj u gate d)
•
He mat ol o g y: re d bl o o d cells c o u nt, he mat ocrit, t otal he m o gl o bi n, w hite
bl o o d cells c o u nt, a bs ol ute ne utr o p hils c o u nt, ne utr o p hils c o u nt %,
a bs ol ute l y m p h oc ytes c o u nt, l y m p h oc ytes c o u nt %, a bs ol ute m o n oc ytes
c o u nt, m o n oc ytes c o u nt %, a bs ol ute e osi n o p hils c o u nt, e osi n o p hils
c o u nt %, a bs ol ute bas o p hils c o u nt, bas o p hils c o u nt %, platelets c o u nt
•
Li ver f u ncti o n: ala ni ne a mi n otra nsferas e ( A L T) a n d as partate
a mi n otra nsfer ase ( A S T)
N or mal ra n g es ar e a vaila ble as pr o vi de d b y t he la b orat or y. 
3. 2. 2  
Deri v ati o n r ules  
•
T he f oll o wi n g a b n or malit y cate g ories will be d efi ne d:
o
L o w: val ue < l o wer li mit of n or mal ra n g e
o
N or mal: l o wer li mit of n or mal ra n ge ≤ v al ue ≤ u p per li mit of n or mal
ra n ge
o
Hi g h: val ue > u p per li mit of n or mal ra n g e
N ote:  classificati o n will be d o ne i n sta n dar di ze d u nits , usi n g n o n-i m p ute d 
val ues a n d n or mal r a n ges. 
3. 2. 3  
Prese nt ati o n of res ults  
T he res ults will be pres e nte d i n sta n dar dize d u nits. 
All la b orat or y data will be liste d . 


P a ge 2 0 of 4 4 
3. 3  
V I T A L SI G N S 
3. 3. 1  
A v ail a ble d at a  
T he f oll o wi n g vital si g ns para meters are c ollect e d:  
•
Vital si g ns: heart rate ( H R), res pirat or y rate ( R R), peri p heral o x y ge n
sat urati o n ( S p O 2), b o d y t e m perat ure ( B T), s yst olic ( S B P) a n d diast olic
bl o o d press ure ( D B P)
•
Hea d cir c u mfere nce, b o d y wei g ht a n d b o d y le n gt h.
3. 3. 2  
Deri v ati o n r ules  
T he f oll o wi n g vital si g ns para meters will be deri v e d:  
•
Hea d cir c u mfere nce perce ntile
•
B o d y wei g ht perce ntile
•
B o d y le n gt h perce ntile
N ote: t he hea d circ u mfere nce, b o d y w ei g ht a n d b o d y le n gt h perce ntiles
will be calc ulated b ase d o n t he U ni versit y of Cal g ar y Fe nt o n Pre- ter m
Gr o wt h C harts f or b a bies u p t o 5 0 wee ks of gest ati o nal a ge. If a ba b y
re mai ns i n t he st u d y be y o n d 5 0 wee ks of g estati o nal a ge, t he W H O
gr o wt h sta n dar ds ca n be use d  f or t he calc ulati o n of t he perce ntiles.
•
Mea n Bl o o d Press ure ( M B P) ( m m H g) = ( S B P + 2 * D B P)/ 3
3. 3. 3  
Prese nt ati o n of res ults  
-
Vital si g ns:
All vital si g ns ( H R, R R, S p O 2, B T, D B P, S B P, M B P) data will be liste d.
-  
Hea d cir c u mfere nce, b o d y wei g ht a n d b o d y le n gt h:
All hea d circ u mfer e nce, b o d y wei g ht a n d b o d y le n gt h  data (i ncl u di n g t he perce ntiles) 
will be liste d.  


P a ge 2 1 of 4 4 
3. 4  
E S C A L A TI O N O F O PI OI D WI T H D R A W A L  
3. 4. 1  
A v ail a ble d at a  
T he f oll o wi n g si g ns of es calati o n of o pi oi d wit h dra wal are c ollecte d:  
•
Cr yi n g - e xcessi ve / c o nti n u o us
•
Persiste nt i na bilit y t o slee p
•
Tre m ors a n d jer ks
•
S weati n g
•
Fe ver
•
M ottli n g
•
Nasal st uffi ness
•
S neezi n g
•
P o or Fee di n g
•
Re g ur gitati o n
•
Pr ojectile v o miti n g
•
L o ose st o ols
•
Water y st o ols
3. 4. 2  
Prese nt ati o n of res ults  
All a vaila ble i nf or mati o n c o ncer ni n g escal ati o n of o pi oi d wit h dra wal will be liste d.  
3. 5  
P H Y SI C A L E X A MI N A TI O N S  
A b n or mal p h ysical e x a mi nati o n fi n di n gs will be liste d. 
3. 6  
N E U R O L O GI C A L A N D B E H A VI O R A L A S S E S S M E N T  
A b n or mal ne ur ol o gical a n d be ha vi oral e x a mi nati o n fi n di n gs will be liste d.  


Page 22 of 44 
4.
GENERAL CHARACTERISTICS ANALYSES
4.1 
SUBJECT DISPOSITION 
The following subject data will be tabulated: 
•
The number of screen failures overall
•
The number of subjects in each analysis set by treatment and overall
•
The number and percentage of subjects for each analysis visit included
in the list below by treatment and overall
o
Screening
o
Day 1
o
Every 5 days of the treatment phase (Day 5, Day 10, Day 15, ...)
o
Day of last dose
o
End of treatment visit
•
The number and percentage of subjects who entered, completed or
discontinued each study phase (initiation, escalation, stabilization,
weaning and cessation)
•
The number and percentage of subjects who completed or discontinued
the study as documented on the study termination page and the number
and percentage of subjects for each study discontinuation reason by
treatment and overall
All information collected in the CRF concerning allocation, code breaking, study 
discontinuation and information on phases, dates of first signed informed consent, last 
visit and last contact (over the whole study) and comments will be listed. 
4.2 
PROTOCOL DEVIATIONS AND ELIGIBILITY 
The number and percentage of subjects with major and minor protocol deviations, per 
category and type, will be tabulated separately, by treatment and overall. 
All available information concerning protocol deviations, violations on eligibility 
criteria (only violated eligibility criteria having DV.DVDECOD = 'VIOLATION OF 
INCLUSION CRITERION' or 'VIOLATION OF EXCLUSION CRITERION') will 
be listed. 


