Validating the Effect of Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum: A Double-Blind Randomised Placebo-Controlled Multicentre Trial
Phase: PHASE2
Conditions: Hyperemesis Gravidarum, Nausea Gravidarum, Vomiting of Pregnancy
Sponsor: Nordsjaellands Hospital

VOMIT 
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Clinical Trial Protocol 
 
Trial ID: VOMIT 
Title of Trial  
Validating the Effect of Ondansetron and Mirtazapine In Treating Hyperemesis Gravidarum.  
A Double-blind Randomised Placebo-Controlled Multicentre Trial. 
 
 
 
Investigational Medicinal Product: 
Mirtazapine and Ondansetron 
EudraCT No.:  
2018-002285-39 
Sponsor, Funder: 
Ellen Christine Leth Løkkegaard 
Central Laboratory: 
 
GCP-Monitor: 
Stine Kjær Hovgaard 
Ethical Committee number: 
H-18047191 
Clinicaltrials.gov number: 
 
Datatilsyn number: 
VD-2018-144, I-suite: 6385 
Date: 
05.12.2018 
Version: 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Signatures 
 
Sponsor: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Ellen Christine Leth Løkkegaard 
MD, Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 48296249 
Eloe0002@regionh.dk 
 
 
It is hereby declared that the trial will be performed according to the latest approved 
trial protocol, ICH-GCP Guidelines and local regulatory requirements and legislation 
 
 
 
 
 
Signature 
 
 
Date 
 
Primary 
Investigator: 
 
(Authorised to 
sign protocol and 
-ammendments) 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Anne Ostenfeld 
MD, Ph.D.-student 
Department of Obstetrics and Gynaecology, Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 20779758 
anne.ostenfeld.02@regionh.dk 
 
 
 
 
 
 
 
 
Signature 
 
 
Date 
 
Study 
Coordinator: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Anne Ostenfeld 
MD, Ph.D.-student 
Department of Obstetrics and Gynaecology, Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 20779758 
anne.ostenfeld.02@regionh.dk 
 
 
 
 
 
 
 
 
 
Signature 
 
 
Date 
 
Protocol 
Author: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Anne Ostenfeld 
MD, Ph.D.-student 
Department of Obstetrics and Gynaecology, Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 20779758 
anne.ostenfeld.02@regionh.dk 
 
 
 
 
 
 
 
 
 
Signature 
 
 
Date 
 
 
 
 
 

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Advisors 
 
Head-advisor: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Ellen Christine Leth Løkkegaard 
MD, Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 48296249 
eloe0002@regionh.dk 
Co-advisor: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Tonny Studsgaard Petersen 
MD, Associate Professor, Consultant, Ph.D. 
Department of Clinical Pharmacology Bispebjerg Hospital 
Bispebjerg Bakke 23, 2400 København NV 
+45 38635855 
tonny.studsgaard.petersen@regionh.dk 
Co-advisor: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Hanne Brix Westergaard 
MD, Associate Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 48296364 
hanne.brix.westergaard@regionh.dk 
Co-advisor: 
Name: 
Title: 
Department: 
 
Address: 
Telephone: 
E-mail: 
Lars Henning Petersen 
MD, Associate Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Aarhus 
Universitetshospital 
Palle Juul-Jensens Blvd. 99, 8200 Aarhus N 
+45 50526512 
lhp@clin.au.dk 
Co-advisor: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Jon Thor Trærup Andersen 
MD, Ph.D. 
Department of Clinical Pharmacology Bispebjerg Hospital 
Bispebjerg Bakke 23, 2400 København NV 
 
jon.thor.traerup.andersen@regionh.dk 
 
Statistician 
 
 
Name: 
Title: 
Department: 
 
 
Address: 
Telephone: 
E-mail: 
Andreas Kryger Jensen 
Assistant Professor, PhD 
Department of Research Nordsjællands Hospital and 
Department of Biostatistics, Institute of Public Health,  
University of Copenhagen 
Øster Farimagsgade 5, 1014 Copenhagen K 
 
andreas.emil.kryger.jensen@regionh.dk 
 
Monitor 
 
 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Stine Kjær Hovgaard 
GCP-coordinator, nurse 
Copenhagen University Hospital GCP-unit 
Bispebjerg Bakke 23, Byg. 51, 3. sal, 2400 Copenhagen NV 
+45 38635626 
Stine.hovgaard@regionh.dk 
 
 

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Study Sites and Local Investigators 
 
Hillerød Hospital: Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Anne Ostenfeld 
MD, Ph.D.-student 
Department of Obstetrics and Gynaecology Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
+45 20779758 
anne.ostenfeld.02@regionh.dk 
Aarhus 
Universitets-
hospital: 
Name: 
Title: 
Department: 
 
