Clinical trial NCT02545127
Conditions: Preterm Delivery Inadequate Milk Production
Keywords: Inadequate Milk Production
Sponsor: Ferring Pharmaceuticals
Start date: 2021-05-28; Completion date: 2022-11-11
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Induction and support of lactation in women with preterm delivery and inadequate milk production.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Merotocin intervention 2: Placebo
Intervention descriptions: intervention 1: Merotocin nasal spray 400 μg/dose, 2 sprays with 1 spray in each nostril administered 6 to 8 times/day (Day 1 to Day 14). intervention 2: Placebo nasal spray, 2 sprays with 1 spray in each nostril administered 6 to 8 times/day (Day 1 to Day 14).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Cover page for Protocol 
 
 
Sponsor name 
Ferring Pharmaceuticals Inc. 
NCT Number: 
NCT02545127 
Sponsor trial ID: 
000050 
Official title of trial: 
A randomized, double-blind, placebo-controlled, 
multicenter trial exploring the efficacy and safety of 
intra-nasal administration of merotocin in increasing 
milk production in maternal subjects with preterm 
delivery and inadequate milk production 
Document Date:  
06 Apr 2022 
 
 
 
 
 


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Clinical Trial Protocol
Ferring Pharmaceuticals
CONFIDENTIAL
CLINICAL TRIAL PROTOCOL
A randomized, double-blind, placebo-controlled, multicenter trial exploring the efficacy and 
safety of intra-nasal administration of merotocin in increasing milk production in maternal 
subjects with preterm delivery and inadequate milk production
MERMAID
Merotocin in Mothers with Inadequate Milk Production and Infants Delivered Prematurely 
Trial 000050
IND Number:
105928
Investigational Medicinal 
Product:
Merotocin, FE 202767 (Selective oxytocin-receptor 
agonist, nasal spray)
Indication:
Induction and support of lactation in women with 
preterm delivery and inadequate milk production
Phase:
2
Name and Address of Sponsor:
Ferring Pharmaceuticals Inc.
100 Interpace Parkway
Parsippany, NJ 07054
United States
Tel: 
GCP Statement:
This trial will be performed in compliance with GCP.
The information in this document is confidential and is proprietary to Ferring Pharmaceuticals Inc. or another 
company within the Ferring Group. It is understood that information in this document shall not be disclosed to any 
third party, in any form, without prior written consent of an authorized officer of Ferring Pharmaceuticals Inc. or 
another company within the Ferring Group.


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SYNOPSIS
TITLE OF TRIAL
A randomized, double-blind, placebo-controlled, multicenter trial exploring the efficacy and 
safety of intra-nasal administration of merotocin in increasing milk production in maternal 
subjects with preterm delivery and inadequate milk production
SIGNATORY INVESTIGATOR
 MD, 
 
TRIAL CENTERS
Approximately 15 trial centers in the United States
PLANNED TRIAL PERIOD
Estimated First Patient First Visit:
Q4 2019
Estimated Last Patient Last Visit:
Q2 2023
CLINICAL PHASE
2
OBJECTIVES
Primary Objective

To evaluate the effect of merotocin on increasing milk production in women with preterm 
delivery and with inadequate milk production
Secondary Objectives

To evaluate the effect of merotocin on milk production after treatment discontinuation 

To evaluate the amount of mother’s own milk (MoM) in the infant enteral nutritional 
intake and changes in infant body weight

To evaluate any amount of merotocin from maternal plasma into the milk expressed by 
women with preterm delivery exposed to merotocin

To characterize the safety profile of merotocin in women with preterm delivery and their 
infants 
Exploratory Objective

To explore the relationship between merotocin exposure in maternal plasma and milk 
volume 

To evaluate composition of milk produced during treatment with merotocin in women 
with preterm delivery 


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Post-trial Objectives

To explore post-trial feeding patterns and key parameters of neonatal intensive care unit 
(NICU) hospitalization of infants from women with preterm delivery and inadequate milk 
production

To assess the post-trial long-term development of infants from women with preterm 
delivery and inadequate milk production
ENDPOINTS
Primary Endpoint

Volume of mother’s own milk produced over Days 1 to 14
Secondary Endpoints

Time to the first occurrence of a daily volume of MoM ≥500 mL and ≥750 mL

Proportion of maternal subjects with a daily volume of MoM ≥500 mL and ≥750 mL over
Days 1 to 14

Volume of MoM produced over Days 15 to 17 (after treatment discontinuation)

Volume of MoM fed to the infant over Days 1 to 14

Volume of formula/donor milk fed to the infant over Days 1 to 14

Merotocin concentration in milk produced at Day 3 and Day 10 visits

Changes in infant body weight over Days 1 to 14

Frequency and intensity of adverse events (AEs) in maternal subjects

Frequency and intensity of AEs in infants 

Changes in routine safety laboratory parameters in maternal subjects and proportion of 
subjects with markedly abnormal changes at Day 15/End-of-Treatment visit
Exploratory Endpoints

Merotocin concentration in maternal plasma at Day 3 and Day 10 visits

Composition of milk (including lipids, protein, caloric content, lactose, and Human Milk 
Oligosaccharides) produced by maternal subjects at Day 3 and Day 10 visits
Post-trial Endpoints

Time to tolerance of full (150 mL/kg/day) enteral feed of the infant

Time to NICU discharge of the infant

Number of days the infant requires total parenteral nutrition (TPN) until time of discharge 
from NICU

Proportion of maternal subjects who are lactating at time of infant’s discharge from NICU


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
Proportion of infants who are fed with MoM/formula/donor milk at time of discharge 
from NICU

Body weight, length, and head circumference of the infant at time of discharge from 
NICU

Incidence of infant’s morbidity events of special interest (including necrotizing 
enterocolitis (NEC), intra-ventricular hemorrhage, bronchopulmonary dysplasia (BPD), 
respiratory distress syndrome (RDS), late-onset sepsis, retinopathy of prematurity (ROP),
and hemodynamically significant patent ductus arteriosus) until time of discharge from 
NICU

Proportion of infants with an Ages and Stages Questionnaire-3 (ASQ-3) score in the black 
zone in any domain at 9 months, 18 months and 24 months of corrected gestational age
METHODOLOGY
This is a randomized, double-blind, placebo-controlled, multicenter trial exploring the efficacy 
and safety of intra-nasal administration of 400 µg merotocin in increasing milk production in 
women with preterm delivery and inadequate initial milk production.
The trial population consists of maternal subjects who have delivered a preterm singleton 
(gestational age from 24 weeks + 0 days to 34 weeks + 2 days), who wish to provide MoM to 
their infants but have inadequate initial milk production and who are willing to express milk at 
least 5 times every 24 hours during the observation period and 6 to 8 times every 24 hours during 
the treatment and post-treatment follow-up periods throughout the trial. No specific trial 
procedures are required for infants.
The trial consists of a screening period, a treatment period and a post-treatment follow-up period. 
In addition, there is a post-trial follow-up of infants.

Screening Period: The screening period starts from the signing of informed consent and 
ends at randomization, which occurs between 96 to 192 (+4) hours of delivery. The 
screening period must include an observation period of a minimum of 48 hours for the 
collection of milk expression data.

Treatment Period: Once the observation period is completed, eligible women will be 
randomized in a 1:1 ratio to receive either merotocin or placebo. The treatment period is 
14 days and includes visits on Days 3 and 10, as well as an End-of-Treatment visit on 
Day 15 or the day after the last dose of investigational medicinal product (IMP) in case of 
premature discontinuation.

Post-treatment Follow-up Period: The post-treatment follow-up period includes a Day 18/
Follow-up visit, scheduled 3 days after the Day 15/End-of-Treatment visit. 
Note that Day 3, Day 10, Day 15/End-of-Treatment and Day 18/Follow-up visits can all be 
postponed for a maximum of 2 days. 


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Trial Activities
Maternal subjects who provide informed consent for participation will enter the screening period 
as soon as possible following delivery. The screening period runs from the signing of informed 
consent to randomization and includes an observation period of a minimum of 48 hours for the 
collection of milk expression data. Maternal subjects should enter the observation period within 
144 hours of delivery as soon as the initial eligibility check has been completed and blood 
sampling for analysis of safety laboratory parameters has been performed. The observation 
period starts with the first milk expression session using the breast pump (i.e., pumping session) 
under supervision at the site. The observation period ends with the last pumping session at the 
trial center prior to randomization. Milk volume produced for the last 24 hours of the observation 
period (i.e., the 24-hour baseline interval) will be calculated to assess the inadequacy of milk 
production.
Throughout the trial, maternal subjects will be instructed to express milk; at least 5 times every 
24 hours during the observation period and 6 to 8 times every 24 hours during the treatment and 
post-treatment follow-up periods, including at least once during the night and with no more than 
5 hours between milk expression sessions (see milk expression procedures detailed later). Each 
session of milk expression will be recorded by subjects themselves every day. 
Before treatment on the day of randomization, a physical examination of eligible subjects will be 
performed and vital signs will be recorded. For the analysis of milk composition, if the volume of 
production is, at the discretion of the investigator, adequate to meet the nutritional needs of the
infant, a sample from the milk expressed prior to randomization will be obtained.
Randomization will occur between 96 and 192 (+4) hours of delivery. Every effort should be 
made to randomize maternal subjects as early as possible, but not earlier than 96 hours of
delivery. To be eligible for randomization, maternal subjects must have 1) attempted initial milk 
expression within 12 hours of delivery; 2) attempted milk expression at least 3 times every 24 
hours from 24 hours of delivery to the start of the observation period; 3) attempted milk 
expression using the breast pump at least 5 times every 24 hours for the last 48 hours of the 
observation period; 4) produced <200 mL milk in total from any expression method (i.e.,
pumping, hand expression and breastfeeding) for the last 24 hours of the observation period (i.e.,
the baseline interval). 
Eligible maternal subjects will be randomly assigned in a 1:1 ratio to intra-nasal treatment with 
either merotocin (400 µg per dose, divided into 2 sprays with 1 spray in each nostril) or placebo.
Randomization is stratified by gestational age group (<27 weeks and ≥27 weeks) and by site.
After instruction and guidance, treatment will be administered intra-nasally as 1 spray in each 
nostril approximately 5 to 10 minutes before each milk expression session. In this trial, treatment 
days start from the time of randomization, with Day 1 being the first 24 hours after 
randomization, Day 2 being 24 to 48 hours after randomization, and so on. The treatment period 


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will include 14 such consecutive intervals of 24 hours from the time of randomization, 
corresponding to 14 treatment days (Days 1 to 14). Trial visits can be scheduled according to 
calendar days without considering 24-hour periods. Each administration of IMP and milk
expression will be self-recorded by maternal subjects on milk container labels. Maternal subjects 
should stop the administration of IMP as soon as having completed 14 days’ treatment, rather 
than continue dosing until the Day 15/End-of-Treatment visit. Trial visits after randomization 
include Day 3, Day 10, Day 15/End-of-Treatment and Day 18/ Follow-up visits. At all of these 
visits, AEs and concomitant medications of maternal subjects will be collected and a review of 
the dosing (as applicable) and milk expression documentation will be performed. 
Specifically, at Day 3 and Day 10 visits at the trial center, milk samples will be taken for the 
analysis of merotocin concentration in the milk and for the analysis of milk composition. Milk 
samples are taken only if the volume of production is, at the discretion of the investigator,
adequate to meet the needs of the infant. In addition, for the analysis of merotocin concentration 
in the blood, 7 blood samples will be drawn for a subset of minimum 20 maternal subjects at
Day 3 and Day 10 visits using an indwelling catheter at predefined time points from pre-dose 
until 1 hour after dosing. For the pre-dose sample of merotocin concentration, blood sampling 
should always be performed a minimum of 3 hours after the previous dose. Vital signs will also 
be measured at Day 3 and Day 10 visits.
Additional Day 15/End-of-Treatment visit procedures consist of a physical examination, vital 
signs and blood sampling (safety laboratory).
All maternal subjects who complete the assigned treatment of Days 1 to 14 will be asked to 
continue daily recording of MoM expression through the end of Day 17. The expressed milk will 
be collected at Day18/Follow-up visit to document the volume of milk produced during the post-
treatment follow-up period. 
No specific trial procedures are required for infants. All infant data are based on hospital records. 
Infant body weight and infant enteral feeds (volume of MoM and formula/donor milk fed to the 
infant) will be collected from hospital records for all days as available from Day 1 to Day 14. 
Concomitant medications and AEs including morbidity events of special interest (NEC, intra-
ventricular hemorrhage, BPD, RDS, late-onset sepsis, ROP, and hemodynamically significant 
patent ductus arteriosus) will be collected from hospital records from signing of informed 
consent. 
Milk Expression Procedures
Maternal subjects will attempt to express milk with a multi-user, electric, double-pumping breast 
pump (Medela Symphony, Medela Inc., McHenry, Illinois) at least 5 times every 24 hours during 
the observation period and 6 to 8 times every 24 hours during the treatment and post-treatment 
follow-up periods, including at least once during the night and with no more than 5 hours 
between milk expression sessions. Both breasts should be pumped and emptied in accordance 


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with the instructions provided in the lactation manual for subjects. Maternal subjects will also 
receive instructions on hand expression and hands-on pumping; use of the two methods is at
subject’s own choice. All maternal subjects will receive detailed and standardized lactation 
instructions and expert lactation support. Steps will be taken to standardize best supportive care 
across trial centers. 
Milk expression will be conducted mostly with the breast pump, occasionally by hand expression 
(as subject wishes) or by breastfeeding the infant (only when the infant is considered by NICU 
staff to be capable of being breastfed). Breastfeeding will always be followed by further 
expression with the breast pump. Hand expression is permitted both immediately after a pumping 
session and in between pumping sessions during the observation period; however, once the 
subject has been randomized, hand expression is permitted only immediately after a pumping 
session. Hand expression in between pumping sessions during the observation period is to be 
recorded as a separate session but will not be included in the stated goal of milk expression 
frequency, i.e., at least 5 times every 24 hours.
The expressed milk will be collected into supplied containers in accordance with the instructions 
provided in the lactation manual for subjects. Maternal subjects may bring bottles of expressed 
milk to the trial center any day during the trial, and the weights of the milk expressed will be 
recorded. The recorded weight of milk expressed in grams will be converted to a volume of milk 
using a conversion of 1 g to 1 mL. Expressed milk will be stored for feeding to the infant after 
recording the milk weights.
Should breastfeeding occur, the amount of breastfed milk is established by weighing the infant
before and after the breastfeeding has been completed by following standardized weighing 
instructions and by using a standardized scale. Breastfeeding will only occur when the trial center
staff consider the infant has the ability to achieve a nutritional feed through breastfeeding. The
weights before and after breastfeeding will be recorded. After breastfeeding her infant, the 
maternal subject should continue to express milk using the breast pump in accordance with 
instructions provided in the lactation manual for subjects and record the milk expression. 
The fed volumes of MoM and of other enteral feedings (formula/donor milk) will be recorded by 
trial center staff based on the hospital records. It is expected that the majority of the infants will 
be hospitalized for the predominant or entire duration of the trial due to their prematurity. If the 
infant is discharged prior to the Day 18/Follow-up visit, the maternal subject will be instructed to 
continue to use the trial medication as planned and continue to record milk expression as
instructed in the lactation manual for subjects and milk weighing procedures manual. Two 
standardized scales will be offered to the maternal subject for the recording of milk expression at 
home, one for measuring the weight of the expressed milk and one for measuring the weight of 
the infant before and after feeds (if the subject is breastfeeding). 


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Post-trial Activities
As part of post-trial activities after the Day18/Follow-up visit, infant AEs and concomitant 
medications will continue to be collected from hospital records through infant’s discharge from 
NICU or until the last milk sample expressed during maternal subject’s treatment with IMP is 
either consumed by the infant or discarded, whichever occurs last. Information on infant’s
morbidity events of special interest is collected through infant’s discharge from NICU based on 
hospital records.
In addition, the following data will be collected from the hospital records as available when the 
infant is discharged from NICU: infant body weight, length and head circumference at time of 
discharge from NICU, time to full enteral feeds, time to discharge from NICU, number of days 
the infant requires TPN until discharge from NICU, type of feeding (MoM and formula/donor 
milk) at time of discharge from NICU, and whether the maternal subject is lactating at time of 
infant’s discharge from NICU. 
A further post-trial activity is to establish a contact with the maternal subject (by phone or other 
means) about one month after the infant’s NICU discharge to inquire about any hospital re-
admission of the infant and the reason for such. 
For long-term follow-up, the Ages and Stages Questionnaire-3 (ASQ-3) will be provided to all 
infants at 9 months, 18 months and 24 months of corrected gestational age. A primary caregiver
of the infant will answer the questionnaire that consists of approximately 30 questions covering 
five domains of development, including communication, gross motor, fine motor, problem-
solving, and personal-social skills. 
Data from post-trial activities will be provided in an addendum to the clinical trial report.
NUMBER OF SUBJECTS
The sample size calculation is based on the comparison of MoM produced over Days 1 to 14 
between the merotocin group and the placebo group using a repeated measures analysis of 
covariance (ANCOVA). The primary analysis will be based on the full analysis set (FAS), 
defined as all randomized and exposed maternal subjects providing data on volume of MoM 
produced for at least 1 day after dosing initiation. The FAS will be based on the actual treatment 
received. A sample size of 100 maternal subjects, allocated equally to each treatment group, is 
estimated to provide approximately 80% power to detect a 50% increase in the daily volume of 
MoM produced over Days 1 to 14, compared to placebo. It is estimated that approximately 
250 maternal subjects will need to be screened.


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CRITERIA FOR INCLUSION
Inclusion criteria for entry into observation period: 
Maternal subject:
Signed and dated informed consent for the maternal subject and parental consent for the 
infant, prior to any trial activity.
Aged 18 to 44 years at the time of informed consent.
Delivered at the hospital system associated with the trial center.
Delivered a preterm singleton at a gestational age of 24 weeks + 0 days to 34 weeks + 
2 days.
Attempted initial milk expression within 12 hours of delivery.
Attempted milk expression at least 3 times every 24 hours from 24 hours of delivery to 
the start of observation period (at least 3 times between 24 and 48 hours of delivery for
subjects who enter the observation period within 48 hours of delivery).
Is willing to express milk at least 5 times every 24 hours during the observation period 
and 6 to 8 times every 24 hours during the treatment and post-treatment follow-up 
periods, including at least once during the night and with no more than 5 hours between 
milk expression sessions, during the trial (up to 23 days).
Is willing to refrain from sexual intercourse during the trial.
Inclusion criteria for randomization (in addition to the criteria above):
Maternal subject:
Attempted milk expression using the breast pump at least 5 times every 24 hours for the 
last 48 hours of the observation period, i.e., the 48 hours prior to the last pumping 
session before randomization.
Accurately recorded timing of milk expression after providing informed consent.
Produced <200 mL milk for the last 24 hours of the observation period (the 24-hour 
baseline interval), i.e., the 24 hours prior to the last pumping session before 
randomization.
Delivered 96 to 192 (+4) hours prior to randomization.
CRITERIA FOR EXCLUSION
At screening, maternal subjects meeting any of the criteria listed below are not eligible for 
participation in the trial.
Maternal subject:
1. Has a pre-pregnancy body mass index (BMI) >50.
2. Has chronic or temporary medical conditions that would cause her to be unable to comply 
with the protocol or be unable to attend all trial visits.
3. Has mastitis.
4. Had known breast trauma, previous breast surgery (including breast augmentation or 


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breast reduction) or nipple piercing.
5. Has known prolactin-releasing pituitary tumor, a history of Sheehan’s syndrome, or had 
previous pituitary surgery or radiation therapy.
6. Has any known maternally driven contraindication to breastfeeding.
7. Has known pre-pregnancy severe cardiovascular disease (e.g., uncontrolled chronic
hypertension, severe arrhythmias, or Grade 3-4 New York Heart Association cardiac 
failure). Note: preeclampsia is allowed.
8. Has known pre-pregnancy insulin-dependent diabetes mellitus, polycystic ovarian 
syndrome, or any other condition that would impact lactation in the opinion of the 
investigator. Note: gestational diabetes is allowed (also when requiring the use of insulin 
for treatment).
9. Has unstable thyroid disease, i.e., has required dose adjustment of thyroid replacement or 
anti-thyroid medication in the 12 months prior to delivery.
10. Has known moderate or severe renal or hepatic impairment.
11. Has significant history of mental illness, including diagnosed postpartum depression, 
which could impede trial participation.
12. Has significant nasal congestion or mucous production that would impede use of a nasally 
administered product in the opinion of the investigator.
13. Has used or is currently using any of the following concomitant medications:

Any anti-psychotic drugs during the previous 12 months. Note: anxiolytic and 
antidepressant medications are allowed

Any other non-registered investigational drugs from 90 days prior to delivery or 
within 5 half-lives of the drugs, whichever is longer 

Any hormonal contraception at any point following delivery 

Any pharmacologic or complementary (e.g., herbal) galactagogue therapy at any point 
following delivery. However, use of oxytocin for prevention or treatment of 
postpartum hemorrhage prior to randomization is not exclusionary

Any concomitant medication that could suppress lactation at any point following 
delivery

Orally or parenterally administered steroids at any dose or inhaled steroids at doses 
>600 µg/day at any point following delivery

Prostaglandins at any point following delivery
14. Had postpartum hemorrhage of >1500 mL requiring transfusion or with current severe 
anemia (hemoglobin <8 g/dL).
15. Currently abuses or has previously abused (within 12 months prior to delivery) drugs or 
currently abuses or has previously abused (within 12 months prior to delivery) alcohol 
(i.e., >7 units/week).
16. Has suspected allergy to oxytocin or merotocin or to any of the excipients in the 
investigational medicinal products (IMPs) used in the trial.
17. Is unable to understand language(s) spoken or provided in writing to her at the trial 
center.