P a ge 2 3 of 4 4 
4. 3  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S  
4. 3. 1  
A v ail a ble d at a  
T he f oll o wi n g para m eters will be a vaila ble:  
•
M ot her de m o gra p hics : race, et h nicit y a n d mater nal c haracteristics as
c ollecte d i n t he e C R F
•
M ot her dr u g scr ee n
•
De m o gra p hics: gestati o n al a ge, se x, race, et h nicit y,  date of birt h, a n d
date of si g ni n g i nf or me d c o nse nt f or m (I C F), mater nal s m o ki n g, alc o h ol
c o ns u m pti o n, m o de of deli ver y, fa mil y hist or y of pr ol o n ge d Q Tc
s y n dr o me, u ne x plai ne d s u d de n deat h i n ot her wis e healt h y fa mil y
me m bers a n d A P G A R sc ore
•
Scree ni n g tests: hea d circ u mfere n ce, w ei g ht , le n gt h a n d vital si g ns , dr u g
scree n
•
Baseli ne c har acteristics: pri mar y fee di n g met h o d, fee di n g t y pe at
ra n d o mizati o n, mater n al pri mar y o pi oi d use ( b u pre n or p hi ne /
met ha d o ne / ot her) a n d use of ot her licit a n d illicit dr u gs, mater nal
c o nc urr e nt use of b e nz o diaze pi nes, a nti de pressa nts or ga ba pe nti n
( p ol y p har mac y)
•
Fee di n g stat us: nas o gastric fee d (e ntire, p artial, n o), t y pe ( mater n al
breast mil k o nl y, f or m ula or d o n or breast mil k, mi xe d), breast fe d
( Y/ N), esti mate d v ol u me of mater nal breast mil k d uri n g breast fee d
( m L), v ol u me of mater n al breast mil k gi ve n b y b ottle ( m L) a n d v ol u me
of f or m ula ( m L)
•
F N A S T sc or e s
4. 3. 2  
Deri v ati o n r ules  
T he f oll o wi n g vital si g ns para meter will be deri v e d:  
•
Mea n Bl o o d Press ure ( M B P) ( m m H g) = ( S B P + 2 * D B P)/ 3
4. 3. 3  
Prese nt ati o n of res ults  
M ot her de m o gra p hics a n d dr u g scree n will o nl y be liste d.  
De m o gra p hics will be pr ese nte d  b y treat me nt a n d o verall usi n g descri pti ve statistics 
f or a ge, h ea d circ u mf ere nce, wei g ht , a n d fre q u e n c y ta b ulati o ns f or se x, race, 
et h nicit y, mater nal s m o ki n g, a n d alc o h ol c o ns u m pti o n. 
Baseli ne c har acteristics ( p ri mar y fee di n g met h o d, fee di n g t y pe at ra n d o mizati o n, 
mater nal pri mar y o pi oi d use ( b u pre n or p hi ne / met ha d o ne / ot her) a n d use of ot her 
licit a n d illicit dr u gs, mater nal c o n c urre nt use of b e nz o diaze pi nes, a nti de pressa nts or 
ga ba pe nti n ( p ol y p har mac y)) will be pres e nte d b y treat me nt a n d o v erall usi n g 
fre q ue n c y ta b ulati o ns. 
F N A S T sc or es will be s u m marize d b y mea ns of d escri pti ve statistics at bas eli ne  o nl y 
(as defi ne d i n s ecti o n 5. 2. 2 ) b y treat me nt. 
Fee di n g stat us will be pr ese nte d b y treat me nt at F oll o w - u p Da y 7, Wee k 2, a n d Wee k 
6 usi n g descri pti ve statistics f or esti mate d v ol u me of mater nal breast mil k d uri n g 


P a ge 2 4 of 4 4 
breast fee d, v ol u me of m ater nal br east mil k gi ve n b y b ottle a n d v ol u me of f or m ula 
a n d fre q u e nc y ta b ul ati o ns f or nas o gastric fee d, t y pe a n d breast fe d. 
I n a d diti o n, t he f oll o wi n g para met ers will be pres e nte d b y treat me nt a n d o verall usi n g 
descri pti ve statistics:  
•
hea d  cir c u mfer e nce, wei g ht a n d le n gt h at Scree ni n g
•
vital si g ns at S cree ni n g
All de m o gra p hic data, b aseli ne c haracteristics , fee di n g stat us a n d F N A S T s c ores  a n d 
scree ni n g tests ( e xce pt w he n liste d i n t he safet y part, i.e. hea d circ u mfere nce, wei g ht , 
le n gt h a n d vital si g ns) will be liste d.  
4. 4  
M
E DI C A L HI S T O R Y A N D C O N C O MI T A N T DI S E A S E S  
4. 4. 1  
A v ail a ble d at a  
Me dical hist or y a n d c o n c o mita nt diseases fi n di n gs are c o d e d usi n g t he me dical 
dicti o nar y f or r e g ulat or y acti vities ( Me d D R A) i nt o s yste m or ga n classes a n d 
preferre d t er ms. F or eac h fi n di n g ( M H. M H C A T is ‘ G E N E R A L M E DI C A L 
HI S T O R Y’) , a start a n d st o p date or o n g oi n g fla g is c ollecte d. 
4. 4. 2  
Deri v ati o n r ules  
T he f oll o wi n g para m eters will be deri ve d: 
•
Me dical hist or y fi n di n g: n ot o n g oi n g at scree ni n g ( M H. M H E N R T P T is
‘ B E F O R E’)
•
C o nc o mi ta nt disease fi n di n g: still o n g oi n g at scree ni n g
( M H. M H E N R T P T is ‘ O N G OI N G’ or missi n g)
4. 4. 3  
Prese nt ati o n of res ults  
Me dical hist or y a n d c o n c o mita nt diseases will be ta b ulate d se paratel y  b y treat me nt 
a n d o verall. E ac h ta ble will s h o w: 
•
T he n u m ber a n d p erce nta ge of s u bjects wit h a n d wit h o ut fi n di n gs
•
T he n u m ber a n d p erce nta ge of s u bjects wit h fi n di n gs b y s yste m or ga n
class a n d preferre d ter m
All me dical hist or y a n d c o nc o mita nt diseases data will be liste d se paratel y.  
4. 5  
P R O C E D U R E S A N D M
E DI C A TI O N S  
4. 5. 1  
A v ail a ble d at a  
All pr oce d ur es ar e c o de d i nt o s yste m or ga n classes a n d preferre d ter ms usi n g t he 
me dical dicti o nar y f or re g ulat or y acti vities ( Me d D R A). F or eac h pr oce d ure start a n d 
st o p date(ti me)s or o n g oi n g fla g ar e c ollecte d.  
All me dicati o ns  are c o de d usi n g W H O-D R U G. A T C selecti o n is perf or me d. A T C 
c o di n g u p t o le vel 5 is a vaila ble i n t he cli nical dat a base. F or eac h me di cati o n, a start 
date (ti me) a n d st o p dat e(ti me) or o n g oi n g fla g are c ollecte d. 