Address: 
Telephone: 
E-mail: 
Lars Henning Petersen 
MD, Associate Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Aarhus 
Universitetshospital 
Palle Juul-Jensens Blvd. 99, 8200 Aarhus N 
+45 50526512 
lhp@clin.au.dk 
Aalborg 
Universitets-
hospital: 
Name: 
Title: 
Department: 
 
Address: 
Telephone: 
E-mail: 
Anne Margrethe Møller 
MD, Associate Professor, Consultant 
Department of Obstetrics and Gynaecology Aalborg 
Universitetshospital 
Reberbansgade 15, 9000 Aalborg 
 
margr@dadlnet.dk 
Herlev Hospital: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Tina Bergmann Futtrup 
MD 
Department of Obstetrics and Gynaecology Herlev Hospital 
Herlev Ringvej 75, 2730 Herlev 
 
tina.bergmann.futtrup@regionh.dk 
Hvidovre 
Hospital: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Benny Kirschner 
MD, Associate Professor, Consultant, Ph.D. 
Department of Obstetrics and Gynaecology Hvidovre Hospital 
Kettegård Alle 30, 2650 Hvidovre 
 
benny.kirschner@regionh.dk 
Odense 
Universitets-
hospital: 
Name: 
Title: 
Department: 
 
Address: 
Telephone: 
E-mail: 
Lise Lotte Torvin Andersen 
MD, Associate Professor, Consultant 
Department of Obstetrics and Gynaecology Odense 
Universitetshospital 
J. B. Winsløws Vej 4, 5000 Odense C 
 
Lise.lotte.andersen@rsyd.dk 
Rigshospitalet: 
Name: 
Title: 
Department: 
Address: 
Telephone: 
E-mail: 
Øjvind Lidegaard 
MD, Professsor, Consultant  
Department of Obstetrics and Gynaecology Rigshospitalet 
Blegdamsvej 9, 2100 København Ø 
 
Oejvind.lidegaard@regionh.dk 
 
 
 
 
 
 
 
 
 
 
 
 

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Laboratories and Biobanks 
 
Hillerød Hospital: Laboratory: 
Address: 
Biobank:  
Department of Biochemistry Nordsjællands Hospital 
Dyrehavevej 29, 3400 Hillerød 
Locked freezer in locked room 101-21 at Forskningsafdelingen 
Aarhus 
Universitets-
hospital: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Aarhus Universitetshospital 
Palle Juul-Jensens Blvd. 99, 8200 Aarhus N 
 
Aalborg 
Universitets-
hospital: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Aalborg Universitetshospital 
Reberbansgade 15, 9000 Aalborg 
 
Herlev Hospital: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Herlev Hospital 
Herlev Ringvej 75, 2730 Herlev 
 
Hvidovre 
Hospital: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Hvidovre Hospital  
Kettegård Alle 30, 2650 Hvidovre 
 
Odense 
Universitets-
hospital: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Odense Universitetshospital 
J. B. Winsløws Vej 4, 5000 Odense C 
 
Rigshospitalet: 
Laboratory: 
Address: 
Biobank: 
Department of Biochemistry Rigshospitalet 
Blegdamsvej 9, 2100 København Ø 
 