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18. Has previously participated in the current trial.
At randomization the following exclusion criteria apply in addition to the screening criteria:
Maternal subject:
19. Has used or is currently using methergine within 12 hours prior to randomization.
20. Has any conditions that would require the concomitant use of any intranasal medications 
or any diuretic drugs throughout the trial.  
21. Any clinically significant abnormal findings of safety laboratory parameters considered 
by the investigator to be unsuitable to participate in the trial. 
Infant:
1. Has low probability of viability, as judged by the investigator.
2. Was transferred to another hospital system during screening, or is likely to be transferred 
to another hospital system during treatment period as judged by the investigator.
3. Has used any non-registered investigational drugs since delivery.
MEDICINAL PRODUCTS
Merotocin nasal spray (400 µg intra-nasally per dose, divided into 2 sprays with 1 spray in each 
nostril) administered 6 to 8 times every treatment day. Placebo nasal spray administered 6 to 8 
times every treatment day. 
The active IMP is a stock solution consisting of merotocin dissolved in an isotonic 
citrate/phosphate buffer of pH 5.5 at a concentration of 2 mg/mL. The placebo IMP is an isotonic 
citrate/phosphate buffer solution of pH 5.5. The IMPs are identical in appearance.
DURATION OF TREATMENT
Maternal subjects will be exposed to either merotocin or placebo for 14 days.
STATISTICAL METHODS
All statistical tests will be two-sided, using a 5% significance level. All statistical analyses will 
be performed using SAS software (SAS Institute, Inc, Cary, North Carolina) (Version 9.2 or 
later). The analysis of efficacy will be performed for the FAS and per protocol (PP) analysis set.
The primary analysis will be performed using the FAS, defined as all randomized and exposed 
maternal subjects providing data on volume of MoM produced for at least 1 day after dosing 
initiation. The FAS will be analyzed according to the actual treatment received. Analysis 
performed using the PP analysis set, defined as all randomized maternal subjects without major 
protocol deviations, will be considered supportive.
Primary Endpoint: Primary Analysis 
The primary objective of this proof of concept (PoC) trial is to evaluate the effect of merotocin
on increasing milk production in women with preterm delivery. The primary endpoint of the trial 


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is the volume of MoM produced over Days 1 to 14.
Repeated Measures ANCOVA Model: 
The primary endpoint will be analyzed using a repeated measures ANCOVA with a general 
(unstructured) covariance matrix. The daily volume of MoM produced will be the dependent 
variable. The model will include the baseline volume of MoM produced as a covariate, with 
treatment group, treatment day, treatment-by-day interaction, and gestational age group
(<27 weeks and ≥27 weeks) as factors. The baseline volume of MoM produced is defined as the 
volume obtained at the 24-hour interval for eligibility during the observation period. The average 
treatment effect across treatment days and the within-day treatment effect will be reported along 
with the corresponding two-sided 95% confidence intervals and p-values. 
PoC will be considered to be established if the repeated measures ANCOVA model results in a 
significant positive average treatment effect of merotocin compared to placebo across the 
treatment period in the FAS.
Primary Endpoint: Sensitivity/Supportive Analyses 
Sensitivity analyses exploring the robustness of the primary analysis results to the underlying 
assumption that missing data is missing completely at random will be carried out for the FAS and 
PP analysis set. For these analyses, missing data will be imputed under a missing-not-at-random 
(MNAR) assumption based on the pattern-mixture model with control-based pattern imputation.
Additional sensitivity analyses will investigate the robustness of the primary analysis results 
based on the choice of the covariance structure and potential treatment interactions with 
gestational age group (<27 weeks and ≥27 weeks).
Although the randomization will be stratified by site, it will not be included in the model for the 
primary analysis because issues may arise when adjusting for a large number of small centers 
(with respect to the number of randomized subjects). Additionally, common methods, such as 
pooling small centers together to form one large center, lack scientific justification. To ensure 
that the trial conclusions are not substantially affected by this exclusion, sensitivity analyses will 
examine the relationship between the effect of treatment and center. This will be carried out by 
including center and the center*treatment interaction as factors in the repeated measures 
ANCOVA model specified for the primary endpoint.
Sensitivity analyses will be performed to assess the relationship between the time of 
randomization from delivery and the effect of treatment on the volume of MoM produced over 
Days 1 to 14. This will be carried out by including the time of randomization from delivery and 
the time of randomization from delivery by treatment interaction in the repeated measures 
ANCOVA model specified for the primary endpoint.
Further, the above primary analysis will be repeated to examine the consistency of the 
relationship between treatment and the volume of MoM produced over Days 1 to 14 after having 


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adjusted for additional covariates (age of maternal subject, ethnicity, presence of fetal growth 
restriction, birth weight, caesarean section, primipara versus multipara, use of antenatal steroids 
and pre-pregnancy BMI). Each covariate will be added to the model one by one and tested at a 
two-sided significance level of 20%. In case 2 or more covariates are significant at the 20% level, 
a forward selection process will be applied with a threshold for adding effects at a two-sided 
significance level of 20% to identify the final model.
Interim Analysis
An unblinded interim analysis for futility assessment is planned once approximately 50% of the 
planned 100 subjects have completed assigned treatment period of Days 1 to 14 of the trial. The 
primary endpoint, volume of MoM produced over Days 1 to 14, will be evaluated for futility. 
Stopping the trial due to lack of merotocin benefit (i.e., futility) could be considered if the 
conditional power is lower than 10%. 
The interim analysis will be performed by an independent Data Monitoring Committee (DMC) 
based on cleaned data, and the recruitment will continue at the time of interim analysis unless 
otherwise notified. The DMC will review unblinded interim data and make a recommendation on 
whether the trial should be terminated early due to the futility (non-binding). 
There is no planned interim analysis with the intention to stop the trial early due to overwhelming 
efficacy.


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TABLE OF CONTENTS
Page
SYNOPSIS....................................................................................................................................................... 2
LIST OF TABLES........................................................................................................................................ 18
LIST OF FIGURES...................................................................................................................................... 18
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................. 19
1
INTRODUCTION ............................................................................................................................. 21
1.1
Background............................................................................................................................. 21
1.2
Scientific Justification for Conducting the Trial..................................................................... 22
1.3
Benefit/Risk Aspects............................................................................................................... 23
2
TRIAL OBJECTIVES AND ENDPOINTS..................................................................................... 25
2.1
Objectives ............................................................................................................................... 25
2.2
Endpoints ................................................................................................................................ 25
3
INVESTIGATIONAL PLAN ........................................................................................................... 27
3.1
Overall Trial Design................................................................................................................ 27
3.1.1
Trial Design Diagram................................................................................................. 27
3.1.2
Overall Design and Control Methods ........................................................................ 28
3.1.3
Trial Schedule............................................................................................................ 33
3.2
Planned Number of Trial Centers and Subjects...................................................................... 33
3.3
Interim Analysis...................................................................................................................... 33
3.4
Data Monitoring Committee ................................................................................................... 34
3.5
Safety Committee.................................................................................................................... 34
3.6
Discussion of Overall Trial Design and Choice of Control Groups ....................................... 35
3.6.1
Trial Design ............................................................................................................... 35
3.6.2
Selection of Endpoints ............................................................................................... 36
3.6.3
Blinding...................................................................................................................... 36
3.6.4
Selection of Doses in the Trial................................................................................... 37
3.6.5
Selection and Timing of Dose for Each Subject........................................................ 37
3.6.6
Selection of the Trial Population ............................................................................... 37
3.6.7
Post-treatment Follow-up Procedures........................................................................ 38
3.6.8
Post-trial Activities .................................................................................................... 38
3.6.9
Access to Therapy after Day 15/End-of-Treatment................................................... 39
4
SELECTION OF TRIAL POPULATION ...................................................................................... 40
4.1
Trial Population....................................................................................................................... 40
4.1.1
Inclusion Criteria ....................................................................................................... 40
4.1.2
Exclusion Criteria ...................................................................................................... 41
4.2
Method of Assigning Subjects to Treatment Groups.............................................................. 42
4.2.1
Recruitment................................................................................................................ 42
4.2.2
Randomization........................................................................................................... 43
4.3
Restrictions ............................................................................................................................. 43
4.3.1
Prior and Concomitant Therapies .............................................................................. 43
4.3.2
Prohibited Therapy..................................................................................................... 44
4.3.3
Other Restrictions ...................................................................................................... 44


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4.4
Discontinuation and Stopping Criteria.................................................................................... 45
4.4.1
Discontinuation Criteria............................................................................................. 45
4.4.2
Trial Stopping Criteria ............................................................................................... 45
4.5
Subject Replacement............................................................................................................... 46
5
TREATMENTS ................................................................................................................................. 47
5.1
Treatments Administered........................................................................................................ 47
5.1.1
Investigational Medicinal Products............................................................................ 47
5.1.2
Non-Investigational Medicinal Product..................................................................... 47
5.2
Characteristics and Source of Supply ..................................................................................... 48
5.3
Packaging and Labelling......................................................................................................... 48
5.4
Conditions for Storage and Use .............................................................................................. 48
5.5
Blinding/Unblinding ............................................................................................................... 49
5.5.1
Blinding...................................................................................................................... 49
5.5.2
Unblinding of Individual Subject Treatment ............................................................. 49
5.6
Dispensing and Accountability, Return and Destruction........................................................ 50
5.7
Auxiliary Supplies................................................................................................................... 51
6
TRIAL PROCEDURES .................................................................................................................... 52
6.1
Trial Flow Chart...................................................................................................................... 52
6.2
Screening Period ..................................................................................................................... 55
6.3
Randomization ........................................................................................................................ 57
6.4
Treatment Period Days 1 to 14 ............................................................................................... 58
6.4.1
All Treatment Days.................................................................................................... 58
6.4.2
Day 3 Visit................................................................................................................. 59
6.4.3
Day 10 Visit............................................................................................................... 60
6.4.4
Day 15/End-of-Treatment Visit ................................................................................. 61
6.5
Post-Treatment Follow-up Period (Days 15 to 18)................................................................. 62
6.5.1
Day 18/Follow-up Visit ............................................................................................. 62
6.6
Post-trial Activities ................................................................................................................. 63
6.6.1
Infant-related Activities at Infant’s Discharge from NICU ....................................... 63
6.6.2
Infant-related Activities about One Month after NICU Discharge............................ 63
6.6.3
Infant-related Activities Long-term Follow-up.......................................................... 63
7
TRIAL ASSESSMENTS ................................................................................................................... 65
7.1
Assessments Related to Primary Endpoint ............................................................................. 65
7.1.1
Volume of MoM Produced over Days 1 to 14........................................................... 65
7.2
Assessments Related to Secondary Endpoints........................................................................ 67
7.2.1
Time to the First Occurrence of a Daily Volume of MoM ≥500 mL and ≥750 mL .. 67
7.2.2
Proportion of Subjects with a Daily Volume of MoM ≥500 mL and ≥750 mL......... 67
7.2.3
Volume of MoM Produced over Days 15 to 17......................................................... 67
7.2.4
Volume of MoM Fed to the Infant............................................................................. 67
7.2.5
Volume of Formula/Donor Milk Fed to the Infant .................................................... 68
7.2.6
Merotocin Concentration in Milk .............................................................................. 68
7.2.7
Infant Body Weight.................................................................................................... 68
7.2.8
Adverse Events (Maternal Subject and Infant).......................................................... 68
7.2.9
Safety Laboratory Parameters (Maternal Subjects) ................................................... 68
7.3
Assessments Related to Exploratory Endpoints...................................................................... 69


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7.3.1
Plasma Concentration of Merotocin .......................................................................... 69
7.3.2
Milk Composition...................................................................................................... 69
7.4
Assessments Related to Post-trial Endpoints.......................................................................... 70
7.5
Other Assessments.................................................................................................................. 70
7.5.1
Vital Signs (Maternal Subject)................................................................................... 70
7.5.2
Physical Examination (Maternal Subject).................................................................. 71
7.6
Handling of Biological Samples ............................................................................................. 71
8
ADVERSE EVENTS ......................................................................................................................... 72
8.1
Adverse Event Definition........................................................................................................ 72
8.2
Collection and Recording of Adverse Events......................................................................... 73
8.2.1
Collection of Adverse Events .................................................................................... 73
8.2.2
Recording of Adverse Events .................................................................................... 73
8.2.3
Collection and Recording of Adverse Events for Maternal Subjects......................... 76
8.2.4
Collection and Recording of Adverse Events for Infants .......................................... 76
8.3
Adverse Events Requiring Special Handling for Maternal Subject........................................ 76
8.3.1
Uterine Contraction.................................................................................................... 76
8.4
Morbidity Events of Special Interest for Infants..................................................................... 77
8.5
Serious Adverse Events .......................................................................................................... 78
8.5.1
Serious Adverse Event Definition.............................................................................. 78
8.5.2
Collection, Recording and Reporting of Serious Adverse Events ............................. 79
8.6
Follow-up of Adverse Events and Serious Adverse Events.................................................... 79
8.6.1
Follow-up of Adverse Events with Onset during the Trial........................................ 79
8.6.2
Collection of Serious Adverse Events with Onset after Last Trial Visit ................... 80
9
STATISTICAL METHODS ............................................................................................................. 81
9.1
Determination of Sample Size ................................................................................................ 81
9.2
Subject Disposition ................................................................................................................. 82
9.3
Protocol Deviations................................................................................................................. 82
9.4
Analysis Sets........................................................................................................................... 82
9.4.1
Intention-to-Treat Analysis Dataset........................................................................... 82
9.4.2
Full Analysis Set........................................................................................................ 83
9.4.3
Per Protocol Analysis Set........................................................................................... 83
9.4.4
Safety Analysis Set .................................................................................................... 83
9.5
Trial Population....................................................................................................................... 83
9.5.1
Demographics and Other Baseline Characteristics.................................................... 83
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations................ 83
9.6
Endpoint Assessments............................................................................................................. 83
9.6.1
General Considerations.............................................................................................. 83
9.6.2
Primary Endpoint....................................................................................................... 84
9.6.3
Secondary Endpoints ................................................................................................. 86
9.6.4
Exploratory Endpoints ............................................................................................... 87
9.6.5
Post-trial Endpoints.................................................................................................... 87
9.7
Extent of Dosing and Treatment Compliance......................................................................... 87
9.8
Safety ...................................................................................................................................... 87
9.8.1
General Considerations.............................................................................................. 87
9.8.2
Adverse Events .......................................................................................................... 88


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9.8.3
Other Safety Variables............................................................................................... 88
9.9
Interim Analysis...................................................................................................................... 88
10
DATA HANDLING ........................................................................................................................... 90
10.1
Source Data and Source Documents....................................................................................... 90
10.2
e-CRF...................................................................................................................................... 91
10.3
Data Management ................................................................................................................... 91
10.4
Provision of Additional Information....................................................................................... 91
11
MONITORING PROCEDURES ..................................................................................................... 92
11.1
Periodic Monitoring................................................................................................................ 92
11.2
Audit and Inspection............................................................................................................... 92
11.3
Confidentiality of Subject Data............................................................................................... 92
12
CHANGES IN THE CONDUCT OF THE TRIAL........................................................................ 93
12.1
Protocol Amendments............................................................................................................. 93
12.2
Deviations from the Protocol .................................................................................................. 93
12.3
Premature Trial Termination................................................................................................... 93
13
REPORTING AND PUBLICATION .............................................................................................. 94
13.1
Clinical Trial Report ............................................................................................................... 94
13.2
Confidentiality and Ownership of Trial Data.......................................................................... 94
13.3
Publications and Public Disclosure......................................................................................... 94
13.3.1 Publication Policy...................................................................................................... 94
13.3.2 Public Disclosure Policy............................................................................................ 95
14
ETHICAL AND REGULATORY ASPECTS................................................................................. 96
14.1
Institutional Review Boards (IRBs)........................................................................................ 96
14.2
Regulatory Authority Approval .............................................................................................. 96
14.3
End-of-Trial and End-of-Trial Notification ............................................................................ 96
14.4
Ethical Conduct of the Trial.................................................................................................... 96
14.5
Subject Information and Consent............................................................................................ 96
14.6
Subject Participation Card ...................................................................................................... 98
14.7
Compliance Reference Documents......................................................................................... 98
15
LIABILITIES AND INSURANCE .................................................................................................. 99
15.1
ICH-GCP Responsibilities...................................................................................................... 99
15.2
Liabilities and Insurance......................................................................................................... 99
16
ARCHIVING.................................................................................................................................... 100
16.1
Investigator File .................................................................................................................... 100
16.2
Trial Master File.................................................................................................................... 100
17
REFERENCES................................................................................................................................. 101


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LIST OF TABLES 
Table 1
Total Daily Dose of Merotocin by Milk Expression Frequency.....................................47
Table 2
Characteristics of Investigational Medicinal Products....................................................48
Table 3
Trial Flow Chart – Mother-related Activities .................................................................53
Table 4
Trial Flow Chart – Infant-related Activities ...................................................................54
Table 5
Instructions on Milk Expression and Milk Collection....................................................66
Table 6
Safety Laboratory Parameters.........................................................................................69
Table 7
Power for Various Combinations of Correlation and Treatment Effect .........................81
LIST OF FIGURES
Figure 1
Overall Trial Design........................................................................................................27
Figure 2
Screening Period, Observation Period and the 24-Hour Baseline Interval.....................29
Figure 3
Frequencies of Milk Expression from Delivery to Randomization................................30


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
List of Abbreviations
AE
adverse event
ANCOVA
analysis of covariance
ATC
Anatomical Therapeutic Chemical Classification System
ASQ-3
Ages and Stages Questionnaire -3 
BMI
body mass index
CRO
Contract Research Organization
DMC 
Data Monitoring Committee
e-CRF
electronic case report form
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance Department
h
hour(s)
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intention-to-treat
LC-MS/MS
liquid chromatography tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
min. 
minimum
MNAR
missing-not-at-random
MoM 
mother’s own milk
NEC 
necrotizing enterocolitis
NICU 
neonatal intensive care unit
PK
pharmacokinetic(s)
PoC 
proof of concept
PP
per protocol
PT
preferred term


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ROP 
retinopathy of prematurity
SAE
serious adverse event
SAP
Statistical Analysis Plan
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reaction
t½
elimination half-life
TEAE
treatment-emergent adverse event
tmax
time to maximum observed concentration
TPN
total parenteral nutrition
WHO
World Health Organization
Definition of Terms
Hand expression 
A method in which breasts are emptied through the use of hands
Hands-on pumping 
A method of massaging the breasts to supplement pumping. Either the 
breasts are massaged during the actual pumping or the massage is 
performed intermittently to pumping
Milk expression session
One session of milk expression is defined as one round of pumping, one 
round of pumping followed immediately by hand expression or one round 
of breastfeeding followed immediately by pumping. In case of pumping 
combined with either breastfeeding or hand expression, the volume/weight
of MoM expressed through pumping and through the other method will be 
recorded separately. However, if hand expression occurs in between
pumping sessions during observation period, this should be considered a
separate session but is not included the stated goal of milk expression 
frequency, i.e., at least 5 times every 24 hours
Pumping
A method in which milk is expressed from the breasts using a breast pump
Time to Tolerance
The infant has been on a feeding volume of 150mL/kg/day for at least 24 to 
48 hours


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1
INTRODUCTION
1.1
Background
Women with preterm delivery encounter special challenges in providing their infants with mother’s 
own milk (MoM). Not only has the breast of the preterm woman not yet fully undergone the 
physiological and morphological changes in preparation for lactation, a woman with a preterm 
infant also faces worry and stress that is counterproductive for lactation. Further, she may also have 
to depend on a breast pump rather than the suckling of the baby, which deprives her of important 
lactation stimuli. Only about 48% of women with preterm delivery wanting to lactate had adequate 
milk production 6 weeks after delivery, as compared to about 83% among women with term 
delivery in the same prospective study.1
MoM is of particular value to the preterm infant’s health and development as numerous studies 
have shown that bovine-based formula milk causes pro-inflammatory changes in the preterm 
infant’s intestines. These effects are correlated with various morbidities of inflammatory origin that 
are often severe and sometimes fatal. Lower incidences of necrotizing enterocolitis (NEC),2,3,4,5
retinopathy of prematurity (ROP),6 sepsis7,8 and bronchopulmonary dysplasia (BPD)9,10,11 have 
been demonstrated in preterm infants receiving human milk than for infants receiving formula 
exclusively. Another documented benefit of providing human milk to preterm infants is a shorter 
time to tolerance of full enteral feedings.3,12,13 Human donor milk is sometimes regarded as a better 
option than formula milk14 but availability is limited. It also has to be pasteurized, which 
compromises nutritional, immunologic, and other milk components.15 MoM is therefore the 
preferred option.
The rationale for the use of an oxytocin receptor agonist for the purpose of supporting lactation is 
based on several physiological observations and experimental data. First, a complete emptying of 
the breasts is of importance both in establishment of lactation and its continuation. Residual milk in 
the mammary glands will otherwise exert a negative feed-back on milk production and lead to an 
associated involution of mammary tissue. Oxytocin is well established as the major hormone 
responsible for milk ejection in humans. It is therefore postulated that enhanced milk ejection by 
administration of an exogenous oxytocin receptor agonist will increase the likelihood of full 
emptying of the mammary glands, and thereby diminish the negative feed-back of residual milk on 
milk production and the associated involution of mammary tissue. Secondly, oxytocin has been 
shown to increase the secretion and release of prolactin,16 the major hormone responsible for milk 
synthesis in animals and humans. An increase in protein transfer in rabbit mammary tissue when 
exposed to oxytocin has also been demonstrated.17 These data suggest that oxytocin plays a role in 
milk synthesis, secretion and ejection. In clinical studies, intramuscular injections of oxytocin were 
able to reverse stress-induced reduction in milk volume in maternal subjects.18 Taken together, 
these data suggest that activation of oxytocin receptors can affect multiple critical pathways in 
lactation physiology with the ensuing possibility of increasing milk production.


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Merotocin is a selective oxytocin receptor agonist that is being developed for the indication of 
induction and support of lactation in women with preterm delivery and inadequate milk production,
with the expectation that it will increase the mother’s milk production so that the infant’s need of 
MoM will be met both in the short-term and long-term perspective, i.e., it will improve milk 
volume output and improve the lactation continuation rate over time. A notable feature of 
merotocin is its very low vasopressin receptor activity. It is therefore expected that merotocin can 
be administered at doses that are higher than what is advisable with natural oxytocin without 
encountering vasopressin receptor-mediated side effects. As the clinically effective dose may be 
higher than what is tolerable with natural oxytocin due to its dose-limiting side effects, merotocin
would be more likely to meet the medical need. Merotocin is also degradable by chymotrypsin, 
which minimizes the risk of systemic exposure in the infant receiving MoM, in case milk transfer 
of merotocin should occur.
1.2
Scientific Justification for Conducting the Trial
The initial clinical development of merotocin was a combined single ascending and multiple 
ascending dose phase 1 trial to assess safety, tolerability and pharmacokinetics (PK) of merotocin
in healthy non-lactating women. No safety or tolerability concerns were raised in that trial with 
doses up to 400 µg intra-nasally every 3 hours for 45 hours.19
Subsequently, the transfer of merotocin from blood to breast milk was investigated in a single-dose 
milk transfer trial in healthy women with full-term delivery. In that trial, merotocin was 
administered as an intravenous dose of 20 µg equivalent to 400 µg intra-nasally. For all subjects, 
the concentration of merotocin in the milk was below the lower limit of quantification.19 The 
infants of maternal subjects exposed to merotocin in this trial can therefore be fed with MoM with 
no expectation that the infants will be exposed to the drug. 
A proportion of mothers with preterm birth that are dependent on a breast pump have difficulty 
establishing adequate milk supply to meet their infants’ nutritional needs. A product to enhance 
lactation so that prematurely born infants to a higher degree can be nourished with MoM would 
address a medical need. The current trial is the first investigation in the target population of women 
with preterm delivery and inadequate initial milk production who are generally breast pump 
dependent. The primary objective of the trial is to explore the efficacy of intra-nasally administered 
merotocin in increasing milk production in the target population and thereby to provide efficacy 
information for the planning of future trials. In the current trial, merotocin will be administered as a 
nasal spray. This is a common mode of administration for peptidic products in order to avoid the 
enzymatic degradation that would occur with oral administration and the subsequent low 
bioavailability. 
Further objectives of the trial are to obtain information on safety in the maternal subjects and their 
infants when infants are fed with MoM from maternal subjects exposed to merotocin.