P a ge 2 5 of 4 4 
4. 5. 2  
Deri v ati o n r ules  
Base d o n t heir start a n d st o p date(ti me), pr oce d ures a n d me dicati o ns will be all ocate d 
t o eac h p has e d uri n g w hi c h t he y were perf or me d/ a d mi nistere d. A 
pr oce d ur e/ me dicati o n ca n t heref or e be re p orte d i n m ore t ha n o ne p has e.  
P hases are d efi ne d i n secti o n 5. 2. 1 . Pr oce d ures/ me dicati o ns wit h ( partiall y) missi n g 
dates will be all ocate d t o eac h p h ase u nless t he a v aila ble parts of t he 
pr oce d ur e/ me dicati o n start or st o p date(ti me) pr o vi de e vi de nce t hat t he 
pr oce d ur e/ me dicati o n w as n ot ta ke n d uri n g t hat p hase. 
Base d o n t heir start a n d st o p date(ti me) pr oce d ures a n d me dicati o ns will be all ocate d 
t o o ne of t he f oll o wi n g cate g ories: 
•
Pri or: t he pr oce d ur e/ me dicati o n st o p pe d pri or t o first st u d y dr u g
a d mi nistrati o n
•
Mai ntai ne d: t he pr oce d ure/ me dicati o n starte d bef ore first st u d y dr u g
a d mi nistrati o n a n d was o n g oi n g at first st u d y dr u g a d mi nistrati o n
•
C o nc o mita nt: t he pr oce d ure/ me dicati o n starte d at or after first st u d y
dr u g a d mi nistrati o n
•
P ost- treat me nt: t he me dicati o n/ pr oce d ure starte d o n or after t h e start of
f oll o w- u p p hase
F or pr o ce d ur es/ me dicati o ns wit h ( partiall y) missi n g date(ti me)s n ot all o wi n g 
all ocati o n t o a n y of t he cate g ories, a w orst-case all ocati o n will be d o ne bas e d o n t he 
a vaila ble parts of  t he me dicati o n/ pr oce d ure start or st o p date(ti me) . T he 
me dicati o n/ pr oce d ure will be all ocate d t o t he first cate g or y all o we d b y t he a vaila ble 
data, acc or di n g t o t he f oll o wi n g or der: 
•
C o nc o mita nt
•
P ost- treat me nt
•
Mai ntai ne d
•
Pri or
N ote: t hese pr oce d ures/ m e dicati o ns will o nl y be all ocate d t o t he p hases t h at matc h t he 
w orst -cas e all ocat e d cate g or y.  
4. 5. 3  
Prese nt ati o n of res ults  
Pr oce d ures:  
T he n u m ber a n d p erce nta ge of s u bjects wit h pr oce d ures a n d t he n u m ber a n d 
perce nt a ge of s u bjects wit h pr oce d ures b y s yste m or ga n class a n d preferre d ter m 
al p ha beticall y s orte d will be ta b ulate d per cat e g or y ( pri or, mai ntai ne d, a n d 
c o nc o mita nt); b y treat me nt a n d o verall  ( pri or pr oce d ures o nl y). Bla n k s yste m or ga n 
classes, if a n y, will be s h o w n as ‘ N ot A vaila bl e’ i n t he ta bles. 
S u bjects ha vi n g m ore t ha n o ne pr oce d ure all ocate d t o t he sa me cate g or y wit hi n t he 
sa me treat me nt, s yste m or ga n class a n d preferre d t er m will be c o u nte d o nl y o nce. 
All pr oc e d ur es data will be liste d.  


P a ge 2 6 of 4 4 
Me dicati o ns:  
T he n u m ber a n d p erce nta ge of s u bjects wit h me dicati o ns a n d t he n u m ber a n d 
perce nt a ge of s u bjects wit h me dicati o ns b y a nat o mical mai n gr o u p (le vel 1), 
t hera pe utic s u b gr o u p (le v el 2), c he mical s u b gr o u p (le vel 4), a nd g e neri c ter m will be 
ta b ulate d per cate g or y ( pri or, mai ntai ne d, a n d c o n c o mita nt); b y treat me nt a n d o verall 
( pri or me dicati o ns o nl y). Bla n k A T C le vels, if a n y, will be s h o w n as ‘ N ot A vaila ble’ 
i n t he ta bles. 
S u bjects ha vi n g m ore t ha n o ne me dicati o n all ocat e d t o t he sa me cate g or y wit hi n t he 
sa me treat me nt, a nat o mical mai n gr o u p, t hera pe utic s u b gr o u p, c he mical s u b gr o u p, 
a n d ge neri c ter m will be c o u nte d o nl y o nce. 
All me dicati o ns data will be liste d.  
4. 6  
E X P O S U R E T O S T U D Y D R U G  
4. 6. 1  
A v ail a ble d at a  
F or eac h st u d y dr u g a d mi nistrati o n, t he dates  (ti me), t he prescri be d d ose, t h e act ual 
v ol u me a d mi nistere d , res c ue d ose fl a g a n d iss ues occ urre d d uri n g d osi n g will be 
rec or d e d. 
4. 6. 2  
Prese nt ati o n of res ults  
All e x p os ure data will be liste d.  


Page 27 of 44 
5.
GENERAL METHODOLOGY
5.1 
ANALYSIS SETS 
5.1.1 
Analysis sets 
The following analysis sets will be considered in the statistical analysis: 
Enrolled Set (ENR): 
all subjects for whom informed consent was signed 
Randomized Set (RND): 
all randomized subjects 
Safety Set (SAF): 
all randomized subjects who receive at least one dose of 
study drug 
Notes: 
•
Having signed an informed consent is defined as having a complete
informed consent signature date in the database.
•
Randomized is defined as having a randomization date in the database
or any information to confirm randomization.
•
Having received at least one dose of study drug is defined as having an
exposure date or any information confirming exposure present in the
database.
Unless stated otherwise, the SAF analysis set will be used for demographics and 
baseline characteristics tables. All listings will be presented for the Randomized Set, 
unless states otherwise in section 8.2. 
In case of local major protocol deviations, only the affected data at the specific time 
point will be excluded from the applicable analysis sets. 
5.1.2 
As planned versus as actual analysis 
For analyses done on the safety analysis set (excluding general characteristics 
analyses), the actual treatment of the subject will be considered. In addition, the 
actual treatment will be presented in the general and safety listings. 
For all other analyses, the planned treatment will be used. 
5.2 
PHASES AND TIME POINTS 
5.2.1 
Phases 
Adverse events, medications, and procedures will be allocated to phases. For 
assessments, the visit and time point labels indicated on the subject’s case report form 
(CRF) will be used to allocate to the correct treatment. 


Page 28 of 44 
Adverse events, procedures and medications: 
Phase 
Start 
End 
Screening 
Date of signing the ICF, with 
00:00 added as time part 
First administration date(time) – 
1 minute 
Treatment 
First administration date(time) 
Last administration date(time) + 
48 hours 
Follow-up 
End date(time) of treatment 
phase + 1 minute 
Date of last contact, with 23:59 
added as time part 
Per definition, and for each subject, the first phase starts on the date of the earliest 
available ICF signature, with 00:00 added as time part. The last available phase ends 
on the date of last contact, with 23:59 added as time part. 
All tables and listings will present treatments rather than phases. 
AEs, medications and procedures will be allocated to phases as described in sections 
3.1.2 and 4.5.2 respectively. 
In addition to the analysis phases described above, a subject will be considered to 
have entered a specific study phase based on the below definitions: 
•
Initiation phase: all subjects in the safety set
•
Escalation phase: all subjects receiving at least one dose higher than the
initial dose
•
Stabilization phase: all subjects who receive at least 2 consecutive doses
without escalation
Note: Subjects can skip the escalation phase and directly enter the
stabilization phase from the initiation phase.
•
Weaning phase: all subjects who receive at least one dose lower than the
previous
•
Cessation phase: all subjects reaching the cessation dose (i.e. between
90-110% of the initial dose for CHF6563 or < 0.025 mg/kg for
morphine) and having a decrease in dose frequency (only subjects
receiving CHF6563, i.e. dosing frequency is decreased q24 hours)
Note: in addition to the above definitions, other information present in SDTM 
(i.e. flags or visits present indicating that a subject has entered a specific 
phase) could be used to determine whether a subject entered a specific phase. 
A phase (and all subsequent phases previously entered by the subject) will be 
considered discontinued whenever a subject discontinues the study during that 
study phase. 
5.2.2 
Baseline and change from baseline 
The baseline value is a non-missing value before the first administration of any study 
drug. 
Unless otherwise specified, Screening will be used as the baseline measurement. In 
case there are no assessments/measurements at Screening, the baseline value will be 
set to missing. 