Plasma-Mirtazapine and plasma-ondansetron will be analysed at a separate laboratory after 
the trial is finished. This will be specified at a later time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contents 
Signatures .................................................................................................................................................. 2 
Advisors ..................................................................................................................................................... 3 
Statistician ................................................................................................................................................. 3 
Monitor ....................................................................................................................................................... 3 
Study Sites and Local Investigators ............................................................................................................ 4 
Laboratories and Biobanks ......................................................................................................................... 5 
List of Abbreviations ................................................................................................................................... 9 
1. 
Protocol Synopsis / Summary ........................................................................................................... 10 
2. 
Trial Schedule ................................................................................................................................... 12 
3. 
Background / Rationale ..................................................................................................................... 13 
3.1 
Disease background and current treatment modalities ............................................................. 13 
3.2 
Trial rationale .......................................................................................................................... 14 
3.3 
Benefit-risk assessments and ethical considerations ............................................................... 14 
4. 
Hypothesis ........................................................................................................................................ 15 
5. 
Objectives ......................................................................................................................................... 15 
5.1 
Primary objective .................................................................................................................... 15 
5.2 
Secondary objectives .............................................................................................................. 15 
5.3 
Primary endpoints ................................................................................................................... 15 
5.4 
Secondary endpoints .............................................................................................................. 15 
6. 
Trial design ....................................................................................................................................... 16 
6.1 
Summary of trial design........................................................................................................... 16 
6.2 
Discussion of Design ............................................................................................................... 17 
6.3 
Patient Involvement................................................................................................................. 18 
6.4 
Trial Schedule ......................................................................................................................... 18 
7. 
Trial population ................................................................................................................................. 18 
7.1 
Inclusion criteria ...................................................................................................................... 18 
7.2 
Exclusion criteria ..................................................................................................................... 18 
7.3 
Recruiting ............................................................................................................................... 19 
7.4 
Discontinuation ....................................................................................................................... 19 
8. 
Randomisation, treatment blinding / unblinding and sample size ....................................................... 19 
8.1 
Randomisation ........................................................................................................................ 19 
8.2 
Blinding ................................................................................................................................... 20 
8.3 
Sample Size............................................................................................................................ 20 
9. 
Trial Products ................................................................................................................................... 20 
9.1 
Administration of Trial Products ............................................................................................... 20 
9.2 
Mirtazapine: IMP1 ................................................................................................................... 21 
9.3 
Ondansetron: IMP2 ................................................................................................................. 21 
9.4 
Placebo .................................................................................................................................. 22 
9.5 
Rescue Medication: Metoclopramide ....................................................................................... 22 
9.6 
Thiamine ................................................................................................................................. 22 
9.7 
IMP Management and accountability ....................................................................................... 22 
10. Procedures ....................................................................................................................................... 23 

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10.1 Visit Schedule ......................................................................................................................... 23 
10.2 Trial Procedures...................................................................................................................... 24 
10.3 Informed Consent ................................................................................................................... 25 
10.4 Future contact ......................................................................................................................... 25 
10.5 Consent for long-term storage of blood samples in a biobank .................................................. 25 
10.6 Access the offspring’s medical journal ..................................................................................... 25 
10.7 Subject ID number .................................................................................................................. 26 
10.8 Demography ........................................................................................................................... 26 
10.9 Medical history and concomitant disease................................................................................. 26 
10.10 Concomitant and previous medication ..................................................................................... 26 
10.11 Vital signs and weight ............................................................................................................. 26 
10.12 Physical Examination .............................................................................................................. 26 
10.13 Ultrasound scan ...................................................................................................................... 27 
10.14 ECG........................................................................................................................................ 27 
10.15 Laboratory Tests ..................................................................................................................... 27 
10.16 Questionnaires ........................................................................................................................ 27 
10.17 Treatment failure ..................................................................................................................... 28 
10.18 Electronic medical record ........................................................................................................ 28 
11. Assessment of Safety ....................................................................................................................... 28 
11.1 Definitions – Adverse Event (AE) ............................................................................................ 28 
11.2 Definitions – Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) ........................ 28 
11.3 Assessments of AEs and SAEs ............................................................................................... 29 
11.4 Reporting ................................................................................................................................ 29 
11.5 Annual reporting...................................................................................................................... 30 
12. Data handling / Data Management .................................................................................................... 30 
12.1 CRF ........................................................................................................................................ 30 
12.2 Laboratory Data ...................................................................................................................... 30 
13. Statistical evaluation ......................................................................................................................... 31 
14. End of trial ........................................................................................................................................ 31 
14.1 Early termination of the trial ..................................................................................................... 31 
14.2 Subject Discontinuation ........................................................................................................... 31 
15. Administrative procedures ................................................................................................................. 32 
15.1 Source data and subject data protection .................................................................................. 32 
15.2 Quality control and assurance ................................................................................................. 32 
15.3 Monitoring ............................................................................................................................... 32 
15.4 Research Biobank ................................................................................................................... 32 
15.5 Biobank .................................................................................................................................. 33 
15.6 Financing ................................................................................................................................ 33 
15.7 Financial compensation to subjects ......................................................................................... 33 
15.8 Insurance ................................................................................................................................ 33 
15.9 Ethical Considerations ............................................................................................................ 33 
16. Publication ........................................................................................................................................ 33 
17. References ....................................................................................................................................... 33 