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1.3
Benefit/Risk Aspects
The present trial will be the first to provide efficacy data in the target population. As a proof of 
concept (PoC) trial, the primary purpose is to test the hypothesis that exposure to merotocin results 
in increased milk production in women with preterm delivery and inadequate milk production. 
A double electric breast pump will be provided to all maternal subjects entering the observation 
period. Maternal subjects will receive lactation counselling comprised of best supportive care for
this population at trial entry and ongoing support throughout the trial. This is an important benefit 
of participation because postnatal lactation support is associated with increased rates of 
breastfeeding and improved infant outcomes.20,21
A potential benefit of the trial in general is identification of a pharmacologic intervention that will 
increase the maternal subjects’ ability to produce an adequate amount of MoM to meet their 
infants’ nutritional needs. There are known clinical benefits to premature infants receiving human 
milk, including shorter time to tolerance of full enteral feedings3,12,13 and reduced risk of NEC,2,3,4,5
ROP,6 sepsis,7,8 BPD9,10,11 and respiratory distress syndrome (RDS)22.  
The risk profile to date is described in the Investigator’s Brochure.19 Merotocin has previously been 
given to healthy women without any significant undesirable effects. During the single ascending 
dose and multiple ascending dose trial in healthy women, the most frequently reported adverse 
events (AEs) were headache, dry mouth, and flushing (hot flush). In that trial, an increased heart 
rate was observed following a constant rate intravenous infusion which gave rise to high plasma 
concentrations. During the other phase 1 trial that investigated the transfer of merotocin from blood 
to breast milk in healthy women, the most frequently reported AEs were uterine spasm, breast 
engorgement, and headache. 
Other effects associated with the pharmacological activity that is possibly mediated by the oxytocin 
receptor may occur. As such, undesirable effects reported for oxytocin following rapid intravenous 
bolus and intravenous infusions include cardiac arrhythmia, hypotension, bradycardia, and 
hypersensitivity.
The present trial is the first investigation in the target population of women with preterm labor and 
the first investigation with merotocin exposure beyond 45 hours. The proposed dosing regimen is 
400 µg intra-nasal dose (divided into two sprays of 200 µg each) administered 6 to 8 times every 24 
hours. The nasal spray can be used at consecutive sessions at least two hours apart for a maximum 
of 8 times every 24 hours. In the multiple ascending dose part of the phase 1 trial, the harmonic 
mean terminal half-life (t½) with the 400 µg intra-nasal dose was 0.56 hours. With this t½,, 
merotocin concentrations are negligible at two hours after dosing (3.6 half-lives) and merotocin is 
considered to be eliminated at three hours after dosing (5 half-lives). 
Regarding exposure of merotocin to the infants, transfer of merotocin from blood to breast milk 
was not observed in the phase 1 trial in healthy postpartum women specifically investigating this 


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risk, as the concentration of merotocin in the milk of all subjects was below the lower limit of 
quantification. Milk samples obtained in the present trial will also be evaluated for merotocin. 
The blood sampling performed as part of the trial might be associated with mild discomfort, 
bruising, and a very rare risk of infection.
In conclusion, the evaluation of the benefits and risks indicates that participation in this trial is 
associated with a favorable benefit-risk ratio.


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2
TRIAL OBJECTIVES AND ENDPOINTS
2.1
Objectives
Primary Objective

To evaluate the effect of merotocin on increasing milk production in women with preterm 
delivery and with inadequate milk production
Secondary Objectives

To evaluate the effect of merotocin on milk production after treatment discontinuation

To evaluate the amount of mother’s own milk (MoM) in the infant enteral nutritional intake
and changes in infant body weight

To evaluate any amount of merotocin from maternal plasma into the milk expressed by 
women with preterm delivery exposed to merotocin

To characterize the safety profile of merotocin in women with preterm delivery and their 
infants
Exploratory Objectives

To explore the relationship between merotocin exposure in maternal plasma and milk 
volume

To evaluate composition of milk produced during treatment with merotocin in women with 
preterm delivery
Post-trial Objectives

To explore post-trial feeding patterns and key parameters of neonatal intensive care unit 
(NICU) hospitalization of infants from women with preterm delivery and inadequate milk 
production

To assess the post-trial long-term development of infants from women with preterm 
delivery and inadequate milk production
2.2
Endpoints
Primary Endpoint

Volume of MoM produced over Days 1 to 14
Secondary Endpoints

Time to the first occurrence of a daily volume of MoM ≥500 mL and ≥750 mL


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
Proportion of maternal subjects with a daily volume of MoM ≥500 mL and ≥750 mL over 
Days 1 to 14  

Volume of MoM produced over Days 15 to 17 (after treatment discontinuation)

Volume of MoM fed to the infant over Days 1 to 14

Volume of formula/donor milk fed to the infant over Days 1 to 14

Merotocin concentration in milk produced at Day 3 and Day 10 visits

Changes in infant body weight over Days 1 to 14

Frequency and intensity of AEs in maternal subjects 

Frequency and intensity of AEs in infants 

Changes in routine safety laboratory parameters in maternal subjects and proportion of 
subjects with markedly abnormal changes at Day 15/End-of-Treatment visit
Exploratory Endpoints

Merotocin concentration in maternal plasma at Day 3 and Day 10 visits

Composition of milk (including lipids, protein, caloric content, lactose, and Human Milk 
Oligosaccharides) produced by maternal subjects at Day 3 and Day 10 visits
Post-trial Endpoints

Time to tolerance of full (150 mL/kg/day) enteral feed of the infant

Time to NICU discharge of the infant

Number of days the infant requires total parenteral nutrition (TPN) until time of discharge 
from NICU

Proportion of maternal subjects who are lactating at time of infant’s discharge from NICU

Proportion of infants who are fed with MoM/formula/donor milk at time of discharge from 
NICU

Body weight, length, and head circumference of the infant at time of discharge from NICU

Incidence of infant’s morbidity events of special interest (including necrotizing enterocolitis 
(NEC), intra-ventricular hemorrhage, bronchopulmonary dysplasia (BPD), respiratory 
distress syndrome (RDS), late-onset sepsis, ROP, and hemodynamically significant patent 
ductus arteriosus) until time of discharge from NICU

Proportion of infants with an Ages and Stages Questionnaire-3 (ASQ-3) score in the black 
zone in any domain at 9 months, 18 months and 24 months of corrected gestational age


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3
INVESTIGATIONAL PLAN
3.1
Overall Trial Design
3.1.1
Trial Design Diagram
A trial design diagram is provided in Figure 1. 
Figure 1
Overall Trial Design
a Gestational age 24 weeks + 0 days to 34 weeks + 2 days. 
b Informed consent form (ICF) should be signed as soon as possible after delivery. Initial eligibility check must be completed 
within 144 hours of delivery.
c Randomization occurs between 96 and 192 (+4) hours of delivery. Treatment is administered intra-nasally as 1 spray in each 
nostril approximately 5 to 10 minutes before each milk expression session. 
d In this trial, treatment days start from the time of randomization, with Day 1 being the first 24 hours after randomization, 
Day 2 being 24 to 48 hours after randomization, and so on. The treatment period includes 14 such consecutive intervals of 
24 hours from the time of randomization, corresponding to 14 treatment days (Days 1 to 14). Maternal subjects should stop the 
administration of IMP as soon as having completed 14 days’ treatment, rather than continue dosing until the Day 15/End-of-
Treatment visit. Day 3, Day 10, Day 15/End-of-Treatment and Day 18/Follow-up visits can be postponed a maximum of 2 
days.
e Maternal subjects will attempt to express milk at least 5 times every 24 hours during the observation period and 6 to 8 times 
every 24 hours during treatment and follow-up periods, including at least once during the night and with no more than 5 hours 
between milk expression sessions. 
f MoM volume from the first milk expression session up to Day 18/Follow-up visit will be recorded.
g Infant’s discharge from NICU or until the last milk expressed during maternal subject’s treatment with IMP is either 
consumed or discarded, whichever occurs last. Long-term follow-up of infants through 24 months of corrected gestational age 
(section 3.6.8).
Abbreviations: ICF=informed consent form, min.=minimum, IMP=investigational medicinal product, MoM=mother’s own milk, 
NICU=neonatal intensive care unit.
Randomizationc
96-192 (+4) hours 
of delivery
Premature 
delivery a
Day 15
Post-trial 
information
Breast milk expression e
400 µg merotocin
Placebo
End-of–
Treatment
Visitd
Day 10
Day 3
Recording of amount of MoM f
Feeding MoM to infant according to needs
Infant’s 
discharge 
from NICUg
Day 1
Day 18
Follow-up
Visitd
Trial Visitd
Day 14
Breast pumping instruction and lactation support
Trial Visitd
ICF and initial 
eligibilityb
within 144 hours 
of delivery
Observation 
Period
(min.48 hours)


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3.1.2
Overall Design and Control Methods
This is a randomized, double-blind, placebo-controlled, multicenter trial exploring the efficacy and 
safety of intra-nasal administration of 400 µg merotocin in increasing milk production in women
with preterm delivery and inadequate initial milk production. 
The trial population consists of maternal subjects who have delivered a preterm singleton 
(gestational age from 24 weeks + 0 days to 34 weeks + 2 days), who wish to provide MoM to their 
infants but have inadequate initial milk production and who are willing to express milk 6 to 8 times 
every 24 hours throughout the trial. No specific trial procedures are required for infants.
The trial consists of a screening period, a treatment period and a post-treatment follow-up period. In 
addition, there is a post-trial follow-up of infants.

Screening Period: The screening period starts from the signing of informed consent and 
ends at randomization, which occurs between 96 to 192 (+4) hours of delivery. The 
screening period must include an observation period of a minimum of 48 hours for the 
collection of milk expression data.

Treatment Period: Once the observation period is completed, eligible women will be 
randomized in a 1:1 ratio to receive either merotocin or placebo. The treatment period is 14 
days and includes visits on Days 3 and 10, as well as an End-of-Treatment visit on Day 15 
or the day after the last dose of investigational medicinal product (IMP) in case of 
premature discontinuation.

Post-treatment Follow-up Period: The post-treatment follow-up period includes a Day 18 / 
Follow-up visit, scheduled 3 days after the Day 15/End-of-Treatment visit. 
Note that Day 3, Day 10, Day 15/End-of-Treatment and Day 18/Follow-up visits can all be 
postponed for a maximum of 2 days.  
Trial Activities
Maternal subjects who provide informed consent for participation will enter the screening period as 
soon as possible following delivery. The screening period runs from the signing of informed 
consent to randomization and includes an observation period of a minimum of 48 hours for the 
collection of milk expression data. Maternal subjects should enter the observation period within 
144 hours of delivery as soon as the initial eligibility check have been completed and a blood 
sampling for analysis of safety laboratory parameters has been performed. The observation period 
starts with the first milk expression session using the breast pump (i.e., pumping session) under 
supervision at the site. The observation period ends with the last pumping session at the trial center 
prior to randomization. Milk volume produced for the last 24 hours of the observation period (i.e., 
the 24-hour baseline interval) will be calculated to assess the inadequacy of milk production. See
Figure 2.


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Figure 2
Screening Period, Observation Period and the 24-Hour Baseline Interval
Throughout the trial, maternal subjects will be instructed to express milk; at least 5 times every 
24 hours during the observation period and 6 to 8 times every 24 hours during the treatment and 
post-treatment follow-up periods, including at least once during the night and with no more than 
5 hours between milk expression sessions (see milk expression procedures detailed later). Each 
session of milk expression will be recorded by subjects themselves.
Before treatment on the day of randomization, a physical examination of eligible subjects will be 
performed and vital signs will be recorded. For the analysis of milk composition, if the volume of 
production is, at the discretion of the investigator, adequate to meet the nutritional needs of the
infant, a sample from the milk expressed prior to randomization will be obtained.
Randomization will occur between 96 and 192 (+4) hours of delivery. Every effort should be made 
to randomize maternal subjects as early as possible, but not earlier than 96 hours of delivery. To be 
eligible for randomization, maternal subjects must have 1) attempted initial milk expression within 
12 hours of delivery; 2) attempted milk expression at least 3 times every 24 hours from 24 hours of 
delivery to the start of the observation period a; 3) attempted milk expression using the breast pump 
at least 5 times every 24 hours for the last 48 hours of the observation period; 4) produced <200 mL 
milk in total from any expression method (i.e., pumping, hand expression and breastfeeding) for the 
last 24 hours of the observation period (i.e., the baseline interval). See Figure 3.
                                                
a At least 3 times between 24 and 48 hours of delivery if subjects enter observation period within 48 hours of delivery.
ICF
Randomization
Milk expression 
session using breast 
pump under 
supervision at site
Last milk expression session
using breast pump at site 
before randomization
Observation Period (a minimum of 48 hours) 
b
Initial eligibility 
check & 
screening 
assessments 
Screening Period a
24-hour baseline interval c
a Screening period runs from the signing of informed consent to randomization.
b The observation period starts with the first pumping session under supervision at the site and ends with the last pumping 
session at the site before randomization. 
c The 24-hour baseline interval goes 24 hours backwards from the last pumping session before randomization. The milk 
expressed at the last pumping session before randomization is included in the 24-hour baseline interval. 


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a ICF should be signed as soon after delivery as possible. Initial eligibility check must be completed within 144 hours of delivery.  
b Observation period should start within 144 hours of delivery and should last a minimum of 48 hours; however, observation may be 
longer as randomization cannot occur before 96 hours of delivery. Subjects are instructed to attempt milk expression at least 
5 times every 24 hours including at least once during the night and with no more than 5 hours between milk expression sessions 
during the observation period. Those who have attempted at least 5 milk expressions with the breast pump every 24 hours for the 
last 48 hours of the observation period and have produced <200 mL milk in total from any expression method (i.e., pumping, hand 
expression and breastfeeding) for the last 24 hours of the observation period (the 24-hour baseline interval) are eligible for 
randomization. Subjects are required to have attempted milk expression at least 3 times every 24 hours from 24 hours of delivery 
to the start of observation period (or at least 3 times between 24 and 48 hours of delivery if they start the observation period early), 
in addition to an initial milk expression attempt within 12 hours of delivery.
c Randomization occurs between 96 and 192 (+4) hours of delivery. Every effort should be made to randomize maternal subjects as 
early as possible, but not earlier than 96 hours of delivery.
Abbreviations: h=hours, ICF=informed consent form, min.=minimum. 
Figure 3
Frequencies of Milk Expression from Delivery to Randomization
Eligible maternal subjects will be randomly assigned in a 1:1 ratio to intra-nasal treatment with 
either merotocin (400 µg per dose, divided into 2 sprays with 1 spray in each nostril) or placebo.
Randomization is stratified by gestational age group (<27 weeks and ≥27 weeks) and by site. 
After instruction and guidance, treatment will be administered intra-nasally as 1 spray in each 
nostril approximately 5 to 10 minutes before each milk expression session. In this trial, treatment 
days start from the time of randomization, with Day 1 being the first 24 hours after randomization, 
Day 2 being 24 to 48 hours after randomization, and so on. The treatment period will include 14 
such consecutive intervals of 24 hours from the time of randomization, corresponding to 14 
treatment days (Days 1 to 14). Trial visits can be scheduled according to calendar days without 
considering 24-hour periods. Each administration of IMP and milk expression will be self-recorded 
Attempting Milk Expression
ICF a and randomization at 
the earliest (observation 
period starts within 48h of 
delivery)
ICF a and randomization 
at the latest (observation 
period starts after 48h of 
delivery)
Delivery
Min. 5 times for the last 48h of 
observation period
Min. 3 times every 24 hours from 24h of delivery to 
the start of observation period
Observation b
min  48 h
Min. 1 time within
12h of delivery
12h
 
48h
72h
24h
ICF
Observation b
min  48 h 
Delivery
Min. 1 time within 
12h of delivery
Min. 5 times for the last 48h of 
observation period
Min. 3 times 
between 24h and 48h 
of delivery 
24h
96 h
Randomization c
12h
48h
ICF
96 h
192 (+4) h
Randomization c


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by maternal subjects. Maternal subjects should stop the administration of IMP as soon as having 
completed 14 days’ treatment, rather than continue dosing until the Day 15/End-of-Treatment visit. 
Trial visits after randomization include Day 3, Day 10, Day 15/End-of-Treatment and Day 18/ 
Follow-up visits. At all of these visits, AEs and concomitant medications of maternal subjects will 
be collected and a review of the dosing (as applicable) and milk expression documentation will be 
performed. 
Specifically, at Day 3 and Day 10 visits at the trial center, milk samples will be taken for the 
analysis of merotocin concentration in the milk and for the analysis of milk composition. Milk 
samples are taken only if the volume of production is, at the discretion of the investigator, adequate 
to meet the needs of the infant. In addition, for the analysis of merotocin concentration in the blood, 
7 blood samples will be drawn for a minimum of 20 maternal subjects at Day 3 and Day 10 visits
using an indwelling catheter at predefined time points from pre-dose until 1 hour after dosing. For 
the pre-dose sample of merotocin concentration, blood sampling should always be performed a 
minimum of 3 hours after the previous dose. Vital signs will also be measured at Day 3 and Day 10 
visits.
Additional Day 15/End-of-Treatment visit procedures consist of a physical examination, vital signs
and blood sampling (safety laboratory).
All maternal subjects who complete the assigned treatment of Days 1 to 14 will be asked to 
continue daily recordings of milk expression through the end of Day 17. The recordings and the 
expressed milk will be collected at the Day 18/Follow-up visit to document the volume of milk 
produced during the post-treatment follow-up period. 
No specific trial procedures are required for infants. All infant data are based on hospital records. 
Infant body weight and infant enteral feeds (volume of MoM and formula/donor milk fed to the 
infant) will be collected from hospital records for all days as available from Day 1 to Day 14. 
Concomitant medications and AEs including morbidity events of special interest (NEC, 
intra-ventricular hemorrhage, BPD, RDS, late-onset sepsis, ROP, and hemodynamically significant 
patent ductus arteriosus) will be collected from hospital records from signing of informed consent. 
See Section 6 for further details.
Milk Expression Procedures
Maternal subjects will attempt to express milk with a multi-user, electric, double-pumping breast 
pump (Medela Symphony, Medela Inc., McHenry, Illinois) at least 5 times every 24 hours during 
the observation period and 6 to 8 times every 24 hours during the treatment and post-treatment 
follow-up periods, including at least once during the night and with no more than 5 hours between 
milk expression sessions. Both breasts should be pumped and emptied in accordance with the 
instructions provided in the lactation manual for subjects. Maternal subjects will also receive 
instructions on hand expression and hands-on pumping; use of the two methods is at subject’s own 


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choice. All maternal subjects will receive detailed and standardized lactation instructions and expert 
lactation support. Steps will be taken to standardize best supportive care across trial centers. 
Milk expression will be conducted mostly with the breast pump, occasionally by hand expression 
(as subject wishes) or by breastfeeding the infant (only when the infant is considered by NICU staff 
to be capable of being breastfed). Breastfeeding will always be followed by further expression with 
the breast pump. Hand expression is permitted both immediately after a pumping session and in 
between pumping sessions during the observation period; however, once the subject has been 
randomized, hand expression is permitted only immediately after a pumping session. Hand 
expression in between pumping sessions during the observation period is to be recorded as a 
separate session but will not be included in the stated goal of milk expression frequency, i.e., at 
least 5 times every 24 hours.
The expressed milk will be collected into supplied containers in accordance with the instructions 
provided in the lactation manual for subjects (see Section 7.1.1). Maternal subjects may bring 
bottles of expressed milk to the trial center any day during the trial, and the weights of the milk 
expressed will be recorded in accordance with instructions provided in the milk weighing 
procedures manual by the trial center staff. The recorded weight of milk expressed in grams will be 
converted to a volume of milk using a conversion of 1 g to 1 mL.23 Expressed milk will be stored 
for feeding to the infant after recording the milk weights. If expressed milk is fed to the infant
before it is weighed, the fed volume should be noted separately.
Should breastfeeding occur, the amount of breastfed milk is established by weighing the infant
before and after the breastfeeding has been completed by following standardized weighing 
instructions and by using a standardized scale.24 Breastfeeding will only occur when the trial center
staff consider the infant has the ability to achieve a nutritional feed through breastfeeding. The 
weights before and after breastfeeding will be recorded. After breastfeeding her infant, the maternal 
subject should continue to express milk using the breast pump in accordance with instructions 
provided in the lactation manual for subjects and record the milk expression. 
The fed volumes of MoM and of other enteral feedings (formula/donor milk) will be recorded by 
trial center staff based on the hospital records. It is expected that the majority of the infants will be 
hospitalized for the predominant or entire duration of the trial due to their prematurity. If the infant
is discharged prior to the Day 18/Follow-up visit, the maternal subject will be instructed to continue 
to use the trial medication as planned and continue to record milk expression as instructed in the 
lactation manual for subjects and milk weighing procedures manual. Two standardized scales will 
be offered to the maternal subject for the recording of milk expression at home, one for measuring 
the weight of the expressed milk and one for measuring the weight of the infant before and after 
feeds (if the subject is breastfeeding). 
Post-trial Activities
As part of post-trial activities after the Day18/Follow-up visit, infant AEs and concomitant 


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medications will continue to be collected from hospital records through infant’s discharge from 
NICU or until the last milk sample expressed during maternal subject’s treatment with IMP is either 
consumed by the infant or discarded, whichever occurs last. Information on infant’s morbidity 
events of special interest is collected through infant’s discharge from NICU based on hospital 
records. 
In addition, the following data will be collected from the hospital records as available when the 
infant is discharged from NICU: infant body weight, length and head circumference at time of 
discharge from NICU, time to full enteral feeds, time to discharge from NICU, number of days the 
infant requires TPN until discharge from NICU, type of feeding (MoM and formula/donor milk) at 
time of discharge from NICU, and whether the maternal subject is lactating at time of infant’s 
discharge from NICU. 
A further post-trial activity is to establish a contact with the maternal subject (by phone or other 
means) about one month after the infant’s NICU discharge to inquire about any hospital re-
admission of the infant and the reason for such. 
For long-term follow-up, the Ages and Stages Questionnaire-3 (ASQ-3) will be administered in all 
infants at 9 months, 18 months and 24 months of corrected gestational age. A primary caregiver of 
the infant will answer the questionnaire that consists of approximately 30 questions covering five 
domains of development, including communication, gross motor, fine motor, problem-solving, and 
personal-social skills. 
Data from post-trial activities will be provided in an addendum to the clinical trial report.
3.1.3
Trial Schedule
Estimated First Patient First Visit:
Q4 2019
Estimated Last Patient First Visit:
Q2 2023
Estimated Last Patient Last Visit/End-of-Trial:
Q2 2023
Post-trial activities completed:
Q2 2025
3.2
Planned Number of Trial Centers and Subjects
Approximately 100 maternal subjects will be randomized at approximately 15 trial centers in the 
United States. It is anticipated that approximately 250 maternal subjects will be screened. See 
Section 9.1.
3.3
Interim Analysis
An unblinded interim analysis for futility assessment is planned when approximately 50% of the 
planned 100 subjects have completed the assigned treatment period of the trial. The interim analysis 


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will assess the futility of merotocin compared to placebo (see Section 9.9).
3.4
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) consisting of medical and biostatistics experts 
will be established to review the interim clinical data for the futility assessment (see Section 9.9). 
The DMC have access to the unblinded interim data and will make a recommendation regarding the 
continuation of the trial. The responsibilities, membership, and procedure for the futility 
assessment, the measures used to protect the blind, the integrity of the trial, and the communication 
pathway to the Sponsor are specified in the DMC charter.
3.5
Safety Committee
A Safety Committee will be established by the Ferring Global Pharmacovigilance Department 
(GPV) and will consist of at least Ferring’s pharmacovigilance physician, Ferring’s global 
regulatory affairs representative, the trial statistician, the medical monitor and an external 
neonatology specialist as specified in the Safety Committee charter. 
The Safety Committee will meet regularly, at least every third month, to evaluate the safety of the 
subjects in terms of AEs, safety laboratory parameters, results from milk composition analyses, and 
any concentration of merotocin in milk on an ongoing basis. In case of any safety concerns, the 
Safety Committee can recommend whether the trial should be stopped or should continue with or 
without modifications to ensure the safety of the subjects and to maintain an appropriate 
benefit/risk ratio for the subjects participating in the trial. 
The Safety Committee will not routinely unblind data on the individual level but may decide to 
unblind data on the group level to allow further analysis. If unblinding on the individual treatment 
level is required, an ad hoc safety group consisting of an independent GPV representative, an 
independent statistician and an external neonatology expert other than the expert in the Safety 
Committee will be formed to analyze the unblinded data. None of the ad hoc safety group members 
will be involved in the conduct of the trial. 
The analyses of merotocin concentrations in milk will be performed by the Bioanalysis Department
on an ongoing basis throughout the trial. Any quantifiable amount of merotocin observed in any of 
the samples will be communicated to the Safety Committee in a blinded manner. If one or more 
milk samples with quantifiable amount of merotocin is reported, the treatment allocation will be 
unblinded on the individual level by an ad hoc safety group, consisting of an independent GPV 
representative, an independent statistician and an external neonatology expert other than the expert 
in the Safety Committee. The ad hoc safety group will also review unblinded safety data. The 
United States Food and Drug Administration (FDA) will be notified of the finding and will be 
provided with observed neonatal AEs. 