P a ge 2 9 of 4 4 
T he f oll o wi n g ta ble s u m marizes t he b aseli ne de fi niti o n f or eac h p ara met er: 
P ar a m eter  
B aseli ne  
Vital si g ns  
Scree ni n g  
Hea d cir c u mfere nce a n d b o d y wei g ht  
Scree ni n g  
Bi oc he mistr y, he mat ol o g y a n d li ver f u ncti o n  
Scree ni n g  
F N A S T sc or es  
Last n o n -missi n g val ue bef ore t h e first 
a d mi nistrati o n of a n y st u d y dr u g 
C ha n ge fr o m bas eli ne is defi ne d as: 
C ha n ge fr o m bas eli ne at ti me p oi nt t = val ue at ti me p oi nt t – baseli ne val ue.  
5. 2. 3  
Rel ati ve d a y  
Relati ve da ys ( D Y) will be calc ul ate d acc or di n g t o t he f oll o wi n g r ule: 
•
C o ncer ne d d ate < r ef ere n ce date: D Y = c o n cer n e d date – refere nce d ate
•
C o ncer ne d d ate ≥ refere n ce date: D Y = c o n cer n e d date – refere nce d ate
+ 1
T he ref er e nce d ate is t he date of first a d mi nistrati o n of st u d y dr u g 
5. 2. 4  
A n al ysis visits  
T he  a nal ysis will use t he visits i n dicate d o n t he s u bject’s C R F.  I n a d diti o n, t he vital 
si g ns assess me nts will be all ocate d t o a nal ysis ti me p oi nt wi n d o ws as defi n e d bel o w 
base d o n t he act ual ti me of t he assess me nt relati ve t o t he first d ose ( n ote: ti me p oi nts 
are n ot c ollecte d  o n t he s u bject’s C R F). 
T he scree ni n g val ue is t h e last a vaila ble a n d n o n- missi n g  val ue bef ore t he 
ra n d o mizati o n visit ( Da y 1). T his val ue c orres p o n ds t o t he scree ni n g visit, e xce pt i n 
case of retesti n g. Reas o n f or t his a p pr oac h is t he u se of retest res ults f or s u bject 
eli gi bilit y assess me nt. 
U nsc he d ule d assess me nts will n ot be use d i n t he a nal ysis u nless a n u nsc he d ule d 
assess me nt was d o ne t o r e place u n a vaila ble/ u n relia ble data. T h e decisi o n w het her a n 
u nsc he d ule d ass ess me nt s h o ul d be use d i nstea d of t he ori gi nal assess me nt will be 
ta ke n d uri n g t he data re vi e w meeti n g bef ore d ata b ase l oc k. T he s electi o n of t he 
u nsc he d ule d ass ess me nts t o be i ncl u de d i n t he a nal ysis i nstea d of t he ori gi nal 
assess me nts will be d o ne i n t he c orres p o n di n g A D a M d atasets usi n g a p pr o priate 
val ues f or A VI SI T( N) a n d A T P T( N). Har d c o di n g ( d oc u me nte d i n t he D R R  a n d b y a 
N ote t o File si g ne d off b y b ot h  
 a n d C hiesi Far mace utici S. p. A) will be 
i m ple me nte d i n t he i m pacte d a nal ysis pr o gra ms b y i ncl u di n g a c o m me nt. 
Baseli ne is defi ne d i n secti o n 5. 2. 2 . 
Sc he d ule d a n d u nsc h e d ule d assess me nts will be liste d. 
F oll o w- u p visits will be  s u m marize d at selecte d ti me p oi nts o nl y. All f oll o w- u p data 
will be  liste d. 
T he a nal ysis visit la bels will be assi g ne d usi n g t he f oll o wi n g r ules: 
•
All pla n ne d scree ni n g, re-scree ni n g, eli gi bilit y rec hec k, etc. visits
occ urr e d d uri n g t he scree ni n g p hase will be prese nte d as ‘ Scree ni n g’.


Page 30 of 44 
•
All planned visits occurred during a scheduled day, will be presented as
‘Day x’ (x = study day, e.g. ‘Day -1’, ‘Day 1’, etc.)
•
Early termination visits will be presented as ‘Early Termination’
•
Follow-up visits will be presented as ‘Follow-up’. In case recurrent
follow-up visits are planned, the label will include details of the
repeated follow-up (e.g. ‘Follow-up Day 1’, ‘Follow-up Week 2’, etc.)
•
Unscheduled visits that occurred during a planned visit day will be
presented with the same label as the planned visit (see rules above)
•
Unscheduled visits that occurred on a day different than a planned visit
will be presented as ‘Unscheduled’
•
Other visits not covered by the rules above will be presented using
similar labels to the ones used in SDTM (XX.VISIT)
5.3 
IMPUTATION AND ROUNDING RULES 
5.3.1 
Missing values 
Potential imputations of missing values will be discussed during the review of the 
data by the Chiesi team. Decisions on whether any imputation rules on missing values 
should be applied to the analysis will be fully documented in the DRR. 
5.3.2 
Values below or above a threshold 
Safety values expressed as below (or above) the limit of quantification will be 
imputed by the value of the quantification limit itself. 
PK concentrations below the quantification limit will be flagged as BLQ in the 
concentration listing. Listings will always show the non-imputed values. 
5.3.3 
Rounding of derived variables 
Derived variables will be rounded to the appropriate number of decimals at TLF 
level: 
•
Duration of treatment/adjunctive therapy (hours) will be presented with
1 decimal.
•
Time to weaning (hours) will be presented with 1 decimal.
•
Percentage of total amount of active study drug which is from rescue
doses will be presented with 1 decimal.
•
Percentiles will be presented with 1 decimal.
•
Mean blood pressure will be presented with 1 decimal.
•
PK concentrations will be presented with 3 significant digits except
values >1000, which will be presented without decimals.
•
AE duration will be presented with 1 decimal.
Rounding will be done using the round half away from zero tie-breaking rule (see 
Definition of terms). 
5.3.4 
Outliers 
No data will be excluded from the analysis. 


P a ge 3 1 of 4 4 
5. 4  
P R E S E N T A TI O N O F R E S U L T S  
5. 4. 1  
C alc ul ati o n of descri pti ve st atistics a n d perce nt a ges  
F or c o nti n u o us para meters, f ull descri pti ve statistics will o nl y be prese nte d if t here 
are at least 2 n o n- missi n g  o bser vati o ns. Alter nati v el y, o nl y t he n u m ber of n o n-
missi n g  data p oi nts a n d mea n ar e s h o w n. 
Descri pti ve  statistics will i ncl u de t he n u m ber of n o n- missi n g  data p oi nts, t he 
arit h metic mea n, t he sta n dar d de viati o n ( S D), t he me dia n, mi ni m u m a n d ma xi m u m.  
F or s pecific para meters, CI ma y b e re q u este d as well.  
F or all para meters e xce pt b o d y te m perat ure a n d hea d circ u mfere n ce,  mea n, me dia n, 
S D a n d CI will be prese nte d wit h o ne m ore deci mal place t ha n t he i n di vi d u al val ues. 
F or b o d y te m perat ure a n d hea d circ u mfere nce , mea n, me dia n, S D a n d CI will be 
prese nte d wit h o ne d eci mal place. Mi ni m u m a n d ma xi m u m will be prese nt e d wit h t he 
sa me n u m ber of d eci mal places t ha n t he i n di vi d ual val ues. 
F or e v e nt -t y pe dat a, t he de n o mi nat or will be all s u bjects i n t he a nal ysis set a n d p hase. 
All treat me nt s will be s h o w n, e ve n if n o e ve nts are prese nt. 
F or fre q ue n c y ta b ulati o ns, missi n g val ues will n ot be i ncl u de d i n t he de n o mi nat or 
c o u nt w he n c o m p uti n g p erce nt a ges. 
Perce nta g es will be s h o w n wit h o ne deci mal place.  
5. 4. 2  
Prese nt ati o n of tre at me nts  
T he f oll o wi n g treat me nt la bels will be use d i n t he ta bles  a n d listi n gs: 
•
C H F 6 5 6 3
•
M or p hi ne
A n o verall c ol u m n, t o s u m marize all s u bjects o ver treat me nts, will be prese nte d o nl y 
i n ta bles s h o wi n g data t hat are n ot affecte d b y t he st u d y dr u g. T he o verall c ol u m n will 
be s h o w n last. 
5. 4. 3  
Or deri n g i n t a bles a n d listi n gs  
If t he treat me nts are pres e nte d as col u m ns, ta bles will be s orte d b y a nal ysis visit a n d 
ti me p oi nt. Ot her wise, ta bles will be s orte d first b y treat me nt, t he n b y a n al ysis visit 
a n d ti me p oi nt. 
T he s orti n g of treat me nts will be ke pt as cl ose as p ossi ble t o t he st u d y desi g n: 
•
T he test treat me nt ( C H F 6 5 6 3) will be s h o w n first a n d t he n t he
refere nce treat me nt ( m or p hi ne)
All ta bles will be prese nt e d per tr eat me nt, u nless s pecifie d ot her wise.  
All listi n gs will be or dere d b y s u bject a n d t he n b y a nal ysis visit a n d ti me p oi nt 
(c hr o n ol o gicall y), u nless specifie d ot her wise.  
I n ta bl es s h o wi n g se veral para meters, eac h para meter will be gi n o n a ne w p a ge a n d 
para meters will be s orte d al p ha beticall y, wit hi n t he para m eter cate g or y if a p plica ble.  
5. 4. 4  
R a w S A S o ut p ut  
N ot a p plica ble.  


P a ge 3 2 of 4 4 
6.
C H A N G E S T O T H E P L A N N E D A N A L Y SI S
6. 1  
C H A N G E S T O T H E P L A N N E D A N A L Y SI S  
A t otal of 5 7 s u bjects were t o be r a n d o mize d i n or der t o o btai n 5 1 e val ua bl e s u bjects 
(secti o n 1. 4). As o nl y 7 s u bjects were ra n d o mize d t he st u d y o bjecti ves of t his st u d y 
will n ot be e val ua ble. N o statistical a nal ysis will be perf or me d o n t he c ollecte d data 
a n d n o data deri vati o n (i. e.: c ha n ge fr o m baseli ne) will be defi ne d i n t he prese nt S A P 
v 2. 0 ( e xce pt f or s o me saf et y para met ers). 
F or t he sa m e reas o ns t he f oll o wi n g a nal ysis sets pla n ne d i n t he st u d y pr ot oc ol, ha ve 
n ot bee n defi ne d i n s ecti o n 5. 1. 1: 
•
I T T s et,
•
P P set.
D urati o n of breast fee di n g will n ot be a nal yze d as state d i n t he C T P si nce t hese data are 
n ot c ollecte d at baseli ne. 
T he af ore me nti o ne d c ha n ges, f urt her detaile d i n secti o n 6. 3 , a n d descri be d i n detail i n 
t his S A P ( v 2. 0), will re place t he a nal ysis as pr o p ose d i n t he st u d y pr ot oc ol. 
6. 2  
C H A N G E S I N T H E C O N D U C T O F T H E S T U D Y  
T he cli nical trial C LI - 0 6 5 6 3 A A 1- 0 2 starte d wit h t he first o btai ne d si g ne d i nf or me d 
c o nse nt a n d e nr ol me nt o n 1 8 Dece m b er  2 0 2 0 a n d was ter mi nate d i n Fe br u ary 2 0 2 2 
d ue t o a ver y l o w recr uit me nt rate, t hat is 7 ne o nates i nstea d of pla n ne d 5 7 i n o ne year 
a n d after a l o n g set u p p h ase w hic h w as act u all y u ne x pecte d a n d far fr o m t he ori gi nal 
esti mates. It lea ds t o a pr ojecti o n of a n ot her 6 y ears t o c o m plete t he trial, t hat d oes n ot 
fit wit h acce pta bl e ti meli nes wit hi n t he C hiesi p ortf oli o de vel o p me nt. C o nse q ue ntl y, 
C hiesi has deci de d t o earl y ter mi nate t he trial.  
6. 3  
C H A N G E S T O T H E F I N A L S T A TI S TI C A L A N A L Y SI S P L A N  
I n t he t a ble bel o w, a detaile d descri pti o n of t he c h a n ges a n d t he i m pacte d s ecti o ns is 
pr o vi de d. 
S A P v er si o n 
n u m b er  
S A P v er si o n 
D at e 
( d d M M M y y y y) 
C h a n g e s  
Fi n al 1. 0  
0 7 M A Y 2 0 2 1  
N ot a p plica ble  
Fi n al 2. 0  
0 7 J UL 2 0 2 2 
C orrecti o n of t y p os, re p hrasi n g, a n d a d diti o n 
of clarificati o ns t hr o u g h o ut te xt. 
Secti o n ( List of A b bre viati o ns): 
•
Re m o val of a b bre vi ati o ns relate d
t o t he statistical a nal ysis t hat will
n ot be perf or m e d.
•
A d diti o n of F N A S T


Page 33 of 44 
Sections 1.3/4 (Study Design / Expected 
Sample Size) 
•
Aligned with protocol version
6.0.
•
Added note referring to protocol
for FNAST assessment
Section 1.8 (Validation Model) 
•
Adjusted to reflect that only
listings will be created, except
for the general subject
characteristics section of the
analysis.
Sections 2.1.1/2/3 (Derivation Rules / 
Inferential Statistics / Presentation of Results) 
•
Only a subset of the primary
efficacy endpoints will be
derived and no statistical
analysis will be performed.
Sections 2.2.2/3/4 (Derivation Rules / 
Inferential Statistics / Presentation of Results) 
•
No statistical analysis will be
performed.
•
Only listings will be created.
Sections 3.1.2/3 (Derivation Rules / 
Presentation of Results) 
•
Except for a summary table only
listings will be created.
•
Added worst-case derivation for
peri-dosing AEs.
Section 3.2.3 (Presentation of Results) 
•
Only listings will be created.
Sections 3.3.2/3 (Derivation Rules / 
Presentation of Results) 
•
Only listings will be created.
Sections 4.3.2/3 (Derivation Rules / 
Presentation of Results) 
•
Parameter duration of breast
feeding removed.
•
No figures will be created.
Section 4.5.3 (Presentation of Results) 