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A Safety Committee charter will specify the relevant details and responsibilities of the Committee.
3.6
Discussion of Overall Trial Design and Choice of Control Groups
3.6.1
Trial Design
This trial will investigate the efficacy and safety of repeated intra-nasal administrations of 
merotocin compared to placebo in increasing milk production in women with preterm delivery and 
inadequate initial milk production. 
The trial design employs best practices for establishing an adequate milk supply. All maternal 
subjects will institute a high frequency milk expression regimen and will receive standardized
lactation counselling and ongoing support consistent with guidelines for promoting lactation in this 
population.
There is no approved product for women with lactation deficiency in the country where the trial 
will be conducted. Some pharmacologic agents are used in clinical practice to increase milk supply, 
but there is only limited medical evidence to support the safety and efficacy of the use of these 
agents to correct lactation deficiency in women with preterm delivery.25,26,27 For these reasons, a 
placebo comparator is necessary to evaluate the potential of merotocin to increase milk production 
in this population. 
The window for randomization, originally set to 96 to 144 hours of delivery, was chosen to enhance 
the probability of selecting maternal subjects who truly have an inadequate milk supply but also to 
ensure that intervention is instituted early enough in the postpartum period to have an impact. By 
the amendment (dated 06-04-2022), the window was expanded to 96 to 192 (+4) hours of delivery 
to allow adequate time for the maternal subjects to appreciate and understand the value of 
participating in the trial, with a negligible risk for any negative impact on induction of lactation.
Allowing randomization earlier in the postpartum period might select maternal subjects, whose 
milk supply appears inadequate due to delayed onset of lactogenesis II but who may ultimately 
establish an adequate milk supply without intervention. 
The treatment period of 14 days was primarily chosen because, if merotocin is effective, it would 
act early in the process of establishing lactation by promoting full emptying of the breast via milk 
ejection and possibly by increasing prolactin levels to increase milk synthesis. Both of these are 
important to establish an adequate milk supply. The duration of treatment needed for merotocin to 
achieve its potential effect in increasing milk production is not known. A treatment duration of 
14 days will allow for exploration of when the treatment effect of merotocin begins and how the 
effect may develop over time. 
To obtain the required number of maternal subjects within the scheduled recruitment period and to 
produce generalizable results, a multicenter design has been chosen. Maternal subjects will be 
randomly assigned to their treatments, and both the maternal subjects and investigators will be 


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blinded to the assignment to reduce bias. 
3.6.2
Selection of Endpoints
The primary endpoint for this trial is volume of MoM produced over Days 1 to 14. The volume of 
MoM produced for each treatment day will be recorded and derived for each subject. These daily 
volumes of MoM produced will be analyzed using a repeated measures analysis of covariance 
(ANCOVA) to allow for investigation of the overall treatment effect in the primary analysis and the 
onset of treatment effect of merotocin compared to placebo in supportive analyses.
The secondary endpoints (Section 2.2) will provide further evaluation of the milk volume produced 
over Days 1 to 14. The recommendation for a lactating mother of a non-nursing preterm infant is to 
establish an adequate milk supply, defined as a daily milk volume of ≥500 mL, during the first two 
weeks after delivery. Evidence suggested that adequate milk production at 1-2 weeks postpartum, 
particularly 1 week postpartum, is highly predictive of milk adequacy at 6 weeks postpartum.1
Therefore it is clinically relevant to assess the time it takes for maternal subjects to reach the target 
daily milk volume of ≥500 mL or a more ambitious goal of ≥750 mL. Striving for reaching these 
targets sooner than later may also motivate mothers to continue milk expression on a regular basis. 
For the same purpose, an additional secondary endpoint, an assessment of the proportion of women 
with an ‘adequate milk supply’ over Days 1 to 14 is also included.
The secondary endpoints will also examine whether any observed treatment effect of merotocin is 
maintained over the three days after discontinuation of treatment. The infant body weight is a
standard growth parameter to indicate that the infant is growing and developing as expected. The 
safety assessments selected are standard for the maternal subjects.
The effect of merotocin on milk composition as well as the relationship between merotocin 
exposure and milk volume will be explored.
For the post-trial endpoint related to time to tolerance of full enteral feed, 150 mL/kg/day is used to 
define full enteral feed in order to standardize the assessment.28,29 For the long-term follow-up of 
infants, the administration of ASQ-3 has been recommended by both FDA and American Academy 
of Pediatrics to screen child developmental disorders.
3.6.3
Blinding
The present trial is double-blind. Investigators, trial center staff and maternal subjects will remain 
blinded to treatment allocation until the database has been locked and the trial has been unblinded.
Blinding is achieved by randomizing subjects in a 1:1 ratio to merotocin nasal spray or placebo 
nasal spray, which are identical in appearance. 
At Ferring, personnel at the Bioanalysis Department analyzing blood and milk samples for 
merotocin will be blinded to treatment allocation when performing the analyses. The rest of the 


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Ferring clinical trial team will be blinded to individual and group treatment allocation until 
breaking of the blind after database lock, except for the Safety Committee members who may be 
unblinded to group treatment allocation under special circumstances (see Section 3.5). DMC 
members will have access to unblinded interim data to assess the futility at the interim analysis (see 
Section 3.4).
3.6.4
Selection of Doses in the Trial
In a combined single ascending and multiple ascending dose trial in healthy non-lactating women, 
there were no safety concerns with intra-nasal doses up to 400 µg every 3 hours for 45 hours.19
A single-dose milk transfer trial in maternal subjects who had recently delivered a full term infant 
has been completed. In that trial, merotocin was administered as an intravenous dose of 20 µg 
equivalent to 400 µg intra-nasally without safety concerns. The concentration of merotocin in the 
milk of these subjects was below the lower limit of quantification in all samples.19
These previous trials provide the basis for a dose of 400 µg to be administered intra-nasally before 
the milk expression session 6 to 8 times every 24 hours in the current trial.
3.6.5
Selection and Timing of Dose for Each Subject
Following intra-nasal administration of merotocin, the time to maximum observed concentration 
(tmax) and t½ are approximately 12 to 15 minutes and 25 to 35 minutes, respectively.19 In the phase 1 
milk transfer trial, pharmacodynamic effect of merotocin in the form of uterine contractions were 
observed within 5 to 10 minutes after an intravenous dose equivalent to 400 µg intra-nasally. 
Therefore, the treatment for the maternal subject is administered intra-nasally as 1 spray in each 
nostril approximately 5 to 10 minutes before each milk expression session.
3.6.6
Selection of the Trial Population
A high proportion of the mothers of premature infants experience challenges in establishing an 
adequate milk supply. Due to the prematurity of the infant and the infant’s diminished ability to 
suckle, these mothers are often deprived of the natural stimulus for lactation and may be dependent 
upon a breast pump. Breast pump dependency means that the pump is the primary driver of milk 
removal and mammary gland stimulation even though the infant may be able to feed at the breast.30
The stress of having a premature infant may further impede milk production. On the other hand, the 
potential benefits of MoM in preterm infants are well documented,2,31 which is likely to highly 
motivate mothers of preterm infants to express milk. For benefits to both mothers and infants, there 
are minimal ethical concerns about requiring a stringent milk expression schedule. 
The trial population is women with infants at a high degree of prematurity. A gestational age range 
of 24 weeks + 0 days to 31 weeks + 6 days was originally chosen. However, by the amendment 


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(dated 06-04-2022), the window was expanded to 34 weeks + 2 days because many women who 
deliver infants at this gestational age are breast pump dependent and struggle to achieve an 
adequate milk supply. The upper limit of the gestational age is chosen to ensure the infants who are 
primarily breastfeeding at the time of enrollment would not be eligible. More breastfeeding may 
occur towards the end of the trial period among women who have delivered infants at the upper end 
of the gestational age range per eligibility criteria; however, that is not necessarily indicative of 
breast pump independence. Prematurity is one of several reasons for breast pump dependency; 
however, it is a focus of this early phase trial because of the high proportion of milk supply 
inadequacy experienced by women with premature birth.
3.6.7
Post-treatment Follow-up Procedures
All maternal subjects who complete the assigned treatment of Days 1 to 14 should continue 
expressing milk and recording milk expression sessions through the end of Day 17. The 
Day 18/Follow-up visit, which can be postponed for a maximum of 2 days. At the Day 18/
Follow-up visit, trial center staff will document the milk expression session data during the post-
treatment follow-up period, which will provide information on the maintenance of any observed 
treatment effect. Collection of AEs and concomitant medications will also be performed. Follow-up 
visit may occur early in case of premature discontinuation (i.e., 3 days after the End-of-Treatment
visit), which can also be postponed for a maximum of 2 days.
3.6.8
Post-trial Activities
Collection of infant AEs and concomitant medications will continue after the Day 18/Follow-up 
visit. These AEs will be collected and reported separately from those collected and reported 
through the Day 18/Follow-up visit. The AE collection will stop on the date the infant is discharged 
from the NICU or the last milk sample expressed during maternal subject’s treatment with IMP is 
either consumed by the infant or discarded, whichever occurs last. 
Additional data will be collected from the hospital records of the infant when the infant is 
discharged from NICU. The additional data (if available) are body weight, length and head 
circumference at time of infant’s discharge from NICU, time to full enteral feeds, time to infant’s 
discharge from NICU, number of days the infant requires TPN until discharge from NICU, type of 
feeding (MoM and formula/donor milk) at time of infant’s discharge from NICU, and whether the 
maternal subject is lactating at time of infant’s discharge from NICU. 
Information on infant’s morbidity events of special interest occurring prior to the infant’s discharge
from NICU, including NEC, intra-ventricular hemorrhage, BPD, RDS, late-onset sepsis, ROP, and 
hemodynamically significant patent ductus arteriosus, are recorded at the time of discharge from 
NICU based on hospital records. The trial is not powered to draw conclusions on the incidences of 
these events, but they are collected in order to capture any trends on the impact of feeding patterns 
on their incidences. 


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A further post-trial activity is to establish a contact with the maternal subject (by phone or other 
means) about one month after the infant’s NICU discharge to inquire about any hospital 
re-admission of the infant and the reason for such. 
For long-term follow-up, the ASQ-3 will be provided for all infants at 9 months, 18 months and 
24-months of corrected gestational age. A primary caregiver of the infant will answer the 
questionnaire that consists of approximately 30 questions covering five domains of development,
including communication, gross motor, fine motor, problem-solving, and personal-social skills. 
Data from post-trial activities will be provided in an addendum to the clinical trial report.
3.6.9
Access to Therapy after Day 15/End-of-Treatment
Concerning access to therapy after completion of the trial, merotocin is currently under clinical 
development and cannot be offered to subjects after participation in this clinical trial. 


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4
SELECTION OF TRIAL POPULATION
4.1
Trial Population
4.1.1
Inclusion Criteria
Inclusion criteria for entry into observation period: 
Maternal subject:
1. Signed and dated informed consent for the maternal subject and parental consent for the 
infant prior to any trial activity.
2. Aged 18 to 44 years at the time of informed consent.
3. Delivered at the hospital system associated with the trial center.
4. Delivered a preterm singleton at a gestational age of 24 weeks + 0 days to 34 weeks + 
2 days.
5. Attempted initial milk expression within 12 hours of delivery.
6. Attempted milk expression at least 3 times every 24 hours from 24 hours of delivery to the 
start of observation period (at least 3 times between 24 and 48 hours of delivery for subjects 
who enter the observation period within 48 hours of delivery).
7. Is willing to express milk at least 5 times every 24 hours during the observation period and 
6 to 8 times every 24 hours during the treatment and post-treatment follow-up periods, 
including at least once during the night and with no more than 5 hours between milk 
expression sessions, during the trial (up to 23 days).
8. Is willing to refrain from sexual intercourse during the trial.
Inclusion criteria for randomization (in addition to the criteria above):
Maternal subject:
9. Attempted milk expression using the breast pump at least 5 times every 24 hours for the last 
48 hours of the observation period, i.e., the 48 hours prior to the last pumping session before 
randomization.
10. Accurately recorded timing of milk expression after providing informed consent.
11. Produced <200 mL milk for the last 24 hours of the observation period (the 24-hour baseline 
interval), i.e., the 24 hours prior to the last pumping session before randomization.
12. Delivered 96 to 192 (+4) hours prior to randomization.


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4.1.2
Exclusion Criteria
At screening, maternal subjects meeting any of the criteria listed below are not eligible for 
participation in the trial.
Maternal subject:
1. Has a pre-pregnancy body mass index (BMI) >50.
2. Has chronic or temporary medical conditions that would cause her to be unable to comply 
with the protocol or be unable to attend all trial visits.
3. Has mastitis.
4. Had known breast trauma, previous breast surgery (including breast augmentation or breast 
reduction) or nipple piercing.
5. Has known prolactin-releasing pituitary tumor, a history of Sheehan’s syndrome, or had 
previous pituitary surgery or radiation therapy.
6. Has any known maternally driven contraindication to breastfeeding.
7. Has known pre-pregnancy severe cardiovascular disease (e.g., uncontrolled chronic
hypertension, severe arrhythmias, or Grade 3-4 New York Heart Association cardiac 
failure). Note: preeclampsia is allowed.
8. Has known pre-pregnancy insulin-dependent diabetes mellitus, polycystic ovarian 
syndrome, or any other condition that would impact lactation in the opinion of the 
investigator. Note: gestational diabetes is allowed (also when requiring the use of insulin for 
treatment).
9. Has unstable thyroid disease, i.e., has required dose adjustment of thyroid replacement or 
anti-thyroid medication in the 12 months prior to delivery.
10. Has known moderate or severe renal or hepatic impairment.
11. Has significant history of mental illness, including diagnosed postpartum depression, which 
could impede trial participation.
12. Has significant nasal congestion or mucous production that would impede use of a nasally 
administered product in the opinion of the investigator.
13. Has used or is currently using any of the following concomitant medications:

Any anti-psychotic drugs during the previous 12 months. Note: anxiolytic and 
antidepressant medications are allowed

Any other non-registered investigational drugs from 90 days prior to delivery or within 
5 half-lives of the drugs, whichever is longer 

Any hormonal contraception at any point following delivery 

Any pharmacologic or complementary (e.g., herbal) galactagogue therapy at any point 
following delivery. However, use of oxytocin for prevention or treatment of postpartum 
hemorrhage prior to randomization is not exclusionary 

Any concomitant medication that could suppress lactation at any point following 
delivery


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
Orally or parenterally administered steroids at any dose or inhaled steroids at doses 
>600 µg/day at any point following delivery

Prostaglandins at any point following delivery
14. Had postpartum hemorrhage of >1500 mL requiring transfusion or with current severe 
anemia (hemoglobin <8 g/dL).
15. Currently abuses or has previously abused (within 12 months prior to delivery) drugs or 
currently abuses or has previously abused (within 12 months prior to delivery) alcohol (i.e.,
>7 units/week).
16. Has suspected allergy to oxytocin or merotocin or to any of the excipients in the 
investigational medicinal products (IMPs) used in the trial.
17. Is unable to understand language(s) spoken or provided in writing to her at the trial center.
18. Has previously participated in the current trial.
At randomization the following exclusion criteria apply in addition to the screening criteria:
Maternal subject:
19. Has used or is currently using methergine within 12 hours prior to randomization
20. Has any conditions that would require the concomitant use of any intranasal medications or 
any diuretic drugs throughout the trial.  
21. Any clinically significant abnormal findings of safety laboratory parameters considered by 
the investigator to be unsuitable to participate in the trial.
Infant:
Has low probability of viability, as judged by the investigator.
Was transferred to another hospital system during screening, or is likely to be transferred to 
another hospital system during treatment period as judged by the investigator.
Has used any non-registered investigational drugs since delivery.
4.2
Method of Assigning Subjects to Treatment Groups
4.2.1
Recruitment
Maternal subjects who have delivered a preterm infant within the previous 144 hours and who meet 
all of the inclusion and none of the exclusion criteria will be recruited from the postpartum area of 
the hospital. Trial center staff will approach potential maternal subjects and discuss the trial, 
including potential risks and benefits, as well as trial procedures and timelines involved with 
participation. Subjects may also be approached prior to delivery where feasible to receive 
information about the trial, but no informed consent should be obtained, nor should any trial-related 
activities be performed, until after delivery.


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Advertisements may be used if approved by the local Institutional Review Boards (IRBs) and 
regulatory authorities, as applicable according to local regulations.
A screening number will be allocated to each subject who has given written informed consent to 
participate in the trial. A subject must always be assigned the lowest available screening number at 
each trial center. A screening log must be maintained by the investigator.
4.2.2
Randomization
Randomization of eligible maternal subjects will occur between 96 and 192 (+4) hours of delivery 
and immediately after completion of the observation period. Every effort should be made to 
randomize maternal subjects as early as possible, but not earlier than 96 hours of delivery. Prior to 
randomization, maternal subjects must be followed during an observation period of at least 
48 hours for the collection of milk expression data. 
For the purpose of determining eligibility for randomization, the volume of milk produced for the 
24-hour baseline interval of the observation period will be calculated automatically in the electronic 
case report form (e-CRF).
Randomization is stratified by gestational age group (<27 weeks and ≥27 weeks) and by site. An 
independent statistician at the Ferring Global Biometrics Department will prepare a computer-
generated randomization list. The randomization will be performed in blocks. The block size will 
only be revealed when the trial database is declared clean and locked.
The randomization is performed centrally and electronically. The randomization number will be 
allocated to the subject together with the treatment allocation. 
4.3
Restrictions
4.3.1
Prior and Concomitant Therapies
Any concomitant medication (from 90 days before delivery) will be recorded in the e-CRF, 
together with the main reason for its prescription. This information will be abstracted from the 
hospital records and provided by the maternal subject, as appropriate. The dose and dosage regimen 
will be documented in the e-CRF. Medication that is considered necessary for the maternal 
subject’s safety and well-being may be given at the discretion of the investigator and recorded in 
the appropriate sections of the e-CRF.


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4.3.2
Prohibited Therapy
The following concomitant medications are prohibited:

Any anti-psychotic drugs during the previous 12 months (e.g., aripiprazole, asenapine 
maleate, clozapine, iloperidone, lurasidone, olanzapine, olanzapine/fluoxetine, paliperidone, 
quetiapine, risperidone, chlorpromazine, chlorprothixene, haloperidol, mesoridazine and 
trifluoperazine) (Note: anxiolytic and antidepressant medications are allowed)

Any other non-registered investigational drugs from 90 days prior to delivery or within 
5 half-lives of the drugs, whichever is longer

Any hormonal contraception at any point following delivery

Any pharmacologic or complementary (e.g., herbal) galactagogue therapy at any point 
following delivery (e.g., oxytocin, prolactin, metoclopramide, domperidone, sulpiride, 
fenugreek, shatavari, torbangun and milk thistle). However, use of oxytocin for prevention or 
treatment of postpartum hemorrhage prior to randomization is allowed

Any concomitant medication that could suppress lactation (e.g., bromocriptine, cabergoline, 
ergotamine, ergometrine, lisuride, levodopa, pseudoephedrine, bupropion) at any point 
following delivery

Orally or parenterally administered steroids at any dose or inhaled steroids at doses 
>600 µg/day at any point following delivery

Prostaglandins at any point following delivery

Methergine from 12 hours prior to randomization

Any intra-nasally administered concomitant medication from the time of randomization

Any diuretic drugs from the time of randomization
4.3.3
Other Restrictions
Other restrictions for maternal subjects continuing in the trial are the following:

Subjects must not abuse drugs or abuse alcohol (i.e., >7 units/week)

Subjects must not have significant nasal congestion or mucous production

Subjects must not use hand expression in between pumping sessions after randomization


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4.4
Discontinuation and Stopping Criteria
4.4.1
Discontinuation Criteria
Maternal subjects will be discontinued from the trial in the following circumstances:

A subject’s substantial non-compliance. Before discontinuing a subject from the trial due to 
substantial non-compliance, the investigator should contact the sponsor to discuss the 
discontinuation

The investigator’s opinion that a subject should be discontinued due to safety concerns, 
including any adverse event indicating that continued participation endangers the safety of 
the subject and the infant. 

Request for termination of the trial by regulatory authorities or sponsor
If, at the time of subject withdrawal, a dose of the IMP has already been administered, the subject 
must be advised on the importance of the follow-up safety investigations as outlined in the protocol.
For all discontinuations, the investigator will obtain all required details and document the date of 
the premature termination and the main reason in the e-CRF.
Withdrawal of consent
The maternal subjects have the right to withdraw from the trial at any time for any reason, without 
the need to justify the decision. However, the investigator should record the reason for the subject’s 
withdrawal, if possible. 
If the subject withdraws her consent, no further data will be obtained. However, already obtained 
samples or data may be analyzed. This will be described in the informed consent. The subject can 
request destruction of samples, which would otherwise have been kept in storage.
4.4.2
Trial Stopping Criteria  
The Safety Committee will evaluate the safety of the maternal subjects in terms of AEs, safety 
laboratory parameters, results from milk composition analyses, and results of merotocin 
concentrations in milk on an ongoing basis.
If one or more milk samples with any quantifiable amount of merotocin in milk is reported, data 
will be unblinded on an individual level by the unblinded ad-hoc safety group consisting of an 
independent GPV representative, an independent statistician and an external neonatology expert
other than the experts in the Safety Committee (see Section 3.5). In such cases, the ad-hoc safety 
group will analyze all infant data available in the database as well as other information in the 
hospital records. If a suspicion arises from these investigations that there is an AE, that is possibly 
related to the administration of merotocin, the Safety Committee will be informed and will consider 
appropriate action including that of a recommendation to stop the trial.