P a ge 3 4 of 4 4 
•
C orrecti o n: re m o val of
‘treat me nt se q u e nce’.
Secti o n 5. 1. 1 ( A nal ysis Sets) 
•
Re m o val of a nal ysis sets (I T T &
P P) t hat will n ot be use d d ue t o
re m o val of e g. effi cac y t a bles.
Secti o n 5. 2. 1 ( P hases) 
•
Re m o val of ‘fi g ures’.
Secti o n s 5. 3. 1/ 2 ( Missi n g Val ues / Val ues 
Bel o w or A b o ve a T hres h ol d) 
•
Re m o val of i m p utati o n r ules f or
efficac y a n al ysis.
Secti o n 5. 3. 3 ( R o u n di n g of Deri ve d Varia bl es) 
•
A d diti o n of r o u n di n g r ules f or
M B P a n d perce ntiles .
Secti o n 5. 3. 4 ( O utliers) 
•
Detecti o n a n d use of o utliers
re m o ve d as n ot nee de d f or t he
re mai ni n g a nal ysis parts.
Secti o n 5. 4. 1 ( Calc ulati o n of Descri pti ve 
Statistics a n d Perce nta ges)  
•
S pecificati o ns f or d escri pti ve
statistics of efficac y para meters,
p- val ues, a n d cr oss-ta b ul ati o ns
re m o ve d.
Secti o n 5. 4. 2/ 3 ( Prese ntati o n of Treat me nts / 
Or deri n g i n Ta bles, Fi g ures a n d Listi n gs) 
•
Refere n ce t o fi g ures re m o ve d.
Secti o n 5. 4. 4 ( Ra w S A S O ut p ut) 
•
Secti o n set t o ‘ n ot a p plica ble’.
Secti o n 6. 2 ( C ha n ges i n t he C o n d uct of t he 
St u d y) 
•
A d de d secti o n t o e x plai n t he
rati o nale f or t h e earl y
ter mi nati o n of t he st u d y.
Secti o n 8 ( List of Ta bles, Listi n gs a n d 
Fi g ures) 
•
U p date d list of o ut p ut i n li ne
wit h t he ne w sc o pe of t he
a nal ysis , u p date d titles w here


P a ge 3 5 of 4 4 
nee de d  a n d u p date d a nal ysis sets 
i n or der t o dis pla y as m u c h data 
as p ossi ble. 
Se cti o n 9. 1 ( S A S c o de) 
•
Re m o ve d as n o statistical
a nal yses are ke pt i n t he st u d y
t hat re q uire S A S e xa m pl e c o de.


Page 36 of 44 
7.
REFERENCES
ICH Topic E6(R2) Guideline for Good Clinical Practice – Step 4, 9 November 2016. 


P a ge 3 7 of 4 4 
8.
LI S T O F T A B L E S  A N D LI S TI N G S
8. 1  
T A B L E S
N u m ber  
Title  
A n al ysis 
Set  
T L Fs Li br ar y 
Te m pl ate 
N u m ber  
G E N E R A L C H A R A C T E RI S TI C S  
1 4. 1. 1. 1  
Scree n F ail ures ( R a n d o mize d  Set)  
E N R  
D S T 0 0 1  
Ta b ulati o n of c o m pleti o n/ disc o nti n uati o n a n d t he reas o n f or 
disc o nti n uati o n.  
1 4. 1. 1. 2  
Dis p ositi o n b y Tre at m e nt ( R a n d o mize d  Set)  
R N D  
D S T 0 0 2  
Ta b ulati o n of c o m pleti o n/ disc o nti n uati o n a n d t he reas o n f or 
disc o nti n uati o n.  
1 4. 1. 1. 3  
A n al ysis Sets ( R a n d o mize d  Set)  
R N D  
D S T 0 0 6  
Ta b ulati o n of t he n u m ber of s u bjects i n eac h of t he a nal ysis sets defi ne d 
i n t he S A P. 
1 4. 1. 1. 4  
Atte n d a nce at St u d y Visits ( R a n d o mize d  Set)  
R N D  
S V T 0 0 1  
Ta b ulati o n of t he n u m ber a n d perce nta ge of s u bjects t hat atte n de d t o 
eac h pla n ne d st u d y visit ( o nl y visits defi ne d i n secti o n 4. 1 ) b y treat me nt.  
1 4. 1. 1. 5  
Atte n d a nce at St u d y P h ases ( R a n d o mize d Set)  
R N D  
S V T 0 0 2  
Ta b ul ati o n of t he n u m ber a n d perce nta ge of s u bjects t hat e ntere d, 
c o m plete d or disc o nti n ue d eac h st u d y p hase (i nitiati o n, escalati o n, 
sta bilizati o n, wea ni n g a n d cessati o n). 
T he te m plate S V T 0 0 2 is use d re placi n g t he treat me nt peri o ds b y t he 
st u d y p hases. 
1 4. 1. 1. 6  
M aj or Pr ot oc ol De vi ati o ns ( S afet y Set)  
S A F  
D V T 0 0 1  
Ta b ulati o n of t he maj or pr ot oc ol de viati o ns (at least o ne), de viati o n 
cate g or y a n d de viati o n t y pe b y treat me nt a n d o verall.  
1 4. 1. 1. 7  
Mi n or Pr ot oc ol De vi ati o ns ( S afet y Set)  
S A F  
D V T 0 0 1  
Ta b ulati o n of t he mi n or pr ot oc ol de viati o ns (at least o ne), de viati o n 
cate g or y a n d de viati o n t y pe b y treat me nt a n d o verall.  
1 4. 1. 2. 1  
De m o gr a p hic C h ar acteristics ( S afet y Set)  
S A F  
D M T 0 0 1  
Descri pti ve statistics of c o nti n u o us para meters a n d fre q ue nc y ta b ulati o n 
of cate g orical para meters.  
1 4. 1. 2. 2  
B aseli ne C h ar acteristics ( S afet y Set) 
S A F  
D M T 0 0 1  
Fre q ue nc y  ta b ulati o n of baseli ne c haracteristics. 
1 4. 1. 2. 3  
F N A S T S c ores at B aseli ne ( S afet y Set) 
S A F  
B L T 0 0 1  
Descri pti ve statistics of F N A S T sc ores  at baseli ne . 
1 4. 1. 2. 4  
M ater n al S m o ki n g St at us ( S afet y Set)  
S A F  
S U T 0 0 1  
Fre q ue nc y ta b ulati o n of t he mater nal s m o ki n g stat us at scree ni n g.  
1 4. 1. 2. 5  
Fee di n g St at us ( S afet y Set)  
S A F  
B L T 0 0 1  
Descri pti ve statistics of c o nti n u o us para meters a n d fre q ue nc y ta b ulati o n 
of cate g orical para meters.  


 
 
 
Page 38 of 44 
 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
14.1.2.6 
Head Circumference and Weight at Screening (Safety Set) 
SAF 
BLT002 
 
Descriptive statistics of head circumference and weight at Screening. 
 
 
14.1.2.7 
Vital Signs at Screening (Safety Set) 
SAF 
BLT002 
 
Descriptive statistics of vital signs results at Screening. 
 
 
14.1.2.8 
Medical History (Safety Set) 
SAF 
MHT001 
 
Tabulation of the number and percentage of subjects with medical 
history findings and number and percentage of subjects with medical 
history findings by system organ class and preferred term. 
 
 
14.1.2.9 
Concomitant Diseases (Safety Set) 
SAF 
MHT001 
 
Tabulation of the number and percentage of subjects with concomitant 
diseases and number and percentage of subjects with concomitant 
diseases by system organ class and preferred term. 
 
 
14.1.2.10 
Prior Procedures (Safety Set) 
SAF 
MHT001 
 
Tabulation of the number and percentage of subjects with prior 
procedures and number and percentage of subjects with prior procedures 
by system organ class and preferred term. 
 
 
14.1.2.11 
Maintained Procedures (Safety Set) 
SAF 
MHT002 
 
Tabulation of the number and percentage of subjects with maintained 
procedures and number and percentage of subjects with maintained 
procedures by system organ class and preferred term. 
 
 
14.1.2.12 
Concomitant Procedures (Safety Set) 
SAF 
MHT002 
 
Tabulation of the number and percentage of subjects with concomitant 
procedures and number and percentage of subjects with concomitant 
procedures by system organ classes and preferred terms. 
 
 
14.1.2.13 
Prior Medications (Safety Set) 
SAF 
CMT001 
 
Tabulation of the number and percentage of subjects with prior 
medications and number and percentage of subjects with medications by 
ATC class (level 1), ATC class (level 2), ATC class (level 4) and 
preferred name. 
 
 
14.1.2.14 
Maintained Medications (Safety Set) 
SAF 
CMT001 
 
Tabulation of the number and percentage of subjects with maintained 
medications and number and percentage of subjects with maintained 
medications by ATC class (level 1), ATC class (level 2), ATC class 
(level 4) and preferred name. 
 
 
14.1.2.15 
Concomitant Medications (Safety Set) 
SAF 
CMT002 
 
Tabulation of the number and percentage of subjects with concomitant 
medications and number and percentage of subjects with concomitant 
medications by ATC class (level 1), ATC class (level 2), ATC class 
(level 4) and preferred name. 
 
 


 
 
 
Page 39 of 44 
 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
SAFETY 
 
ADVERSE EVENTS 
 
14.3.1.1 
Summary of TEAEs (Safety Set) 
SAF 
AET001 
 
Tabulation of the number and percentage of subjects with at least one of 
the events described in the SAP. The number of events will also be 
shown. 
 
 
 
 


 
 
 
 
P a ge 4 0 of 4 4 
 
8. 2  
L I S TI N G S 
N u m ber  
Title  
A n al ysis 
Set  
T L Fs Li br ar y 
Te m pl ate 
N u m ber  
G E N E R A L C H A R A C T E RI S TI C S  
 
1 6. 1. 7  
R a n d o miz ati o n  Sc he d ule ( R a n d o mize d  Set)  
R N D  
D S L 0 0 1  
 
Listi n g of s u bject n u m bers a n d ra n d o mizati o n i nf or mati o n  
All discre pa ncies (as -ra n d o mize d vers us as -treate d) will be prese nte d. 
 
 
1 6. 2. 1. 1  
Scree ni n g F ail ures  (R a n d o mize d  E nr olle d Set)  
E N R  
D S L 0 0 2  
 
Listi n g of all s u bjects t hat disc o nti n ue d after ra n d o mizati o n. T he st u d y 
disc o nti n uati o n reas o n will als o be liste d.  
 
 
1 6. 2. 1. 2  
St u d y Disc o nti n u ati o n After R a n d o miz ati o n  (R a n d o mize d  Set)  
R N D  
D S L 0 0 3  
 
Listi n g of all s u bjects t hat disc o nti n ue d after ra n d o mizati o n. T he st u d y 
disc o nti n uati o n reas o n will als o be liste d.  
 
 
1 6. 2. 1. 3  
S u bject Dis p ositi o n  (R a n d o mize d  Set)  
R N D  
D S L 0 0 4  
 
Listi n g of t he reas o ns f or c o m pleti o n / disc o nti n uati o n a n d t he n u m ber 
of da ys si nce first st u d y dr u g a d mi nistrati o n at st u d y disc o nti n uati o n. 
I n case t he disc o nti n uati o n was d ue t o A E, t he A E will be prese nte d i n 
t his listi n g. If t here is a n ot her e x pla nati o n o n t he disc o nti n uati o n reas o n 
c ollecte d i n t he C R F, t his will als o be pre se nte d i n t his listi n g. 
 
 
1 6. 2. 1. 4  
R a n d o miz ati o n  C o de Br o k e n  (R a n d o mize d  Set)  
R N D  
D S L 0 0 5  
 
Listi n g of t he c o de brea ki n g i nf or mati o n. O nl y s u bjects f or w hic h t he 
c o de was br o ke n are prese nte d i n t his listi n g.  
 
 
1 6. 2. 1. 5  
A n al ysis Set Dis p ositi o n  (E n r olle d Set)  
E N R  
D S L 0 0 6  
 
Listi n g of all s u bjects a n d a nal ysis set i n dicat ors.  
 
 
1 6. 2. 1. 6  
S u bject Dis p ositi o n: A n al ysis P h ases a n d Peri o ds (E nr oll e d Set)  
E N R  
D S L 0 0 8  
 
Listi n g of t he p hases a n d peri o ds i n t he st u d y t o get her wit h t he start 
a n d e n d date(ti me)s.  
 
 
1 6 . 2. 1. 7 
St u d y Visits  (E nr olle d Set)  
E N R  
S V L 0 0 1  
 
Listi n g per s u bject n u m ber of all s u bject visits, t o get her wit h t he start 
a n d e n d date of eac h visit. Listi n g is s orte d c hr o n ol o gicall y b y visit 
start date wit hi n eac h s u bject. 
 
 
1 6 . 2. 1.8  
First a n d L ast C o nt act i n t he St u d y ( E nr olle d Set ) 
E N R  
 
 
List of t he date of t he first si g ne d I C F, last visit date a n d last date of 
c o ntact i n t he st u d y. All dates are prese nte d o verall, n ot b y treat me nt.  
 
 
1 6 . 2. 2. 1 
Vi ol ati o n of Eli gi bilit y Criteri a  (E nr olle d Set)  
E N R  
D V L 0 0 1  
 
O nl y vi olate d i n - a n d e xcl usi o n criteria will be liste d. O nl y de viati o ns 
wit h D V D E C O D = “ VI O L A TI O N O F I N C L U SI O N C RI T E RI O N” or 
“ VI O L A TI O N O F E X C L U SI O N C RI T E RI O N” will be sele cte d.  
 
 
1 6 . 2. 2. 2 
Pr ot oc ol De vi ati o n  (E nr olle d Set)  
E N R  
D V L 0 0 2  
 
Listi n g of all pr ot oc ol de viati o ns i nf or mati o n  
 
 
1 6. 2. 4. 1  
De m o gr a p hic C h ar acteristics ( M ot her) (E nr olle d Set)  
E N R  
D M L 0 0 1  
 
Listi n g of all de m o gra p hic para meters.  
F or la y o ut p ur p oses, a te m plate prese nti n g para meters as r o ws rat her 
t ha n c ol u m ns c o ul d be use d i nstea d (si milar t o te m plate S C L 0 0 3). 
 
 


 
 
 
Page 41 of 44 
 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.4.2 
Urine Drug Screen (Mother) (Enrolled Set) 
ENR 
SCL003 
 
Listing of all results of urine drug screen tests performed. 
 