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In case of the following safety concerns, the Safety Committee can recommend to stop or modify 
the trial (e.g. continue with reduced dose):

Concentration of merotocin in the milk above the pre-defined safety margin (63.8 ng/mL)
In addition, the DMC may recommend to stop the trial depending on the finding of futility during 
the planned interim analysis.
4.5
Subject Replacement
Subjects who discontinue prematurely from the trial after randomization are not to be replaced. 
Randomization numbers are uniquely linked to each subject and cannot be re-used. 


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5
TREATMENTS
5.1
Treatments Administered
5.1.1
Investigational Medicinal Products 
The IMPs of the trial include merotocin nasal spray and placebo nasal spray.
Eligible maternal subjects will be randomly assigned in a 1:1 ratio to receive either merotocin nasal 
spray (400 µg per dose, divided into 2 sprays with 1 spray in each nostril) or placebo nasal spray. 
Maternal subjects will use their assigned nasal spray a maximum of 8 times every 24 hours (a 
maximum daily dose of 3200 µg) from the time of randomization for 14 treatment days (i.e., Days 1 
to 14). Treatment is administered intra-nasally as 1 spray in each nostril approximately 5 to 
10 minutes before a milk expression session. Each single spray constitutes half a dose (200 µg) and 
maternal subject must administer the spray in both nostrils to receive the 400 µg dose.
Subjects should aim to express milk 6 to 8 times every 24 hours including at least once during the 
night and with no more than 5 hours between milk expression sessions. As the IMPs will be 
administered only prior to milk expression, the exact daily dose of merotocin may vary for each 
maternal subject on each treatment day. Table 1 presents the total daily dose of merotocin 
administered to maternal subjects based on milk expression frequency. The IMP should be 
administered prior to consecutive milk expression sessions at least 2 hours apart for a maximum of 
8 times per treatment day. Subjects should follow instructions on how to use the nasal spray 
correctly and take precautions (e.g., washing hands after IMP administration but before milk 
expression) to avoid potential indirect transfer of IMP into milk. 
Table 1
Total Daily Dose of Merotocin by Milk Expression Frequency
Milk Expression Frequency 
Total Daily Dose of 
Merotocin (µg)
5 times per treatment day
2000
6 times per treatment day
2400
7 times per treatment day
2800
8 times per treatment day
3200 
9 or more times per treatment day
3200 
In this trial, treatment days start from the time of randomization, with Day 1 being the first 24 hours after randomization, Day 2 
being 24 to 48 hours after randomization and so on. The treatment period will include 14 such consecutive intervals of 24 hours from 
the time of randomization, corresponding to 14 treatment days (Days 1 to 14). 
Maternal subjects will be exposed to merotocin or placebo for 14 days, depending on 
randomization. 
5.1.2
Non-Investigational Medicinal Product
No non-investigational medicinal product will be provided.


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5.2
Characteristics and Source of Supply
All IMPs are provided by Ferring and will be handled according to the principles of Good 
Manufacturing Practice (GMP). Table 2 provides an overview of the presentation and manufacturer 
of each medicinal product.
Table 2
Characteristics of Investigational Medicinal Products
Medicinal 
Product
Compound 
Code 
INN
Presentation/Packaging
Manufacturer
Merotocin
FE 202767
Merotocin
Merotocin is provided as a 9-mL
nasal spray bottle containing 9 mL of 
25 mM citrate/phosphate buffer 
solution (pH 5.5) with merotocin at a
concentration of 2.0 mg/mL. The 
solution is clear and colorless. 
Ferring 
Pharmaceuticals 
Placebo
－
－
The placebo product is provided as a 
9-mL nasal spray bottle containing 
9 mL of 25 mM citrate/phosphate 
buffer solution (pH 5.5). The solution 
is clear and colorless.
Ferring 
Pharmaceuticals 
Ferring will provide the trial center or the pharmacy at the trial center with merotocin and matching 
placebo nasal spray in amounts sufficient for the trial.
5.3
Packaging and Labelling
Packaging and labelling of the IMP will be done under the responsibility of the Ferring Clinical 
Trial Supply Department in accordance with GMP and national regulatory requirements.
The IMP will be labelled with trial-specific labels in accordance with applicable requirements in the 
country where the trial is conducted.
Each kit will be labelled with an unique IMP number.
5.4
Conditions for Storage and Use
The investigator will ensure that the IMP will be stored under appropriate conditions in a secure 
location with controlled access. The IMP should be stored refrigerated (2°C to 8°C) (36°F to 46°F, 
Do not freeze) until dispensed to the maternal subject. The storage compartment shall be monitored 
regularly and the temperature shall be documented. Deviations in storage temperature must be 
reported to the sponsor as instructed in the IMP guideline.
After dispensing the IMP to the maternal subject, the IMP can be stored under refrigeration or at 
room temperature over the course of the treatment period. Prior to initial use, the nasal spray should 


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be primed according to instructions provided with the product. The trial center staff will prime all 
nasal spray bottles of IMP prior to weighing and dispensing to the subject.
5.5
Blinding/Unblinding
5.5.1
Blinding
This trial is a double-blind design in which the investigators and the maternal subjects will be 
blinded to treatment allocation throughout the trial. 
The IMP will be packaged according to a computer-generated randomization list prepared for all 
trial centers. Merotocin and placebo nasal spray will be indistinguishable with identical appearance. 
The Ferring Global Biometrics Department will store the randomization list according to Ferring’s 
standard operating procedures. Maternal subject randomization numbers will be linked to IMP
numbers via treatment codes. The randomization list will not be available to any person involved in 
the conduct and evaluation of the trial until the trial database is released to the statistician. All staff 
at each trial center including the trial medication delegates will be blinded to treatment allocation 
throughout the trial.
Ferring personnel at the Bioanalysis Department analyzing blood and milk samples for merotocin
will be blinded to treatment allocation when performing the analyses. The rest of the Ferring 
clinical trial team will be blinded to individual and group treatment allocation until after database 
lock, except for Safety Committee members who may be unblinded to the group treatment 
allocation under special circumstances. DMC members will have access to unblinded interim data 
to assess the futility at the interim analysis and will keep the data and analyses confidential.
5.5.2
Unblinding of Individual Subject Treatment
An emergency procedure will be available to the investigator and designated persons at Ferring
through the e-CRF. Breaking of the blind for individual subjects in emergency situations can be 
required in case of a suspected unexpected serious adverse reaction (SUSAR), in case of an 
important AE where the knowledge of the IMP in question is required for therapeutic decisions for 
the management of the maternal subject, or in case a quantifiable amount of merotocin in the milk 
(see Section 3.5).
As far as the emergency permits, the need to break the blind will be agreed by the investigator and 
Ferring. If the event requires immediate unblinding by the investigator, the sponsor must be 
informed of the unblinding as soon as possible and be provided with the rationale for unblinding.
The investigator who unblinds a maternal subject’s treatment will use the e-CRF and is required to 
enter a password and record the reason for unblinding before the treatment code can be broken. The 
e-CRF records when and by whom the code is broken. The investigator must record the event of 


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unblinding in the maternal subject’s medical record, including the reason for unblinding, but not the 
treatment allocation if this can be avoided.
Under special circumstances (Section 3.5), the treatment allocation will be unblinded on an 
individual level by an ad hoc safety group, consisting of an independent GPV representative, an 
independent statistician and an external neonatology expert other than the expert in the Safety 
Committee.
If Ferring needs to unblind a maternal subject’s treatment, the e-CRF will be used for unblinding. It 
is required to enter a password and record the reason for unblinding before the treatment code can 
be broken. The e-CRF records also when and by whom the code is broken. The code break will 
occur according to corporate operational procedures for unplanned unblinding of trial subjects. It 
may be necessary to unblind an individual maternal subject’s treatment for the purposes of 
expedited reporting to the authorities or IRBs. In that situation, every effort will be made to 
maintain blinding of Ferring personnel involved in data analysis and interpretation. Other personnel 
may be unblinded for SUSARs, including trial center staff as well as staff acting on behalf of 
Ferring.
Information on whether the blind has been broken for any maternal subjects is available in the 
e-CRF and must be collected before the database is declared clean, locked, and released to the 
statistician.
In case the e-CRF cannot be accessed by the investigator, and hence the emergency unblinding 
cannot be performed within the e-CRF system, the investigator should contact Ferring 
Pharmacovigilance using the contact details below: 
Ferring Pharmacovigilance
US Toll-free number: 
 
If Ferring Pharmacovigilance cannot access the e-CRF, a back-up procedure involving the e-CRF
vendor is in place.
5.6
Dispensing and Accountability, Return and Destruction
The IMP must only be dispensed to subjects who meet the eligibility criteria and are randomized in 
this trial. The delegated trial staff will use an interactive response technology (IRT) system to 
assign and dispense IMP kits per the randomization performed within the e-CRF. The delegated 
trial staff will also record the dates and quantities dispensed to and returned by each subject, as well 
as manage the overall drug accountability for each subject within the IRT system. The trial staff
will be blinded to treatment allocation throughout the trial.
The monitor will verify drug accountability of IMP throughout the trial and will document any 
discrepancies. All dispensed IMP will be returned by maternal subjects for drug accountability. 


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Concerning destruction, the delegated trial staff must ensure destruction of dispensed IMP in 
accordance with local legislation after drug accountability has been verified by the monitor within 
the IRT system, while non-dispensed IMP will be returned for destruction as instructed by the 
Ferring Clinical Trial Supply Department.
5.7
Auxiliary Supplies
Ferring will be responsible for providing every maternal subject with a multi-user, electric, 
double-pumping breast pump, a breast pumping kit (with connectors and other necessities), a cooler 
set, weighing scale(s) with a carrying case (if applicable), breast shields, containers, labels,
weighing worksheet (if applicable), scales for weighing milk and infant (if applicable) and a 
supplementary kit. Ferring will also ensure the trial centers receive sufficient amount of all 
auxiliary supplies for the maternal subjects.


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6
TRIAL PROCEDURES
Before performing any trial procedures, consent for potential maternal subjects and infants will be 
obtained. The investigator must address all questions raised by the parent participants and a copy of 
the signed and dated informed consent form(s) will be provided to the maternal subjects and their 
partners (as applicable).
This trial will consist of the following:

A screening period starting when informed consent has been obtained and ending at 
randomization between 96 to 192 (+4) hours of delivery; the screening period must have an 
observation period of a minimum of 48 hours for the collection of milk expression data.

A treatment period of 14 days, including a Day 3 visit, a Day 10 visit and a Day 15/
End-of-Treatment visit. These visits can be postponed for a maximum of 2 days. In this trial, 
treatment days start from the time of randomization, with Day 1 being the first 24 hours after 
randomization, Day 2 being 24 to 48 hours after randomization, and so on. The treatment 
period will include 14 such consecutive intervals of 24 hours from the time of 
randomization, corresponding to 14 treatment days (Days 1 to 14). Trial visits can be 
scheduled according to calendar days without considering 24-hour periods. Maternal subjects 
should stop the administration of IMP as soon as having completed 14 days’ treatment, 
rather than continue dosing until the Day 15/End-of-Treatment visit.

A post-treatment follow-up period with a Follow-up visit on Day 18 for all maternal subjects 
who complete the assigned treatment of Days 1 to 14 or a Follow-up visit 3 days after the 
End-of-Treatment visit in case of premature discontinuation. The visit can be postponed for a 
maximum of 2 days.
No specific trial procedures are required for the infant.
6.1
Trial Flow Chart
Maternal subjects will undergo the procedures at the time points specified in the schedule of events 
as shown in Table 3. Infants will undergo the procedures at the time points specified in the schedule 
of events as shown in Table 4.


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Table 3
Trial Flow Chart – Mother-related Activities 
Procedure
Screening 
Visita
0-144 hours 
of delivery
Randomization
Visit 
96-192 (+4)
hours of
delivery
Treatment
Follow-up
Day 3 
Visitb
Day 10
Visitb
Day 15b/
End-of-
Treatment Visit
Day 18b/
Follow-
up 
Visit
Written informed consent
X
Inclusion/exclusion criteria 
X
Xc
Demographics
X
Medical history
X
Obstetric historyd
X
Lactation historye
X
Antenatal and peripartum historyf
X
Pre-pregnancy BMI
X
Instructions and support for providing MoM
X....………………………………………………………………............X
Breast pump and data collection instructions
X
Record weights of milkg
  X…..………….Xc………………………………………………….........X
Dosing (as applicable) and milk expression
documentation review
X…..………….Xc………………………………………………….........X
Physical examination
Xc
X
Vital signs
Xc
X
X
X
Blood sampling (safety parameters)
X
X
Randomization
X
IMP dispensing and weighing
X
X
X
IMP administration at trial center
Xh
Xh
Xh
Milk expression at trial center
X
Xc , Xi
X
X
Milk sampling for merotocin concentrationj
X
X
Milk sampling for milk compositionk
Xc
X
X
Blood sampling (PK)l
X
X
Drug accountability
X
X
X
Concomitant medications
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
End-of-Trial formm
X
a Screening period runs from the signing of informed consent to randomization and includes an observation period of a minimum of 
48 hours. Maternal subject-related activities may be performed at more than 1 screening visit.
b Day 3, Day 10, Day 15/End-of-Treatment and Day 18/Follow-up visits can be postponed a maximum of 2 days. The maternal 
subjects should stop the administration of IMP as soon as having completed 14 days’ treatment, rather than continue dosing until
the Day 15/End-of-Treatment visit.
c Performed before randomization.
d Including parity and pregnancy outcomes.
e Including number and duration of lactation following previous deliveries (if any) and lactation data from the current postpartum 
period (number of milk expression sessions, timing of the first milk expression attempt, occurrence of skin-to-skin contact, and 
use of hand expression).
f Including gestational age, time and method of delivery, reason for preterm delivery, other pregnancy complications, presence of 
fetal growth restriction, birth weight, spontaneous or induced labor, use of antenatal steroids, and any use of oxytocin postpartum.
g Milk weights are to be recorded for all containers brought to sites during unscheduled and scheduled visits in accordance with 
instructions provided in the milk weighing procedures manual. Should breastfeeding occur, the amount of breastfed milk is 
established by weighing the infant before and after the breastfeeding has been completed by following standardized weighing 
instructions and by using a standardized scale.


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h IMP should be administered approximately 5 to 10 minutes before a milk expression session. IMP administration at sites at Day 3 
and Day 10 visits for PK sampling should occur a minimum of 3 hours after the previous dose.
i Two milk expression sessions are to be performed at the site at randomization: one prior to randomization, the other after IMP 
administration. 
j At Day 3 and Day 10 visit, a milk sample will be taken from milk expressed at the trial center for analysis of merotocin 
concentration in the milk. Samples are taken only if milk production is, at the discretion of the investigator, adequate to meet the 
needs of the infant. 
k At randomization, a milk sample will be taken from milk expressed at the trial center prior to randomization for milk composition 
analysis. At Day 3 and Day 10 visits, milk samples will be taken from milk expressed at the trial center. Samples are taken only if 
milk production is, at the discretion of the investigator, adequate to meet the needs of the infant. 
l Seven PK samples for measurement of merotocin concentration will be collected at Day 3 and Day 10 visits using an indwelling 
catheter at the following time points: pre-dose, 5, 10, 20, 30, 45, and 60 minutes after dosing in a minimum of 20 maternal 
subjects.
m End-of-Trial form should be completed at the subject’s last scheduled visit or at the time of premature discontinuation.
Abbreviations: BMI=body mass index, IMP=investigational medicinal product, MoM=mother’s own milk, PK=pharmacokinetic
Table 4
Trial Flow Chart – Infant-related Activities 
Procedure
Screen-
ing
Visit
0-144
hours 
of
deliver
y
Randomi-
zation
Visit
96-192 
(+4) hours 
of
delivery
Treatment
Post-
treatment
Follow-up
Post-trial Activities
Day 3
Visita
Day 10
Visita
Day 15a/
End-of-
Treatment
Visit
Day 18a/
Follow-up 
Visit
At 
infant’s 
discharge
from 
NICU
One 
month 
after 
NICU 
discharge
Long-
term 
Follow-
up
Exclusion criteria
Xb
Collecting the following data from hospital records
Medical history
Xc
Body weight 
Xd
Xd
Xd
Xd
X
Length and head circumference
X
Concomitant medicationse
X
X
X
X
X
X
X
Adverse eventse
X
X
X
X
X
X
X
Morbidity events of special 
interestf
X
X
X
X
X
X
X
Infant enteral feeds
Xg
Xg
Xg
Xh
Collection of additional NICU 
data
Xh
Collecting the following data by phone or other means
Hospital re-admission and 
reason
X
Administration of ASQ-3
Xi
a Day 3, Day 10, Day 15/End-of-Treatment and Day 18/Follow-up visits can be postponed a maximum of 2 days.
b These assessments may be performed 0 to 144 hours of delivery but must be performed prior to randomization.
c Medical history for the infant refers to congenital conditions and events occurring from birth to signing of informed 
consent by the maternal subject. Events that occur following signing of informed consent are recorded as adverse events.
d Collected for all days from Day 1 to Day 14 as available from hospital records.
e Collected from hospital records from signing of informed consent through time of infant’s discharge from NICU or until 
the last milk sample expressed during maternal subject’s treatment with IMP is either consumed by the infant or 
discarded, whichever occurs last.
f Collected from hospital records from signing of informed consent through infant’s discharge from NICU.
g Infant enteral feeds including volume of MoM and formula/donor milk fed to the infant as available from hospital records 
from Day 1 to Day 14.
h Including time to full enteral feeds, time to infant’s discharge from NICU, number of days the infant requires TPN until 


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discharge from NICU, type of feeding (MoM and formula/donor milk) at time of infant’s discharge from NICU, whether 
maternal subject is lactating at time of infant’s discharge from NICU.
i Completion of the ASQ-3 by a primary caregiver at infants’ 9 months, 18 months and 24 months of corrected gestational 
age. 
Abbreviations: ASQ-3=Ages and Stages Questionnaire-3, MoM=mother’s own milk, NICU=neonatal intensive care unit, TPN=total 
parenteral nutrition 
6.2
Screening Period
Maternal subjects who provide informed consent for participation will enter the screening period as 
soon as possible following delivery. The screening period runs from the signing of informed 
consent to randomization and includes an observation period of a minimum of 48 hours to confirm 
maternal subjects’ compliance with required milk expression frequency. Initial eligibility check and 
screening assessments for a maternal subject should be performed within 144 hours of delivery.
Subjects willing to participate in the trial will undergo the following screening procedures 
(performed by trial center staff unless otherwise specified): 
Maternal subject-related activities at the screening visit:

Maternal subject signs and dates the informed consent and provides parental consent for the 
infant

Perform inclusion and exclusion criteria check

Record demographic and baseline characteristics (date of birth, smoking history, race, 
ethnicity, and education level)

Record medical history 

Record obstetric history, including previous pregnancy and delivery (parity) outcomes

Record lactation history, including number and duration of lactation following previous 
deliveries (if any) and lactation data from the current postpartum period (number of milk 
expression sessions, timing of the first milk expression attempt, occurrence of skin-to-skin 
contact, and use of hand expression) 

Record antenatal and peripartum data from the most recent pregnancy, including gestational 
age, time and method of delivery, reason for preterm delivery, other pregnancy 
complications, presence of fetal growth restriction, birth weight, spontaneous or induced 
labor, use of antenatal steroids, and use of oxytocin in the postpartum period 

Record pre-pregnancy BMI

Record concomitant medications (from 90 days before delivery to the date of signed 
informed consent; prohibited therapy listed in section 4.3.2)

Collect and record AEs occurring since signing of informed consent

Collect blood sample for safety laboratory parameters (Table 6) analysis 


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Prior to the observation period: 

Provide detailed and standardized lactation instructions and support

Provide a multi-user, electric, double-pumping breast pump to maternal subject and an 
adequate number of containers, labels and other relevant trial supplies

Provide training to maternal subject on how to record expression sessions

Instruct maternal subject to express milk from both breasts with the breast pump at least 
5 times every 24 hours during the observation period. Both breasts should be pumped and 
emptied in accordance with the instructions in the lactation manual for subjects. Milk 
expression may also be conducted occasionally by hand expression (as subject wishes) or 
exceptionally by breastfeeding (only when the infant is considered by NICU staff to be 
capable of being breastfed). See Section 7.1.1
At the start of the observation period:

Have the maternal subject express milk using a breast pump under the supervision of trial 
center staff. The observation period (a minimum of 48 hours) will start with this milk 
expression session

Instruct maternal subject to bring all the milk collected to the trial center at each scheduled 
visit, including the randomization visit (if it has not been brought to the trial center)
During the observation period:

Lactation support is available to maternal subject

Maternal subject expresses milk with a breast pump for at least 5 times every 24 hours 
including at least once during the night and with no more than 5 hours between any sessions

Maternal subject collects the milk in the supplied containers and labels and stores the 
containers appropriately

Maternal subject records the milk expression properly on the milk container label in 
accordance with instructions provided in the lactation manual for subjects
Infant-related activities at the screening visit:
Collect the following data from hospital records:

Record medical history 

Record information on morbidity events of special interest (Section 8.4)

Record concomitant medications after signing of informed consent

Collect and record AEs after signing of informed consent


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6.3
Randomization
Randomization of eligible maternal subjects will occur at 96 to 192 (+4) hours of delivery. Every 
effort should be made to randomize maternal subjects as early as possible, but not earlier than 
96 hours of delivery.
Maternal subject-related activities at the randomization visit:
End of observation period

Provide detailed and standardized lactation instructions, support, and training in how to 
weigh milk.

Have maternal subject express milk at the site and record the milk expression properly on the 
milk container label, in accordance with instructions provided in the lactation manual

Weigh the milk collected during the observation period, including the milk from the milk 
expression session just performed, in accordance with instructions provided in the milk 
weighing procedures manual

Review milk expression documentation for completeness and compliance

Perform remainder of inclusion and exclusion criteria check (prohibited therapy listed in 
Section 4.3.2)

Perform physical examination

Measure vital signs (sitting blood pressure and heart rate)

If the maternal subject is still eligible and if the amount of available milk exceeds the needs 
of the infant, collect a milk sample for analysis of milk composition (Section 7.3.2). Sample 
should be taken from the milk expressed at the trial center prior to randomization
Randomization

Randomly assign the trial treatment to the maternal subject through the e-CRF

Prime and weigh each nasal spray bottle before dispensing the IMP kit

Have maternal subject administer first dose of trial medication at the trial center, express 
milk, and record the milk expression properly on milk container labels in accordance with 
instructions provided in the lactation manual for subjects

Instruct maternal subject to bring all the milk collected (if it has not been brought to the trial 
center), her nasal spray bottles, and the milk container labels with recordings of the milk 
expression to the trial center at the Day 3 visit

Record concomitant medications 

Collect and record AEs
Infant-related activities at the randomization visit:
Prior to randomization

Ensure infant exclusion criteria check is performed


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Randomization
Collect the following data from hospital records:

Record infant body weight (for the day of randomization or last recorded value as available)

Record concomitant medications. Each concomitant medication needs to be reported in the 
electronic system only once (dose and frequency may be omitted), as a complete list of 
medications (including dose and frequency, as applicable) may be printed from the hospital 
records, de-identified and sent to the sponsor following discharge of the infant from the 
NICU only if more information is later needed.