 
16.2.4.3 
Demographic Characteristics (Enrolled Set) 
ENR 
DML001 
 
Listing of all demographic parameters. 
For layout purposes, a template presenting parameters as rows rather 
than columns could be used instead (similar to template SCL003). 
 
 
16.2.4.4 
Baseline Characteristics (Enrolled Set) 
ENR 
SCL003 
 
Listing of all baseline characteristics. 
 
 
16.2.4.5 
FNAST Scores (Enrolled Set) 
ENR 
SCL003 
 
Listing of all FNAST scores results. 
 
 
16.2.4.6 
Drug Screen (Enrolled Set) 
ENR 
SCL003 
 
Listing of all results of urine, meconium and umbilical cord drug 
screen tests performed. 
 
 
16.2.4.7 
Maternal Smoking Status (Enrolled Set) 
ENR 
SUL001 
 
Listing of all smoking data available in the CRF 
 
 
16.2.4.8 
Feeding Status (Enrolled Set) 
ENR 
 
 
Listing of all feeding status data available in the CRF 
 
 
16.2.4.9 
Medical/Surgical History (Enrolled Set) 
ENR 
MHL001 
 
Listing of the medical history data findings available in the CRF 
 
 
16.2.4.10 
Concomitant Diseases (Enrolled Set) 
ENR 
MHL002 
 
Listing of the concomitant diseases data findings available in the CRF 
 
 
16.2.4.11 
Procedures (Enrolled Set) 
ENR 
PRL001 
 
Listing of all data on procedures 
 
 
16.2.4.12 
Medications (Enrolled Set) 
ENR 
CML001 
 
Listing of all data on medications 
 
 
16.2.4.13 
Comments (Enrolled Set) 
ENR 
COL001 
 
Listing of all remarks and comments written in the CRF 
 
 
16.2.5.1 
Exposure (Randomized Set) 
RND 
 
 
Listing per subject number of all data related to exposure 
 
 
 
PHARMACOKINETICS 
 
16.2.5.2 
Actual Sampling Times and Concentrations (Randomized Set) 
RND 
PCL001 
 
Listing per treatment, visit, subject and planned time point of actual 
blood sampling times and concentrations. 
 
 
EFFICACY 
 
16.2.6.1 
Primary Efficacy Endpoint: Full Listing (Randomized Set) 
RND 
SCL002 
 
Listing per subject number of all data related to the primary efficacy 
endpoint. 
 
 


 
 
 
Page 42 of 44 
 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.6.2 
Secondary Efficacy Endpoint: Time to First Weaning Full Listing 
(Randomized Set) 
RND 
SCL002 
 
Listing per subject number of all data related to the secondary efficacy 
endpoint: time to first weaning. 
 
 
16.2.6.3 
Secondary Efficacy Endpoint: Adjunctive Drug Therapy Full 
Listing (Randomized Set) 
RND 
SCL002 
 
Listing per subject number of all data related to the secondary efficacy 
endpoint: requirement for adjunctive drug therapy. 
 
 
16.2.6.4 
Secondary Efficacy Endpoint: Rescue Doses Full Listing 
(Randomized Set) 
RND 
SCL002 
 
Listing per subject number of all data related to the secondary efficacy 
endpoint: requirement for rescue doses, number of doses. 
 
 
16.2.6.5 
Secondary Efficacy Endpoint: Opioid Related Hospital Stay and 
incidence of Relapse of NOWS (Randomized Set) 
RND 
SCL002 
 
Listing per subject number of all data related to the secondary efficacy 
endpoints: hospital stay and relapse of NOWS. 
 
 
SAFETY 
 
ADVERSE EVENTS 
 
16.2.7.1 
Pre-Treatment Adverse Events (Enrolled Set) 
ENR 
AEL001 
 
Listing of all pre-treatment AE information collected in the CRF and of 
the onset day and duration. All information of one AE will be 
presented on the same line. 
 
 
16.2.7.2 
Treatment Emergent Adverse Events (Randomized Set) 
RND 
AEL002 
 
Listing of all AE information collected in the CRF and of the phase / 
period dates and onset day and duration. All information of one AE 
will be presented on the same line. 
 
 
16.2.7.3 
Serious Treatment Emergent Adverse Events (Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing serious TEAEs only. 
 
 
16.2.7.4 
Non-Serious Treatment Emergent Adverse Events (Randomized 
Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing non-serious TEAEs only. 
 
 
16.2.7.5 
Adverse Drug Reactions (Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing ADRs only. 
 
 
16.2.7.6 
Serious Adverse Drug Reactions (Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing serious ADRs only. 
 
 
16.2.7.7 
Severe Treatment Emergent Adverse Events (Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing severe TEAEs only. 
 
 
16.2.7.8 
Treatment Emergent Adverse Events Leading to Study Drug 
Discontinuation (Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing TEAEs leading to study drug 
discontinuation only 
 
 
 
 
 
 


 
 
 
Page 43 of 44 
 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.7.9 
Treatment Emergent Adverse Events Leading to Death 
(Randomized Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing TEAEs leading to death only 
 
 
16.2.7.10 
Post-Treatment Adverse Events (Randomized Set) 
RND 
AEL001 
 
Listing of all post-treatment AE information collected in the CRF and 
of the onset day and duration. All information of one AE will be 
presented on the same line. 
 
 
16.2.7.11 
Escalation of Opioid Withdrawal (Randomized Set) 
RND 
 
 
Listing of all data on escalation of opioid withdrawal 
 
 
16.2.7.12 
Physical Examination Abnormalities (Randomized Set) 
RND 
PEL001 
 
Listing of all data on abnormal physical examinations findings 
 
 
16.2.7.13 
Neurological and Behavioral Examination Abnormalities 
(Randomized Set) 
RND 
PEL001 
 
Listing of all data on abnormal neurological and behavioral 
examination findings. 
 
 
LABORATORY DATA 
 
16.2.8.1 
Laboratory Results: Hematology Full Listing (Enrolled Set) 
ENR 
LBL001 
 
Listing of all hematology results. The (non-imputed) values will be 
shown, as well as normal ranges, abnormality flags (L/H) and clinical 
significance flag. 
 
 
16.2.8.2 
Laboratory Results: Biochemistry Full Listing (Enrolled Set) 
ENR 
LBL001 
 
Same as listing 16.2.8.1 but listing biochemistry results instead. 
 
 
16.2.8.3 
Laboratory Results: Liver Function Full Listing (Enrolled Set) 
ENR 
LBL001 
 
Same as listing 16.2.8.1 but listing liver function results instead. 
 
 
VITAL SIGNS 
 
16.2.9.1 
Vital Signs: Full Listing (Enrolled Set) 
ENR 
VSL001 
 
Listing of all vital signs results. The values will be shown but no 
changes from baseline will be shown. 
 
 
16.2.9.2 
Vital Signs: Head Circumference, Body Weight and Length 
(Enrolled Set) 
ENR 
VSL001 
 
Listing of all head circumference, body weight and length results 
(including percentiles). The values will be shown but no changes from 
baseline will be shown. 
 
 
 
 


 
 
 
 
P a ge 4 4 of 4 4 
 
9.  
A P P E N DI C E S 
9. 1  
S C H E D U L E O F A S S E S S M E N T S