Collect and record AEs including information on morbidity events of special interest 
(Section 8.4)
6.4
Treatment Period Days 1 to 14
All maternal subjects will begin treatment as soon as they are randomized. In this trial, treatment 
days start from the time of randomization, with Day 1 being the first 24 hours after randomization, 
Day 2 being 24 to 48 hours after randomization and so on. For example, if a subject is randomized
at 10 AM, her first treatment day or Day 1 is from 10 AM on that day to 10 AM on the next day.
The treatment period will include 14 such consecutive intervals of 24 hours from the time of 
randomization, corresponding to 14 treatment days (Days 1 to 14). Trial visits can be scheduled 
according to calendar days without considering 24-hour periods. The maternal subjects should stop 
the administration of IMP as soon as having completed 14 days’ treatment, rather than continue 
dosing until the Day 15/End-of-Treatment visit, as reminded by the trial center staff on or before
Day 14.
6.4.1
All Treatment Days
Maternal subject-related activities: 

Lactation support is available to maternal subject

Maternal subject administers the trial medication approximately 5 to 10 minutes prior to each 
milk expression session

Maternal subject expresses milk 6 to 8 times every 24 hours including at least once during 
the night and with no more than 5 hours between sessions (Section 7.1.1)

Maternal subject records the required details of dosing and milk expression on milk 
container labels in accordance with instructions provided in the lactation manual

Maternal subject collects the milk into the supplied containers and labels and stores the 
containers appropriately

Maternal subject will be contacted by the trial center staff to ensure compliance with the 
instructions for administration of the medication and recording of the milk expression


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6.4.2
Day 3 Visit 
Day 3 visit can be postponed a maximum of 2 days.
Maternal subject-related activities: 

Weigh the milk collected since the randomization visit and record the corresponding weights
for each milk expression session (this can also be performed any day when the maternal 
subject brings collected milk to the trial center)

Review dosing and milk expression documentation for completeness and compliance

Measure vital signs (sitting blood pressure and heart rate) 

If applicable, insert indwelling catheter, collect blood sample for plasma concentration of 
merotocin (pre-dose sample; a minimum of 3 hours after the previous dose)b

Prime and weigh each nasal spray bottle before dispensing the IMP kit

Have maternal subject administer trial medication prior to milk expression 

If applicable, collect blood sample for plasma concentration of merotocin at 5 minutes after 
dosingb

Have maternal subject express milk at the site and record the milk expression on milk 
container labels in accordance with instructions provided in the lactation manual for subjects

Collect a milk sample for analysis of merotocin concentration (Section 7.2.6) and a second 
milk sample for analysis of milk composition (Section 7.3.2). Samples should be taken from
the milk expressed at this visit. Samples are taken only if the amount of available milk
exceeds the needs of the infant at the discretion of the investigator

If applicable, collect blood samples for plasma concentration of merotocin at 10, 20, 30, 45, 
and 60 minutes after dosingb

Record concomitant medications

Collect and record AEs

Perform drug accountability, including weighing and collection of used IMP  

Instruct maternal subject to bring all the milk collected (if it has not been brought to the trial 
center), the milk container labels with recordings of dosing and milk expression, and her
nasal spray bottles to the trial center at the Day 10 visit
                                                
b Blood samples for the analysis of merotocin concentration are taken in a minimum of 20 maternal subjects.


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Infant-related activities:
Collect the following data from hospital records for all treatment days as available since last visit:

Record body weight

Record infant enteral feeds (volume of MoM and formula/donor milk fed to the infant)

Record concomitant medications

Collect and record AEs including information on morbidity events of special interest 
(Section 8.4) 
6.4.3
Day 10 Visit 
Day 10 visit can be postponed a maximum of 2 days.
Maternal subject-related activities: 

Weigh the milk collected since the Day 3 visit, and record corresponding weights for each 
milk expression session (this can also be performed any day when the maternal subject 
brings collected milk to the trial center)

Review dosing and milk expression documentation for completeness and compliance

Measure vital signs (sitting blood pressure and heart rate) 

If applicable, inset indwelling catheter, collect blood sample for plasma concentration of 
merotocin (pre-dose sample; a minimum of 3 hours after the previous dose)c

Prime and weigh each nasal spray bottle before dispensing the IMP kit

Have maternal subject administer the trial medication prior to milk expression

If applicable, collect blood sample for plasma concentration of merotocin at 5 minutes after 
dosingc

Have maternal subject express milk at the site and record the milk expression on milk 
container labels in accordance with instructions provided in the lactation manual for subjects

Collect a milk sample for analysis of merotocin concentration (Section 7.2.6) and a second 
milk sample for analysis of milk composition (Section 7.3.2). Samples should be taken from
the milk expressed at this visit. Samples are taken only if the amount of available milk
exceeds the needs of the infant at the discretion of the investigator

If applicable, collect blood samples for plasma concentration of merotocin at 10, 20, 30, 45, 
and 60 minutes after dosingc

Record concomitant medications

Collect and record AEs

Perform drug accountability, including weighing and collection of used IMP  
                                                
c Blood samples for the analysis of merotocin concentration are taken in a minimum of 20 maternal subjects.


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
Instruct maternal subject to bring the milk collected (if it has not been brought to the trial 
center), the milk container labels with recordings of dosing and milk expression, and her
nasal spray bottles to the trial center at the Day 15/End-of-Treatment visit

Remind maternal subject to stop administer the trial medication on Day 14

Consider if infant is expected to be discharged prior to maternal subject completion of trial 
and, if needed, provide scales, weighing worksheet, and training to the maternal subject for 
milk and infant weighing (in case of breastfeeding) prior to discharge.
Infant-related activities:
Collect the following data from hospital records for all treatment days as available since last visit:

Record body weight

Record infant enteral feeds (volume of MoM and formula/donor milk fed to the infant)

Record concomitant medications

Collect and record AEs including information on morbidity events of special interest 
(Section 8.4)
6.4.4
Day 15/End-of-Treatment Visit 
End-of-Treatment assessments are performed on Day 15 or the day after the maternal subject’s last 
dose of IMP in case of premature discontinuation. Day 15/End-of-Treatment visit can be postponed 
a maximum of 2 days.
Maternal subject-related activities: 

Weigh the milk collected since the Day 10 visit (if applicable) and record corresponding 
weights for each milk expression session (this can also be performed any day when the 
maternal subject brings collected milk to the trial center)

Review dosing and milk expression documentation for completeness and compliance

Perform physical examination

Measure vital signs (sitting blood pressure and heart rate) 

Collect blood sample for safety laboratory parameters (Table 6) analysis

Record concomitant medications

Collect and record AEs

Perform drug accountability, including weighing used IMP and collection of all used and 
unused IMP

Instruct maternal subject that milk expression information should continue to be collected 
through the end of Day 17 


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Infant-related activities:
Collect the following data from hospital records for all treatment days as available since last visit:

Record body weight 

Record infant enteral feeds (volume of MoM and formula/donor milk fed to the infant)

Record concomitant medications

Collect and record AEs including information on morbidity events of special interest 
(Section 8.4)
6.5
Post-Treatment Follow-up Period (Days 15 to 18)
Maternal subject-related activities:

Lactation support is available to maternal subject

Maternal subject expresses milk 6 to 8 times every 24 hours including at least once during 
the night and with no more than 5 hours between sessions (Section 7.1.1)

Maternal subject records milk expression in accordance with instructions provided in the
lactation manual. For subjects who complete the assigned treatment of Days 1 to 14, milk 
expression information is to be recorded through the end of Day 17 

Maternal subject collects the milk in the supplied containers and labels and stores the 
containers appropriately
6.5.1
Day 18/Follow-up Visit 
All maternal subjects who complete the assigned treatment of Days 1 to 14 will have a Follow-up 
visit on Day 18 or 3 days after the End-of-Treatment visit in case of premature discontinuation. The 
visit can be postponed a maximum of 2 days.
Maternal subject-related activities:

Weigh the milk collected since the Day 15/End-of-Treatment visit (if applicable) and record 
corresponding weights for each milk expression session from Days 15 to 17

Collect and review milk expression documentation for completeness and compliance

Collect scales (if applicable)

Record concomitant medications

Collect and record AEs

Complete End-of-Trial form


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Infant-related activities:
Record the following (from hospital records) for all days as available since last visit: 

Record concomitant medications

Collect and record AEs including information on morbidity events of special interest 
(Section 8.4)
6.6
Post-trial Activities 
6.6.1
Infant-related Activities at Infant’s Discharge from NICU
Collect the following from hospital records for all days as available since last visit, unless otherwise 
noted:

Record body weight, length, and head circumference (for the day of discharge only or last 
recorded values as available)

Record information on morbidity events of special interest (Section 8.4)

Record concomitant medications until the time of infant’s discharge from NICU or until the 
last milk sample expressed during maternal subject’s treatment with IMP is either consumed 
by the infant or discarded, whichever occurs last

Collect and record AEs until the time of infant’s discharge from NICU or until the last milk 
sample expressed during maternal subject’s treatment with IMP is either consumed by the 
infant or discarded, whichever occurs last

Record the date when the infant becomes tolerant to full enteral feeding, date of discharge 
from NICU, number of days the infant requires TPN until discharge from NICU, type of 
feeding (MoM and formula/donor milk) at time of infant’s discharge from NICU, and 
whether the maternal subject is lactating (i.e., breastfeeding or breast pumping) at time of 
infant’s discharge from NICU
6.6.2
Infant-related Activities about One Month after NICU Discharge

Contact the maternal subject, by phone or other means, to establish whether the infant has 
been re-admitted to hospital since the NICU discharge and, if so, the reason for the 
re-admission
6.6.3
Infant-related Activities Long-term Follow-up 

Completion of the ASQ-3 by a primary caregiver at infants’ 9 months of corrected 
gestational age

Completion of the ASQ-3 by a primary caregiver at infants’ 18 months of corrected 
gestational age


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
Completion of the ASQ-3 by a primary caregiver at infants’ 24 months of corrected 
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7
TRIAL ASSESSMENTS
A laboratory manual will cover all blood and milk analyses and describe sampling and shipment 
procedures including contact details, sampling window, storage conditions, equipment, volume, 
analytical method, reference range, etc. The manual will be provided to the trial centers before the 
start of the trial. The total blood volume collected for each maternal subject will be approximately 
9 mL for safety measurements only and approximately 65 mL for both safety and PK 
measurements (only applicable for a subset of minimum 20 subjects).
7.1
Assessments Related to Primary Endpoint
7.1.1
Volume of MoM Produced over Days 1 to 14
In this trial, milk expression will be conducted mostly with the breast pump, occasionally by hand 
expression or exceptionally by breastfeeding the infant. Each milk expression session will be 
conducted in accordance with instructions provided in the lactation manual for subjects. In this trial, 
one session of milk expression is defined as one round of pumping, one round of pumping followed 
immediately by hand expression or one round of breastfeeding followed immediately by pumping. 
In case of pumping combined with either breastfeeding or hand expression, MoM expressed 
through pumping and through the other method will be recorded separately. However, if hand 
expression occurs in between pumping sessions during the observation period, this should be 
considered a separate session but is not included in the stated goal of milk expression frequency, 
i.e., at least 5 times every 24 hours. The expressed milk through pumping and through hand 
expression is collected into supplied containers provided by Ferring and labelled appropriately as 
detailed in the lactation manual for subjects. Milk weighing will be performed as instructed in the 
milk weighing procedures manual. If the infant is discharged to home prior to the Day 18/
Follow-up visit, two standardized scales will be offered to the maternal subject for the recording of 
milk expression, one for measuring the weight of the expressed milk and one for measuring the 
weight of the infant before and after feeds (if the subject is breastfeeding).
Instructions on different milk expression methods and milk collection are summarized in Table 5.


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Table 5
Instructions on Milk Expression and Milk Collection 
Milk 
expression 
method 
Milk expression a,b
Milk collection
Observation period
Treatment and 
follow-up periods
Observation 
period
Treatment
and 
follow-up 
periods
Milk expression 
using the breast 
pump (i.e., 
pumping) 
At least 5 times every 24 
hours including at least once 
during the night and with no 
more than 5 hours between 
milk expression sessions
6-8 times every 24 hours
including at least once 
during the night and with 
no more than 5 hours 
between milk expression 
sessions
Milk collected into separate 
bottles for milk expressed from 
left/right breast and for each 
session. No milk pooling
Hand expression 
Permitted both immediately 
after a pumping session and 
in between pumping 
sessions. b Use of hand 
expression is at subject’s 
own choice
Permitted only 
immediately after a 
pumping session. Use of 
hand expression is at 
subject’s own choice
Milk expressed from left/right 
breast can be pooled into one 
bottle and separate bottles 
should be used for each hand 
expression session
Breastfeeding
Only when the infant is considered by NICU staff to be 
capable of being breastfed and always followed by further 
breast pumping
Results of weighing the infant
before and after breastfeeding
a In this trial, one session of milk expression is defined as one round of pumping, one round of pumping followed immediately by 
hand expression or one round of breastfeeding followed immediately by pumping.
b Hand expression in between pumping sessions during observation period is to be recorded as a separate milk expression session 
and the volume will be included in the MoM calculation, but is not included the stated goal of milk expression frequency, i.e., at 
least 5 times every 24 hours.
The maternal subject will record the required information in accordance with instructions provided 
in the lactation manual. The milk collected at each milk expression session will be weighed in 
accordance with instructions provided in the milk weighing procedures manual by the trial center
staff (if limited availability, the maternal subject may weigh the milk) and recorded when brought 
to the trial center. The recorded weight of milk expressed in grams will be converted to a volume of 
milk using a conversion of 1 g to 1 mL. Expressed milk will be stored for feeding to the infant after 
recording the milk weights.
Breastfeeding will only occur when the trial center staff consider the infant has the ability to 
achieve a nutritional feed through breastfeeding. It is expected that the infant will be hospitalized 
for the predominant or entire duration of the trial due to their prematurity. Should breastfeeding
occur, the amount of breastfed milk is established by weighing the infant before and after the 
breastfeeding has been completed by following standardized weighing instructions and by using a 
standardized scale.24 The weights before and after breastfeeding will be recorded with assistance 
from the NICU staff, if breastfeeding occurs at NICU. If the infant is discharged to home prior to 
the Day 18/Follow-up visit, the maternal subject will be provided with a standardized scale to use at 
home for measuring the weight of the infant before and after feeding and will record the required 
information for each breastfeeding session in accordance with instructions provided in the lactation 


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manual for subjects. After breastfeeding her infant, the maternal subject should continue to express 
milk using the breast pump.
The milk volume collected on each day from Days 1 to 14, including any amount given to the 
infant by breastfeeding, will be calculated as the total production in each treatment day. In this trial, 
treatment days start from the time of randomization, with Day 1 being the first 24 hours after 
randomization, Day 2 being 24 to 48 hours after randomization and so on. For example, if a subject 
is randomized at 10 AM, her first treatment day or Day 1 is from 10 AM on that day to 10 AM on 
the next day. The treatment period will include 14 such consecutive intervals of 24 hours from the 
time of randomization, corresponding to 14 treatment days (Days 1 to 14). Trial visits can be 
scheduled according to calendar days without considering 24-hour periods.
7.2
Assessments Related to Secondary Endpoints
7.2.1
Time to the First Occurrence of a Daily Volume of MoM ≥500 mL and ≥750 mL
The volume of MoM produced on each treatment day will be calculated by using recorded weights 
of expressed milk in the same method as described in Section 7.1.1. The time from randomization 
to the first treatment day when maternal subjects produce a daily volume of MoM ≥500 mL and 
≥750 mL will be calculated. 
7.2.2
Proportion of Subjects with a Daily Volume of MoM ≥500 mL and ≥750 mL
The volume of MoM produced on each treatment day will be calculated by using recorded weights 
of expressed milk in the same method as described in Section 7.1.1. The proportion of maternal 
subjects who produce a daily volume of MoM ≥500 mL and ≥750 mL will be calculated for every 
treatment day from Days 1 to 14. 
7.2.3
Volume of MoM Produced over Days 15 to 17
Maternal subjects who complete Days 1 to 14 of assigned treatment will be asked to continue 
recordings of milk expression on milk container labels through the end of Day 17. The volume of 
MoM produced over Days 15 to 17 will be calculated by using recorded weights of expressed milk 
in the same way as described in Section 7.1.1.
7.2.4
Volume of MoM Fed to the Infant
The volume of MoM fed to the infant over Days 1 to 14 will be recorded from hospital records. The 
volume of breastfed milk over Days 1 to 14 will be recorded.


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7.2.5
Volume of Formula/Donor Milk Fed to the Infant
The volume of formula or donor milk fed to the infant over Days 1 to 14 will be recorded from 
hospital records.
7.2.6
Merotocin Concentration in Milk 
At Day 3 and Day 10 visits, a milk sample of approximately 2 mL for merotocin concentration 
analysis will be taken from the milk expressed at the trial center. Samples are taken only if milk 
production is, at the discretion of the investigator, adequate to meet the needs of the infant.
Analysis of milk concentration of merotocin will be performed by Ferring Bioanalysis Department 
by means of a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method 
using the milk samples obtained at Day 3 and Day 10 visit, if available. The personnel analyzing 
the milk samples for merotocin will be blinded to treatment allocation when performing the 
analyses.
7.2.7
Infant Body Weight
Infant body weight will be collected for the day of randomization (or last recorded measurements as 
available) and for all treatment days from Day 1 to Day 14 where data are available. Infant body 
weight may not be measured daily, so data can be missing for some treatment days.
7.2.8
Adverse Events (Maternal Subject and Infant)
Frequency and intensity of AEs will be recorded for maternal subjects and for the infant (as 
available from hospital records). See Section 8.2 regarding collection and recording of AEs. A 
search for predefined preferred terms (PTs) and reported terms will be conducted on all treatment-
emergent AEs (TEAEs) for maternal subjects to identify those that can indicate nasal local 
tolerability issues.    
7.2.9
Safety Laboratory Parameters (Maternal Subjects)
Blood samples for safety laboratory evaluations of clinical chemistry and hematology will be 
collected at screening and at Day 15/End-of-Treatment visit. The clinical chemistry and 
hematology analyses will be performed by a central laboratory. Safety laboratory parameters are 
listed in Table 6.


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Table 6
Safety Laboratory Parameters
Clinical Chemistry
Hematology
Alanine aminotransferase
Hematocrit
Albumin
Hemoglobin
Alkaline phosphatase
Mean cellular volume 
Aspartate aminotransferase
Mean corpuscular hemoglobin content 
Glucose
Mean corpuscular hemoglobin concentration 
Calcium
Platelet count
Chloride
Red blood cell count
Cholesterol
White blood cell count with differential count
C-reactive protein
White blood cell morphology
Creatinine
Gamma-glutamyltransferase
Phosphate
Potassium
Sodium
Total bilirubin
Urea (blood urea nitrogen)
The investigator will review the laboratory results and evaluate and document whether the results 
are clinically significant or non-significant.
7.3
Assessments Related to Exploratory Endpoints
7.3.1
Plasma Concentration of Merotocin
Blood samples for plasma concentration of merotocin will be collected using an indwelling catheter 
at pre-dose and at 5, 10, 20, 30, 45, and 60 minutes after dosing at site at Day 3 and Day 10 visits.
For the pre-dose sample, sampling should occur a minimum of 3 hours after the previous dose. 
Blood samples for the analysis of merotocin concentration will be taken in a minimum of 
20 maternal subjects.
Analysis of plasma concentration of merotocin will be performed by means of a validated 
LC-MS/MS method.
7.3.2
Milk Composition
At randomization, Day 3, and Day 10 visits, a milk sample of approximately 4 mL for milk 
composition analysis will be taken from the milk expressed at the trial center. The milk sample at 
randomization will be taken prior to randomization. Milk composition including lipids, protein, 
caloric content, lactose, and Human Milk Oligosaccharides will be assessed by a central laboratory 
(detailed in the laboratory manual) for each of the 3 milk samples, if available. Samples are taken 
only if milk production is, at the discretion of the investigator, adequate to meet the needs of the 


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infant.
7.4
Assessments Related to Post-trial Endpoints
Additional data will be collected from the hospital records of the infant when the infant is 
discharged from NICU. The additional data (if available) are infant body weight, length and head 
circumference at time of infant’s discharge from NICU, the date when the infant becomes tolerant 
to full enteral feeding, date of discharge from NICU, number of days the infant requires TPN until 
discharge from NICU, type of feeding (MoM and formula/donor milk) at time of infant’s discharge
from NICU, and whether the maternal subject is lactating (i.e., breastfeeding or breast pumping) at 
time of infant’s discharge from NICU. 
Concomitant medications and AEs will be collected from hospital records through time of infant’s
discharge from NICU or until the last milk sample expressed during maternal subject’s treatment 
with IMP is either consumed by the infant or discarded, whichever occurs last. Information on 
infant’s morbidity events of special interest occurring prior to the infant’s discharge from NICU, 
including NEC, intra-ventricular hemorrhage, BPD, RDS, late-onset sepsis, ROP, and 
hemodynamically significant patent ductus arteriosus, are recorded at the time of infant’s discharge
from NICU based on hospital records. The trial is not powered to draw conclusions on the 
incidences of these events, but they are collected in order to capture any trends on the impact of 
feeding patterns on their incidences. 
From the follow-up contact about one month after the infant’s NICU discharge, the date of any 
hospital re-admission of the infant occurring since NICU discharge, and the reason for the re-
admission will be recorded. Investigators should assess the causal relationship between the reason 
for such re-admissions and the IMP. 
For long-term follow-up, the ASQ-3 will be provided for all infants at 9 months, 18 months and 
24 months of corrected gestational age. A primary caregiver of the infant will answer the 
questionnaire that consists of approximately 30 questions covering five domains of development,
including communication, gross motor, fine motor, problem-solving, and personal-social skills. It 
takes about 15-30 minutes to complete the questionnaire. If a score falls into the black zone of any 
domain on the scoring summary sheet, standard referral procedures should be followed. 
Data from post-trial activities will be provided in an addendum to the clinical trial report.
7.5
Other Assessments
7.5.1
Vital Signs (Maternal Subject)
Vital signs include blood pressure and heart rate. Systolic and diastolic blood pressure and heart 
rate will be measured for maternal subjects at randomization, Day 3, Day 10 and Day 15/


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End-of-Treatment visits. Vital signs will be measured while maternal subject is in sitting position 
after resting for at least 3 minutes. Vital signs should always be measured before blood sampling. 
All recordings will be performed using validated standard equipment. Vital sign assessments may 
be repeated for quality reasons and the repeat will be used for analysis.
7.5.2
Physical Examination (Maternal Subject)
A full physical examination of the maternal subject will be performed at randomization and at 
Day 15/End-of-Treatment visit. The physical examination of the maternal subject comprises 
examination of general appearance, central and peripheral nervous system, head and neck 
(including ears, eyes, nose, mouth, and throat), cardiovascular system, respiratory system, 
gastrointestinal system, lymphatic system, urinary system, breasts, skin, and musculoskeletal 
system. 
7.6
Handling of Biological Samples
A detailed description of all sample collections and shipment procedures will be included in a 
separate laboratory manual. 
All biological samples will be analyzed at central laboratories and will be maintained in storage 
after the end of the trial. Destruction will take place within 2 years after reporting of the trial. For 
all biological samples collected in the trial, it applies that analyses beyond those described in the 
protocol can only be performed after obtaining the required approvals. The processes related to 
handling of biological samples will be described in the informed consent forms (ICFs), and 
biobank/data protection legislation including local legislation will be adhered to.


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8
ADVERSE EVENTS
8.1
Adverse Event Definition
An AE is any untoward medical occurrence in a subject participating in a clinical trial. It includes:

Any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP

AEs commonly observed and AEs anticipated based on the pharmacological effect of the 
IMP

Any laboratory abnormality, vital sign or finding from physical examination assessed as 
clinically significant by the investigator [note: findings from assessments and examinations 
done during screening are not AEs but are recorded as medical history]

Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation or reasons for admission to hospital or 
surgical procedures
Overdoses, medication errors and technical malfunctions of IMP will be captured by the e-CRF and 
will be reviewed by Ferring Pharmacovigilance on an ongoing basis. 
Pre-treatment Adverse Event for Maternal Subjects
A pre-treatment AE for a maternal subject is any untoward medical occurrence arising or observed 
between informed consent and administration of the IMP.
Treatment-emergent Adverse Event for Maternal Subjects
A TEAE for a maternal subject is any AE occurring after start of the IMP and before the 
Day 15/End-of-Treatment visit. A pre-treatment AE or pre-existing medical condition that worsens 
in intensity after start of IMP and before the Day 15/End-of-Treatment visit is also considered 
treatment emergent.
Pre-treatment Adverse Event for Infants
A pre-treatment AE for an infant is any untoward medical occurrence arising or observed between 
the signing of the parental informed consent and the infant’s first exposure to MoM expressed 
during maternal subject’s treatment period.
Treatment-emergent Adverse Event for Infants
A TEAE for an infant is any AE occurring from the infant’s first exposure to MoM expressed 
during maternal subject’s treatment period until the infant’s last exposure to MoM expressed during 
maternal subject’s treatment period (i.e., the last milk sample expressed during maternal subject’s
treatment with IMP is either consumed by the infant or discarded). A pre-treatment AE or 
pre-existing medical condition that worsens in intensity during the interval stated above is also 
considered treatment emergent.


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8.2
Collection and Recording of Adverse Events
8.2.1
Collection of Adverse Events
The sources of AEs cover:

The subject’s response to questions about her health (a standard non-leading question such 
as ‘How have you been feeling since your last visit?’ is asked at each visit). (This is only 
applicable to maternal subjects)

Symptoms spontaneously reported by the subject. (This is only applicable to maternal 
subjects)

Investigations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities

Other information relating to the subject’s health becoming known to the investigator (e.g.,
hospitalization)
8.2.2
Recording of Adverse Events
The investigator must record all AEs in the Adverse Event Log provided in each subject’s e-CRF
with information about:

Adverse event

Date and time of onset (time can be omitted, if applicable)

Intensity

Causal relationship to IMP

Action taken to IMP

Other action taken

Date and time of outcome (time can be omitted, if applicable)

Outcome

Seriousness
Each of the items in the Adverse Event Log is described in detail in the following sections.
Adverse Events
AEs should be recorded as diagnoses, if available. If not, separate signs and symptoms should be 
recorded. One diagnosis/symptom should be entered per record.
If a subject suffers from the same AE more than once and the subject recovers in between the 
events, the AEs should be recorded separately. If an AE changes in intensity, a worst-case approach 
should be used when recording the event, i.e., the highest intensity and the longest duration of the 
event.


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However, if an AE with onset before the first IMP administration (i.e., a pre-treatment AE) changes 
in intensity, this must be recorded as 2 separate events. The initial AE should be recorded with 
outcome ‘not recovered’ and the date and time of outcome is when the intensity changed. The 
second AE should be recorded with date and time of onset when the intensity changed. 
Note the following: A procedure is not an AE; the reason for conducting the procedure is. 
Hospitalization is not an AE; the reason for hospitalization is. Death is not an AE, but the cause of 
death is (an exception is sudden death of unknown cause, which is an AE).
Date and Time of Onset
The date of onset is the date when the first sign(s) or symptom(s) was first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the 
date the sample was taken or the examination was performed. 
Intensity
The intensity of an AE must be classified using the following 3-point scale:
Mild:
Awareness of signs or symptoms, but no disruption of usual activity
Moderate:
Event sufficient to affect usual activity (disturbing)
Severe:
Inability to work or perform usual activities (unacceptable)
Causal Relationship to IMP
The possibility of whether the IMP caused the AE must be classified as one of the following:
Reasonable possibility: 
There is evidence or argument to suggest a causal relationship 
between the IMP and the AE. The AE may occur as part of the 
pharmacological action of the IMP or may be unpredictable in its 
occurrence
Examples: 

AEs that are uncommon but are known to be strongly 
associated with IMP exposure

AEs that are not commonly associated with IMP exposure, but the 
event occurs in association with other factors strongly suggesting 
causation, such as a strong temporal association with the IMP or 
the event recurs on rechallenge with the IMP


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No reasonable possibility: 
There is no reasonable evidence or argument to suggest a causal 
relationship between the IMP and the AE
Examples:

Known consequences of the underlying disease or condition 
under investigation

AEs common in the trial population, which are also anticipated to 
occur with some frequency during the course of the trial, 
regardless of IMP exposure
Action Taken to IMP
The action taken to the IMP in response to an AE must be classified as one of the following:

No change (medication schedule maintained or no action taken)

Discontinued

Interrupted

Dose reduced
Other Action Taken
AEs requiring therapy must be treated with recognized standards of medical care to protect the 
health and well-being of the maternal subject. 
If medication is administered to treat the AE, this medication should be entered in the Concomitant 
Medication Log. Infant concomitant medication needs to be reported in the electronic system only 
once (dose and frequency may be omitted), as a complete list of medications (including dose and
frequency, as applicable) may be printed from the hospital records (de-identified) and sent to the 
sponsor following discharge of the infant from the NICU if more information is later needed.
Date and Time of Outcome
The date and time the subject recovered or died.


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Outcome
The outcome of an AE must be classified as one of the following:

Recovered (fully recovered or the condition has returned to the level observed at initiation 
of trial treatment)

Recovered with sequelae (resulted in persistent or significant disability/incapacity)

Recovering

Not yet recovered

Fatal
8.2.3
Collection and Recording of Adverse Events for Maternal Subjects
Events that occur in maternal subjects following the signing of informed consent are to be collected 
as AEs. Data regarding these AEs are to be recorded in the e-CRF. Maternal subject AEs will be 
collected and recorded from the time of signing ICF through the Day 18/Follow-up visit.
8.2.4
Collection and Recording of Adverse Events for Infants
Events that occur in infants following the signing of parental consent are to be collected as AEs. 
Data regarding these AEs are to be recorded in the e-CRF using information obtained from the 
infant’s hospital records (as available). Infant AEs will be collected and recorded from the time 
informed consent is obtained through the Day 18/Follow-up visit during the trial. As part of post-
trial activities after the Day18/Follow-up visit, infant AEs will also be collected and recorded 
through time of infant’s discharge from NICU or until the last milk sample expressed during 
maternal subject’s treatment with IMP is either consumed by the infant or discarded, whichever
occurs last. These AEs will be reported separately from those collected through the Day 18/Follow-
up visit.
About one month after the infant’s NICU discharge, the maternal subject will be contacted (by 
phone or other means) to inquire about any hospital re-admission and the reason for such.
8.3
Adverse Events Requiring Special Handling for Maternal Subject
8.3.1
Uterine Contraction
As uterine contraction during postpartum is considered a physiological phenomenon, uterine 
contraction is not to be reported as AEs unless it requires active management, e.g., analgesic use.


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8.4
Morbidity Events of Special Interest for Infants
Infants’ morbidity events of special interest are events of special interest because there is support or 
indications in the literature that their incidences and severities are associated with the degree to 
which premature infants are fed with mother’s milk or inversely with formula based on cow-milk. 
The incidences of these events are therefore included in the trial design as a post-trial exploratory 
endpoint. These morbidities are not identified as safety parameters in the sense that there is any 
rationale why merotocin should have a causative effect upon them. The following infant events are 
regarded as morbidity events of special interest and will be followed until they are resolved or until 
the medical condition is stable. Additional information on NEC, intra-ventricular hemorrhage, 
BPD, RDS, late-onset sepsis, ROP, and hemodynamically significant patent ductus arteriosus will 
be collected in the e-CRF. 


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8.5
Serious Adverse Events
8.5.1
Serious Adverse Event Definition
Serious Adverse Events (SAEs) during the Trial
An event is defined a SAE if it:
Guidance
Results in death
Any event resulting in a fatal outcome must be fully documented and 
reported, including deaths occurring within 4 weeks after the treatment 
ends and irrespective of the causal relationship to the IMP. The death of a 
subject enrolled in a trial is per se not an event but an outcome.
Is life threatening
The term life threatening refers to an AE in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an 
event that may have caused death if it were more severe.
Requires in-patient
hospitalization or prolongation 
of existing hospitalization
The term hospitalization means that the subject was admitted to hospital or 
that existing hospitalization was extended as a result of an event. 
Hospitalization describes a period of at least 24 hours. Overnight stay for 
observation, stay at emergency room or treatment on an outpatient basis 
do not constitute a hospitalization. However, medical judgement must 
always be exercised and when in doubt the case should be considered 
serious (i.e., if case fulfils the criterion for a medically important event). 
Hospitalizations for administrative or social purposes do not constitute an 
SAE. Hospital admissions and/or surgical operations planned before trial 
inclusion are not considered AEs, if the illness or disease existed before 
the subject was enrolled in the trial, provided that the condition did not 
deteriorate during the trial.
Results in persistent or signify-
cant disability/incapacity
Disability/incapacity means a substantial disruption of a person’s ability 
to conduct normal life functions. In doubt, the decision should be left to 
medical judgement by the investigator.
Is a congenital anomaly/birth 
defect
Congenital anomaly/birth defect observed in any offspring of the subject 
conceived during treatment with the IMP.
Is an important medical event
Medical and scientific judgment should be exercised in deciding whether 
other situations should be considered serious such as important medical 
events that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the patient or might require 
intervention to prevent one of the other outcomes listed in the definition 
above. 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 hospitalization, or development of drug 
dependency or drug abuse.


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8.5.2
Collection, Recording and Reporting of Serious Adverse Events
SAE Reporting by the Investigator
All SAEs must be reported immediately to Ferring Pharmacovigilance as soon as it becomes 
known to the investigator and not later than within 24 hours of their knowledge of the occurrence of 
an SAE.
The investigator is responsible for submitting the completed SAE Report Form with the fullest 
possible details within 3 calendar days of his/her knowledge of the SAE.
The SAE Report Form is included in the e-CRF system, and must be completed and submitted 
according to the instructions provided on the form. In case the e-CRF cannot be accessed and hence 
the SAE Report Form cannot be filled in within the e-CRF system, a paper SAE Report Form 
should be used and sent to Ferring Pharmacovigilance using the contact details below.
Ferring Pharmacovigilance
E-mail:
Fax: 
Completion of the Demographics, Adverse Event Log, Medical History Log and Concomitant 
Medication Log are mandatory for initial reports and for follow-up reports if any relevant changes 
have been made since the initial report. Data entries must have been made in the e-CRF for Ferring 
Pharmacovigilance to access the information.
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g., laboratory parameters (that are not already uploaded in the e-CRF), invasive procedures, scans
and X-rays and autopsy results can be faxed or scanned and e-mailed to Ferring Pharmacovigilance
using the contact details in the section above. In any case this information must be supplied by the
investigator upon request from Ferring. On any copies provided, details such as maternal subject’s
name, address and hospital ID number should be concealed and instead maternal subject number
should be provided.
The investigator will supply Ferring and the IRBs with any additional requested information such 
as results of post-mortem examinations and hospital records.
Ferring will report all SAEs according to local regulations. 
8.6
Follow-up of Adverse Events and Serious Adverse Events 
8.6.1
Follow-up of Adverse Events with Onset during the Trial
During the trial, the investigator must follow-up on each AE, maternal or infant, until it is resolved 
or until the medical condition is stable.


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After the Day 18/Follow-up visit, the investigator must follow-up on any AE classified as serious or 
considered to have a reasonable possible causality to the IMP until it is resolved or until the 
medical condition is stable. All such relevant follow-up information must be reported to Ferring. If 
the event is a chronic condition, the investigator and Ferring may agree that further follow-up is not 
required.
8.6.2
Collection of Serious Adverse Events with Onset after Last Trial Visit
If an investigator becomes aware of an SAE of the maternal subject after the Day 18/Follow-up
visit, and he/she assesses the SAE to have a reasonable possible causality to the IMP, the case will 
have to be reported to Ferring, regardless of how long after the end of the trial this takes place. 
If an investigator is informed of a hospital re-admission of the infant from the follow-up call about 
one month after infant’ discharge from NICU, and he/she assesses the reason for the re-admission 
to have a reasonable possible causality to the IMP, the case will be reported as an SAE to Ferring. 
Similarly, if an investigator becomes aware of an SAE of the infant during the infant’s long-term 
follow-up, and he/she assesses the SAE to have a reasonable possible causality to the IMP, the case 
will have to be reported to Ferring. The SAE will be followed up until the event is resolved or until 
the medical condition is stable.


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9
STATISTICAL METHODS
The Ferring Global Biometrics Department will be responsible for the statistical analyses of the 
primary, secondary and exploratory endpoints. This section details the planned statistical analyses 
for the primary endpoint and outlines the planned statistical analyses for the secondary and 
exploratory endpoints. All analyses and further descriptions of the statistical methodology for the 
primary, secondary and exploratory endpoints will be included in the Statistical Analysis Plan 
(SAP) available before breaking the blind of the trial. A separate SAP will be prepared to cover the 
post-trial information.
9.1
Determination of Sample Size
The primary objective of this trial is to evaluate the effect of merotocin on increasing milk 
production in women with preterm delivery. The comparison is based on the primary endpoint of 
the volume of MoM produced over Days 1 to 14.
Since neither the onset nor the duration of effect of merotocin is known, the initial sample size 
calculation is based on a comparison of the time-averaged difference between the merotocin group 
and the placebo group over Days 1 to 14. A sample size of 100 maternal subjects, allocated equally 
to each treatment group, will provide roughly 80% power to detect a 50% increase in the volume of 
MoM produced over Days 1 to 14, compared to placebo. 
The primary analysis of the volume of MoM obtained over Days 1 to 14 will be based on a repeated 
measures ANCOVA. For a given sample size, the power is a function of the assumed (constant) 
treatment effect and the assumed correlation of observations within subjects. The power for a 
sample size of 100 maternal subjects equally distributed between the two treatment groups for 
various combinations of correlation and treatment effect is shown in Table 7. As shown in the table, 
a sample size of 100 subjects has approximately 80% power to detect a 50% increase in the volume 
of MoM produced, unless the within subject correlation is greater than 0.8.
Table 7
Power for Various Combinations of Correlation and Treatment Effect
Correlation
Treatment effect a (merotocin relative to placebo)
30% increase
40% increase
50% increase
0.6
64.2 %
81.1 %
92.3 %
0.7
57.2 %
74.4 %
86.1 %
0.8
52.1 %
66.5 %
80.2 %
a Assuming 100 subjects will be equally distributed between the two groups, with a uniform 30% drop-out rate in the trial.
The results presented in Table 7 are based on simulations. For each scenario, 1,000 datasets with 
100 subjects equally distributed between the 2 treatment groups were generated. In each simulation, 
14 observations from a multivariate log-normal distribution were generated for each subject. The 
means and variances of the multivariate log-normal distribution used to draw samples from, were 
based on external data received by Ferring. The correlation between the volume of MoM expressed 


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on any two given days by the same individual was assumed to be constant and is provided in 
Table 7 for each scenario. To account for subjects not completing the trial, a 30% drop-out rate 
over the duration of the trial was built into each simulation. It is estimated that approximately 
250 maternal subjects will need to be screened.
9.2
Subject Disposition
The number of maternal subjects screened will be presented, and the number of maternal subjects 
randomly assigned to receive trial treatment, completing the treatment period and completing the 
trial will be summarized by treatment group and analysis sets. The number of subjects providing 
data in the full analysis set (FAS) will be tabulated by treatment day. Reasons for discontinuation 
will be summarized by treatment group.
9.3
Protocol Deviations
Protocol deviations will be rated as either minor or major. Protocol deviations impacting the 
primary endpoint will be rated as major. Maternal subjects will be excluded from the per protocol 
(PP) analysis set from the day where the first major protocol deviations occurred and onwards. Data 
will not be excluded from the PP analysis set in case of minor protocol deviations. Major protocol 
deviations include but are not limited to the following:

For a given treatment day:
Less than 5 milk expression attempts
Less than 80% compliance with intra-nasal administration of assigned treatment prior 
to milk expression
The Ferring clinical team will perform a blinded review of protocol deviations before declaration of 
clean file and lock of database. If the blinded review identifies serious unforeseen deviations 
deemed to impact the primary endpoint and affect the conclusions of the trial, these will also be 
rated as major deviations. A comprehensive list of major protocol deviations will be detailed and 
documented in the clean file document prior to database release. Major protocol deviations will be 
tabulated by treatment day and treatment group. 
9.4
Analysis Sets
Analysis sets’ definitions are based on the randomized maternal subject but will apply accordingly 
to the infant as well.
9.4.1
Intention-to-Treat Analysis Dataset
The Intention-to-Treat (ITT) analysis set is defined as all randomized maternal subjects.


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9.4.2
Full Analysis Set
The FAS is defined as all randomized and exposed maternal subjects providing data on volume of 
MoM produced for at least 1 day after dosing initiation. Since this is a PoC trial, subjects will be 
analyzed according to actual treatment received.
9.4.3
Per Protocol Analysis Set
The PP analysis set will consist of data from all maternal subjects in the FAS without major 
protocol deviations (Section 9.3). Since this is a PoC trial, subjects will be analyzed according to 
actual treatment received. 
9.4.4
Safety Analysis Set
The safety analysis set comprises all treated maternal subjects and infants and is analyzed according 
to the actual treatment received.
9.5
Trial Population
9.5.1
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for all 
randomized maternal subjects by treatment group.
9.5.2
Medical History, Concomitant Medication and Other Safety Evaluations
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
will be summarized by treatment group. Prior and concomitant medications will be coded using the 
World Health Organization (WHO) Drug Dictionary and will be summarized by Anatomical 
Therapeutic Chemical Classification System (ATC) classification 1st level (alphabetically), ATC 
classification 2nd level (in decreasing order of frequency) and treatment group.
Reporting of other safety data prior to randomization and start of treatment is detailed together with 
reporting of safety data after randomization and start of treatment in Section 9.8.
9.6
Endpoint Assessments
9.6.1
General Considerations
Statistical analysis will be performed using SAS software Version 9.2 or later (SAS Institute, Inc, 
Cary, North Carolina) unless stated otherwise. 


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Analysis and Presentation of Primary and Secondary Endpoints
Results for the primary endpoint and secondary efficacy endpoints will be presented for both the 
FAS and the PP analysis sets. The primary endpoint and selected secondary efficacy endpoints will 
also be presented by gestational age group (<27 weeks and ≥27 weeks).
Continuous variables will be summarized using the mean, standard deviation, median, minimum 
value and maximum value. Categorical variables will be summarized using frequency counts and 
percentages. All primary and secondary efficacy endpoints will be presented in data listings.
Treatment differences will (where appropriate) be presented with 95% two-sided confidence 
intervals and p-values corresponding to the statistical test of the hypothesis ‘equal effect’ against 
the alternative ‘different effect’. All statistical tests will be performed using a two-sided test at a 5% 
significance level, unless otherwise stated.
Multiplicity
Concerning the secondary efficacy endpoints, no formal adjustment for multiplicity will be utilized. 
Statistical significant results will be interpreted cautiously.
Missing Data
Missing data on the primary endpoint will not be imputed for the primary analysis. As this is a PoC 
trial, the interest is in assessing the difference in the amount of MoM expressed during treatment 
adherence. Furthermore, the repeated measures ANCOVA model is robust against dropouts under 
the assumption that the drop-out is not related to treatment. The reason for premature 
discontinuation will be compared between treatment groups. Sensitivity analyses examining the 
robustness of the primary analysis results with respect to the above missing data assumption will be 
carried out by imputing missing data under a missing-not-at-random (MNAR) assumption. The 
imputation will be carried out using the pattern mixture model with control based pattern 
imputation.32
Missing values for the secondary endpoints will not be imputed.
9.6.2
Primary Endpoint
Primary Endpoint: Primary Analysis
The primary objective of this PoC trial is to evaluate the effect of merotocin on increasing milk 
production in women with preterm delivery. The primary endpoint of the trial is the volume of 
MoM produced over Days 1 to 14. 
Repeated Measures ANCOVA Model:
The primary endpoint will be analyzed using a repeated measures ANCOVA with a general 
(unstructured) covariance matrix. The daily volume of MoM produced will be the dependent 


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variable. The model will include the baseline volume of MoM produced as covariate, with 
treatment group, treatment day, treatment-by-day interaction, and gestational age group
(<27 weeks and ≥27 weeks) as factors. The baseline volume of MoM produced is defined as the 
volume obtained at the 24-hour interval for eligibility during the observation period. The average 
treatment effect across treatment days and the within-day treatment effect will be reported along 
with the corresponding two-sided 95% confidence intervals and p-values. 
The analyses based on the FAS will be considered the primary, while the analyses based on the PP 
analysis set will be considered supportive. PoC will be considered to be established if the repeated 
measures ANCOVA model results in a significant positive average treatment effect of merotocin
compared to placebo across the treatment period in the FAS.
Primary Endpoint: Sensitivity/Supportive Analyses 
The Safety Committee may choose to reduce the dose in case of any safety concerns. In that case, 
the analyses will be performed both by combining the merotocin dose groups into one and by using 
the actual merotocin dose groups separately. 
Sensitivity analyses exploring the impact of the missing data assumption on the results of the 
primary analysis will be performed for the FAS and PP analysis sets. Missing data will be imputed 
under a MNAR assumption using the pattern-mixture model with control-based pattern imputation.
The sensitivity of the results with respect to choice of the covariance structure will be investigated 
using more restrictive covariance structures (compound symmetry, Toeplitz, separate compound 
symmetry for each treatment group, and separate Toeplitz pattern for each treatment group). Nested 
models will be compared using the likelihood ratio test. In addition, interactions of treatment and 
gestational age group will be tested in the model with a general covariance structure.
Although the randomization will be stratified by site, it will not be included in the model for the 
primary analysis because issues may arise when adjusting for a large number of small centers (with 
respect to the number of randomized subjects). Additionally, common methods, such as pooling 
small centers together to form one large center, lack scientific justification. To ensure that the trial 
conclusions are not substantially affected by this exclusion, sensitivity analyses will examine the 
relationship between the effect of treatment and center. This will be carried out by including center 
and the center*treatment interaction as factors in the repeated measures ANCOVA model specified 
for the primary endpoint.
Sensitivity analyses will be performed to assess the relationship between the time of randomization  
from delivery and the effect of treatment on the volume of MoM produced over Days 1 to 14. This 
will be carried out by including the time of randomization from delivery and the time of 
randomization from delivery by treatment interaction in the repeated measures ANCOVA model 
specified for the primary endpoint.


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The above primary analysis will be repeated to examine the consistency of the relationship between 
treatment and the volume of MoM produced over Days 1 to 14 after having adjusted for additional 
covariates (age of maternal subject, ethnicity, presence of fetal growth restriction, birth weight, 
caesarean section, primipara versus multipara, use of antenatal steroids and pre-pregnancy BMI). 
Each covariate will be added to the model one by one and tested at a two-sided significance level of 
20%. In case two or more covariates are significant at the 20% level, a forward selection process 
will be applied with a threshold for adding effects at a two-sided significance level of 20% to 
identify the final model.
9.6.3
Secondary Endpoints
Secondary efficacy endpoints will be analyzed using the FAS and the PP analysis set, whereas 
secondary safety endpoints will be reported using the safety analysis set.
The time from randomization to the first occurrence of a daily volume of MoM ≥500 mL and 
≥750 mL will be analyzed by fitting a discrete time survival model adjusted for gestational age 
group, as well as the baseline volume of MoM.  
The proportion of maternal subjects producing at least 500 mL and 750 mL of MoM over Days 1 to 
14 will be analyzed by repeated logistic regression adjusted for treatment day, treatment-by-day
interaction and gestational age group.
The volume of MoM produced over Days 15 to 17 will be compared between treatment groups 
using a repeated measures ANCOVA model adjusting for the volume of MoM produced on Day 14.
Volume of MoM fed to the infant over Days 1 to 14 and volume of formula/donor milk fed to the 
infant over Days 1 to 14 will be analyzed and presented using an ANCOVA approach similar to the 
one used for the primary endpoint but gestational age will be adjusted for as a continuous covariate. 
The proportion of subjects with quantifiable amount of merotocin in the milk will be summarized
for the merotocin group. 
Infant body weight will be summarized by treatment day, treatment group and gestational age 
measured in weeks, together with change from baseline values.
Maternal subject TEAEs will be summarized by treatment group, including separate summaries by 
intensity. All infant AEs will be summarized by treatment group, again including separate 
summaries by intensity. Further details are provided in Section 9.8.2.
Routine safety laboratory parameters of maternal subjects will be summarized by time point and 
treatment group, together with change from baseline values. For each laboratory parameter, a 
summary table will be prepared displaying the proportion of maternal subjects who have at least
one markedly abnormal value. Markedly abnormal criteria for the safety laboratory parameters will 


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be specified in the SAP.
9.6.4
Exploratory Endpoints
A population PK model will be developed describing merotocin concentrations in plasma and the 
relationship between merotocin exposure and milk volume will be explored. The analysis methods 
will be described in detail in a separate modelling analysis plan prepared by Ferring’s Translational 
Medicine Department. This analysis plan will be available before breaking the blind of the trial and 
results of the analysis will be reported separately.
Milk composition variables will be summarized by time point and treatment group. 
9.6.5
Post-trial Endpoints
Post-trial endpoints will be presented in summary tables.
9.7
Extent of Dosing and Treatment Compliance 
Extent of actual dosing is defined as the number of intra-nasal trial treatment spray administrations 
and also as the number of days receiving trial treatment. Both variables will be summarized by 
treatment group.
Compliance is defined in terms of the number of milk expression attempts and the use of the nasal 
spray. For women attempting less than 6 milk expressions on a given day, their daily compliance is 
calculated as number of IMP administrations divided by 5 (the minimum number of milk 
expression attempts stated in the protocol). For women who perform 6-8 milk expression attempts, 
compliance is calculated as the number of IMP administrations divided by number of milk 
expressions. For women expressing milk more than 8 time per day, compliance is calculated as the 
number of IMP administrations divided by 8 (the maximum number of IMP administrations 
specified in the protocol). This will be done for both the overall treatment period and each 
treatment day. Compliance over Days 1 to 14 will be summarized by treatment group as the number 
of maternal subjects with at least 80% compliance.
Drug dosing will be evaluated by weighing each nasal spray bottle before dispensing and after 
return to the site taking into account the number of doses administered as reported by the maternal 
subject.
9.8
Safety
9.8.1
General Considerations
Safety parameters will be evaluated for the safety analysis set.


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9.8.2
Adverse Events
All AEs recorded for maternal subjects and infants will be coded using MedDRA. Maternal subject 
TEAEs will be tabulated by System Organ Class (SOC) and PT, and separately all infant TEAEs 
will also be tabulated by SOC and PT. The total number of maternal subjects reporting a TEAE, the 
percentage of maternal subjects (%) with a TEAE and the number of events reported will be 
presented.
Summary tables will be prepared for:

All TEAEs

TEAEs by causality (related/unrelated)

TEAEs leading to death

TEAEs by intensity

Treatment-emergent adverse drug reactions by intensity

Treatment-emergent SAEs

TEAEs leading to withdrawal
Separate data listings will be provided for AEs for maternal subjects and infants. Pre-treatment AEs 
will be flagged.
9.8.3
Other Safety Variables
Physical examination data will be presented as shift tables from baseline by treatment group. 
Maternal subject blood pressure and heart rate will be summarized in shift tables by treatment 
group.
9.9
Interim Analysis
An unblinded interim analysis for futility assessment is planned once approximately 50% of the 
planned 100 subjects have completed assigned treatment period of Days 1 to 14 of the trial. The 
primary endpoint, volume of MoM produced over Days 1 to 14, will be evaluated for futility. 
Stopping the trial due to lack of merotocin benefit (i.e., futility) could be considered if the 
conditional power is lower than 10%. 
The futility analysis has an impact on the overall power of the trial. A simulation study was 
performed to assess the power of the trial when including the proposed futility analysis. Under an  
alternative hypothesis of treatment effect (i.e., 50% increase), the overall power of the trial with 
inclusion of futility analysis is 77.2% and 91.1% and the probability of declaring futility during the 
interim analysis is 4.6% and 1.1% when the within subject correlation is 0.8 and 0.6, respectively. 
Assuming no treatment effect, the probability of declaring futility during the interim analysis is


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37.0% and 31.0% when the within subject correlation is 0.8 and 0.6, respectively. In this simulation 
study, the conditional power was evaluated with an assumption that the future data after the interim 
analysis would be generated under the treatment effect of 50% increase for merotocin relative to 
placebo.
The interim analysis will be performed by the DMC (see Section 3.4) based on cleaned data, and 
the recruitment will continue at the time of interim analysis unless otherwise notified. The DMC 
will review unblinded interim data and make a recommendation on whether the trial should be 
terminated early due to the futility (non-binding). 
There is no planned interim analysis with the intention to stop the trial early due to overwhelming 
efficacy.


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10
DATA HANDLING
10.1
Source Data and Source Documents
Source Data - International Conference on Harmonisation Definition
Source data are defined as all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies).
Source Documents - International Conference on Harmonisation Definition
Source documents are defined as original documents, data and records (e.g., hospital records, 
clinical and office records, laboratory notes, memoranda, maternal subjects’ evaluation checklists, 
milk container labels and weighing worksheet, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays, maternal subject files, 
and records kept at the pharmacy, at the laboratories and at medico-technical departments involved 
in the clinical trial).
Trial-specific Source Data Requirements
Source documents need to be preserved for the maximum period of time required by local 
requirements. For each subject screened, the investigator will indicate as a minimum in the source 
documents that informed consent is obtained and the reason for screening failure if applicable. For 
each subject randomized, the investigator will indicate in the source documents that the subject 
participates in this trial, and will record at least the following information, if applicable: 

Existence of subject (e.g., date of birth)

Confirmation of participation in trial (trial ID, subject ID)

Informed consent(s) (date and time of obtaining written informed consent(s))

Eligibility for participation in the trial (documenting all inclusion/exclusion criteria)

Relevant medical history 

Visit dates

Records of MoM weights 

Dispensing of IMP 

Dates and doses of concomitant medications

Adverse events (description as well as start/stop date and time)

Reason for discontinuation

Event of unblinding, including the reason for unblinding
The source data for analytical parameters of blood samples will be available at the central 
laboratory. 


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10.2
e-CRF
An e-CRF system provided by an independent third-party contract research organization (CRO) 
will be used for data capture. The system is validated, and access at all levels to the system is 
granted/revoked following Ferring and vendor procedures, in accordance with regulatory and 
system requirements.
Trial data should be entered into the e-CRF in a timely manner.
The investigator will approve/authorize the e-CRF entries for each maternal subject and infant with 
an electronic signature which is equivalent to a handwritten signature. 
The e-CRF system and the database will be hosted at the independent third party CRO. After the 
trial database is declared clean and released to the statistician, a final copy of the database will be 
stored at Ferring. The investigator will also receive a copy of the trial center’s final and locked data 
(including audit trail, electronic signature and queries) as write-protected PDF-files produced by the 
independent third party CRO. The PDF-files will be stored in an electronic format and will be 
provided to the investigator before access to the e-CRF is revoked.
Entry errors occurring in the e-CRF will be corrected electronically. Such corrections/modifications 
will be automatically tracked by an audit trail detailing the date and time of the correction and the 
name of the person making the correction.
10.3
Data Management 
All data management activities will be specified in a data management plan prepared under the 
responsibility of the Global Biometrics Department of Ferring. The data management plan will be 
issued before data collection begins and will describe all functions, processes, and specifications for 
data collection, cleaning and validation. The data management plan will also include information 
about the intended use of computerized systems, a description of the security measures employed to 
protect the data and a description of the electronic data flow.
10.4
Provision of Additional Information
On request, the investigator will provide Ferring with additional data relating to the trial, duly 
anonymized and protected in accordance with applicable requirements.


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11
MONITORING PROCEDURES
11.1
Periodic Monitoring
The monitor will contact and visit the investigator periodically to ensure adherence to the protocol, 
International Conference on Harmonisation-Good Clinical Practice (ICH-GCP), standard operating 
procedures and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy and verifiability of e-CRF entries compared to source data, verification of 
drug accountability and compliance to safety reporting instructions.
The investigator will permit the monitor direct access to all source data, including electronic 
medical records, and/or documents in order to facilitate data verification. The investigator will co-
operate with the monitor to ensure that any discrepancies that may be identified are resolved. The 
investigator is expected to be able to meet the monitor during these visits. When the first subject is 
randomized at the trial site, a monitoring visit will take place shortly afterwards. For this trial, the 
frequency of the monitoring visits per site will be determined through a risk-based approach 
depending on recruitment rate, observed data quality and overall site performance.
The monitoring procedures are described in further detail in the monitoring plan for this trial.
11.2
Audit and Inspection
The investigator will make all the trial-related source data and records available at any time to 
quality assurance auditor(s) mandated by Ferring, or to domestic/foreign regulatory inspectors or 
representatives from IRBs who may audit/inspect the trial.
The main purposes of an audit or inspection are to assess compliance with the trial protocol and the 
principles of ICH-GCP including the Declaration of Helsinki33 and all other relevant regulations.
The maternal subjects must be informed by the investigator and in the ICFs that authorized Ferring 
representatives and representatives from regulatory authorities and IRBs may wish to inspect their 
medical records. During audits/inspections the auditors/inspectors may copy relevant parts of the 
medical records. No personal identification apart from the screening/randomization number will 
appear on these copies.
The investigator should notify Ferring without any delay of any inspection by a regulatory authority 
or IRB.
11.3
Confidentiality of Subject Data
The investigator will ensure that the confidentiality of the maternal subjects’ and infants’ data will 
be preserved. In the e-CRF and any other documents submitted to Ferring, the maternal subjects 
and infants will not be identified by their names, but by an identification system, which consists of 
an assigned number in the trial. Documents that are not for submission to Ferring, e.g., the 
confidential maternal subject identification code and the signed ICFs, will be maintained by the 
investigator in strict confidence.


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12
CHANGES IN THE CONDUCT OF THE TRIAL
12.1
Protocol Amendments
Any change to this protocol will be documented in a protocol amendment, issued by Ferring, and 
agreed upon by the investigator and Ferring prior to its implementation. Amendments may be 
submitted for consideration to the approving IRB(s) and regulatory authorities, in accordance with 
local regulations. Changes to the protocol to eliminate immediate hazard(s) to maternal subjects 
may be implemented prior to IRB’s approval/favorable opinion.
12.2
Deviations from the Protocol
If deviations from the protocol occur, the investigator must inform the monitor, and the 
implications of the deviation must be reviewed and discussed. Any deviation must be documented, 
either as answer to a query in the e-CRF, in a protocol deviation report or a combination of both. A 
log of protocol deviation reports will be maintained by Ferring. Protocol deviation reports and 
supporting documentation must be kept in the Investigator’s File and in the Trial Master File.
12.3
Premature Trial Termination
Both the investigator (with regard to his/her participation) and Ferring reserve the right to terminate 
the trial at any time. Should this become necessary, the procedures will be agreed upon after 
consultation between the two parties. In terminating the trial, Ferring and the investigator will 
ensure that adequate consideration is given to the protection of the best interests of the subjects. 
Regulatory authorities and IRB(s) will be informed.
In addition, Ferring reserves the right to terminate the participation of individual trial centers. 
Conditions that may warrant termination include, but are not limited to, insufficient adherence to 
protocol requirements and failure to enter maternal subjects at an acceptable rate.


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13
REPORTING AND PUBLICATION
13.1
Clinical Trial Report
The data and information collected during this trial will be reported in a clinical trial report 
prepared by Ferring and submitted for comments and signature to the signatory investigator.
The additional data collected from the infant hospital records when the infant is discharged from 
the NICU will be reported in an addendum to the clinical trial report.
13.2
Confidentiality and Ownership of Trial Data
Any confidential information relating to the IMP or the trial, including any data and results from 
the trial will be the exclusive property of Ferring. The investigator and any other persons involved 
in the trial will protect the confidentiality of this proprietary information belonging to Ferring.
13.3
Publications and Public Disclosure
13.3.1
Publication Policy
At the end of the trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Ferring. In a multicenter trial 
based on the collaboration of many trial centers, any publication of results must acknowledge all 
trial centers. Results from multicenter trials must be reported in entirety in a responsible and 
coherent manner and results from subsets should not be published in advance or without clear 
reference to the primary publication of the entire trial.
Authorship is granted based on the International Committee of Medical Journal Editors (ICMJE) 
criteria (refer to current official version: www.ICMJE.org).34 The total number of authors is based 
on the guideline from the relevant journal or congress. In the event of any disagreement in the 
content of a publication, both the investigators’ and Ferring’s opinion will be fairly and sufficiently 
represented in the publication.
Any external CRO or laboratory involved in the conduct of this trial has no publication rights 
regarding this trial.
If the investigator wishes to independently publish/present any results from the trial, the draft 
manuscript/presentation must be submitted in writing to Ferring for comment prior to submission. 
Comments will be given within 4 weeks from receipt of the draft manuscript. This statement does 
not give Ferring any editorial rights over the content of a publication, other than to restrict the 
disclosure of Ferring’s intellectual property. If the matter considered for publication is deemed 
patentable by Ferring, scientific publication will not be allowed until after a filed patent application 
is published. Under such conditions the publication will be modified or delayed at the investigator’s 


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discretion, to allow sufficient time for Ferring to seek patent protection of the invention.
13.3.2
Public Disclosure Policy 
The ICMJE member journals have adopted a trial-registration policy as a condition for publication. 
This policy requires that all clinical trials be registered in a public, clinical trials registry. Thus, it is 
the responsibility of Ferring to register the trial in an appropriate registry, i.e.,
www.ClinicalTrials.gov, a website maintained by the National Library of Medicine at National 
Institutes of Health in the United States. Trial registration may occur in other registries in 
accordance with local regulatory requirements. A summary of the trial results is made publicly 
available in accordance with applicable regulatory requirements.


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14
ETHICAL AND REGULATORY ASPECTS
14.1
Institutional Review Boards (IRBs)
An IRB will review the protocol and any amendments and advertisements used for recruitment. The 
IRB will review the ICFs, their updates (if any), and any written materials given to the maternal 
subjects. A list of all IRBs to which the protocol has been submitted and the name of the IRB
chairmen will be included in the clinical trial report.
14.2
Regulatory Authority Approval
The regulatory permission to perform the trial will be obtained in accordance with applicable 
regulatory requirements. All ethical and regulatory approvals must be available before a maternal 
subject is exposed to any trial-related procedure, including screening tests for eligibility.
14.3
End-of-Trial and End-of-Trial Notification
At the end of the trial, i.e., when the last subject completes the Day 18/Follow-up visit, Ferring will 
notify the appropriate regulatory authority and the IRB about the trial completion in accordance 
with the local requirements of the country where the trial is conducted. 
In case of early termination for safety reasons, Ferring must notify the end of the trial to the 
national regulatory authority and the IRB in accordance with national/local regulations.
In addition, results of the trial will be provided to the relevant regulatory authority when available 
and within one year of the trial completion (last maternal subject last visit).
14.4
Ethical Conduct of the Trial
This trial will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki,33 in compliance with the approved protocol, ICH-GCP and applicable 
regulatory requirements.
14.5
Subject Information and Consent
Informed Consent Forms Regarding Participation in the Trial – Maternal Subject
The investigator (or the person delegated by the investigator) will obtain a freely given written 
consent from each maternal subject after an appropriate explanation of the aims, methods, 
anticipated benefits, potential hazards and any other aspects of the trial which are relevant to the 
maternal subject’s decision to participate. Maternal subjects are also informed of the importance of 
providing their infants with MoM according to written and oral instructions. The maternal subject
must be given ample time to consider participation in the trial, before the consent is obtained. The 
ICF must be signed and dated by the maternal subject and the investigator who has provided 


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information to the maternal subject regarding the trial before the maternal subject is exposed to any 
trial-related procedure, including screening tests for eligibility. Subjects must be given the option of 
being informed about the general outcome and the results of the trial.
The investigator (or the person delegated by the investigator) will explain that the maternal subject
is completely free to refuse to enter the trial or to withdraw from it at any time, without any 
consequences for her further care and without the need to justify her decision.
The maternal subject will receive a copy of the ICF.
If new information becomes available that may be relevant to the maternal subject’s willingness to 
continue participation in the trial, a new ICF will be forwarded to the IRB(s) (and regulatory 
authority, if required). The maternal subjects will be informed about this new information and re-
consent will be obtained.
Each maternal subject will be informed that the monitor(s), quality assurance auditor(s) mandated 
by Ferring, IRB representatives, or regulatory authority inspector(s), in accordance with applicable 
regulatory requirements, may review her source records and data. Data protection will be handled 
in compliance with national/local regulations.
Informed Consent Forms Regarding Data Collection on the Infant – Parental
If a separate information and informed consent form is required to collect data on the infant, the 
investigator (or the person delegated by the investigator) will obtain a freely given written consent 
from the parent participant, i.e., the maternal subject. Paternal consent of the infant will be 
obtained, if required according to local regulations. The parent participant must be given ample 
time before the consent is obtained. The ICF must be signed and dated by the parent participant and 
the investigator who has provided information to the parent participant. Written consent by the 
parent participant regarding collection of data on the infant must be obtained before the subject is 
randomized and preferably at the time of obtaining written consent by the maternal subject 
regarding participation on the trial.
The investigator (or the person delegated by the investigator) will explain that the parent 
participants are completely free to refuse to consent to this data collection or to withdraw consent at 
any time, without any consequences and without the need to justify their decision.
The parent participant will receive a copy of the ICF.
The parent participant will be informed that the monitor(s), quality assurance auditor(s) mandated 
by Ferring, IRB representatives or regulatory authority inspector(s), in accordance with applicable 
regulatory requirements, may review the source records and data of the infant. Data protection will 
be handled in compliance with national/local regulations.


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14.6
Subject Participation Card
The maternal subject will be provided with a Subject Participation Card bearing the following 
information:

That she is participating in a clinical trial

That she is treated with merotocin (an oxytocin receptor agonist) or placebo (treatment 
allocation must not be revealed on the Subject Participation Card)

The name and phone number of the investigator

Name and address of Ferring (if required by local regulations)
The maternal subject will be asked to return the Subject Participation Card at the last trial visit, if 
applicable.
Additionally, each subject’s primary care physician will be notified of their participation in the trial 
by the investigator, if the subject agrees and if applicable. 
14.7
Compliance Reference Documents
The Helsinki Declaration, the consolidated ICH-GCP, and other national law(s) in the country 
where the trial will be conducted shall constitute the main reference guidelines for ethical and 
regulatory conduct.


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15
LIABILITIES AND INSURANCE
15.1
ICH-GCP Responsibilities
The responsibilities of Ferring, the monitor and the investigator are defined in the ICH-GCP 
consolidated guideline, and applicable regulatory requirements in the country where the trial will be 
conducted. The investigator is responsible for adhering to the ICH-GCP responsibilities of 
investigators, for dispensing the IMP in accordance with the approved protocol or an approved 
amendment, and for its secure storage and safe handling throughout the trial.
15.2
Liabilities and Insurance
Ferring is, as sponsor, responsible for ensuring appropriate general/product liability insurance and, 
as required in accordance with applicable laws and regulations, country-specific liability insurance 
coverage for claims made by a trial subject for injury arising from the subject’s participation in the 
trial.


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16
ARCHIVING
16.1
Investigator File
The investigator is responsible for maintaining all the records, which enable the conduct of the trial 
at the trial center to be fully understood, in compliance with ICH-GCP. The trial documentation 
including all the relevant correspondence should be kept by the investigator for at least 15 years or 
longer if so required by local law after the completion or discontinuation of the trial, if no further 
instructions are given by Ferring.
The investigator is responsible for the completion and maintenance of the confidential maternal 
subject identification code which provides the sole link between named maternal subject source 
records and anonymous e-CRF data for Ferring. The investigator must arrange for the retention of 
this Subject Identification Log and signed Informed Consent Forms for at least 15 years or longer if 
so required by local law after the completion or discontinuation of the trial.
No trial center document may be destroyed without prior written agreement between the 
investigator and Ferring. Should the investigator elect to assign the trial documents to another party, 
or move them to another location, Ferring must be notified. If the investigator retires and the 
documents no longer can be archived by the trial center, Ferring can arrange having the documents 
archived at an external archive.
16.2
Trial Master File
Ferring will archive the trial master file in accordance with ICH-GCP and applicable regulatory 
requirements.


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17
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