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Appendix 1 ............................................................................................................................................... 36 
PUQE-score (Pregnancy Unique Quantification of Emesis and Nausea- score) ................................. 36 
Appendix 2 ............................................................................................................................................... 36 
Schematic overview of case-reports where NVP/HG has been treated with mirtazapine .................... 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
AE 
Adverse Event  
BP 
CGM 
Blood Pressure 
Continuous Glucose Monitor 
CRF 
Case Report From 
ECG 
Electrocardiogram 
e-CRF 
Electronic Case Report Form 
GCP 
HG 
Good Clinical Practice 
Hyperemesis gravidarum 
ICH 
International Conference of Harmonisation 
IMP 
NVP 
Investigational Medicinal Product 
Nausea and Vomiting of Pregnancy 
MD 
Medical Doctor 
OD 
Once Daily 
PUQE 
SAE 
SAP 
Pregnancy-Unique Quantification of Emesis and Nausea 
Serious Adverse Event 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SUSAR Suspected Unexpected Serious Adverse Reaction 
 
 
 

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1. 
Protocol Synopsis / Summary 
Title of trial:  
Validating the Effect of Ondansetron and Mirtazapine In Treating Hyperemesis Gravidarum (VOMIT). A double-
blind randomised placebo-controlled multicentre trial. 
Objectives: 
The primary objective is to compare the efficacy of mirtazapine versus placebo on nausea and vomiting in 
patients with hyperemesis gravidarum. 
The secondary objectives are to compare the efficacy of ondansetron versus placebo and mirtazapine versus 
ondansetron on nausea and vomiting in patients with hyperemesis gravidarum. 
Trial design: 
A double-blind randomized placebo-controlled multi-centre trial. The subjects will be randomised 1:1:1 to 
receive treatment with either mirtazapine, ondansetron or placebo. The intervention will last for 14 days. 
Trial population: 
We will include approximately 180 pregnant women with hyperemesis gravidarum, 60 in each group.  
Main inclusion criteria:  
• 
Pregnant with gestational age between 5+0 and 11+6 
• 
Nausea and vomiting without other obvious reason 
• 
PUQE-24 score ≥13 OR  
PUQE-24 score ≥7 AND  
1. weight loss >5% of pre-pregnancy weight OR 
2. hospitalisation due to nausea and vomiting of pregnancy 
• 
Normal singleton pregnancy 
Main exclusion criteria:  
• 
Mola-, multiple- or non-vital pregnancy 
• 
Congenital long QT-syndrome 
• 
Ongoing treatment with antidepressant medication  
• 
Not able to take medicine orally 
• 
Not able to understand spoken and written Danish 
 
Methods: 
The trial is dimensioned to find a difference in PUQE-24 score of 2 with a power of 80% based on a standard 
deviation of 3 in change in PUQE-24 score, a type 1 error rate of 2,5% and 25% drop out.  
PUQE-score (Pregnancy-Unique Quantification of Emesis and Nausea) is a validated scoring system used to 
grade the severity of nausea and vomiting of pregnancy. It ranges 3-15. 
Trial endpoints: 
The coprimary endpoints are: 
• 
change in PUQE-24 score from baseline to Day 2 (short term) in the mirtazapine group versus the 
placebo group. 
• 
change in PUQE-24 score from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus the 
placebo group. 
Secondary endpoints include: 
• 
Change in PUQE-24 score on short and long term in the ondansetron group versus the placebo group. 
• 
Change in PUQE-24 score on short and long term in the mirtazapine group versus the ondansetron 
group. 
• 
Area under the curve for PUQE-24 score during the intervention. 

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• 
PUQE well-being score. 
• 
Number of daily vomiting episodes. 
• 
Nausea VAS. 
• 
NVPQOL (health-related quality of life for nausea and vomiting during pregnancy). 
• 
HELP (hyperemesis level prediction). 
• 
EQ-5D (health-related quality of life). 
• 
Modified PSQI (Pittsburg Sleep Quality Index) 
• 
Patient satisfaction with treatment VAS. 
• 
Patient consideration of termination of pregnancy. 
• 
Occurrence of treatment failure. 
• 
Use of rescue medication. 
• 
Request for dosage increase. 
• 
Days on sick leave. 
• 
Amount of treatments with i.v.-fluids. 
• 
Days of hospitalization. 
• 
Weight change. 
• 
Request for continuation of trial medication after end of intervention. 
• 
Pregnancy outcome (birth weight, gestational age, APGAR, umbilical cord pH, placenta weight, sex, 
hospitalisations on neonatal ward during the first month, congenital malformations, loss/termination of 
pregnancy). 
Trial medication: 
All trial medication will be provided by Glostrup Apotek in accordance with GMP. The investigational medicinal 
products (IMPs) will be similar in appearance, smell and taste due to the IMPs being encapsulated in gelatine. 
Each subject will be given two containers one labelled ‘Morning’ and one labelled ‘Bedtime’ to be administered 
orally in the morning and at bedtime for 14 days. 
 
In the mirtazapine group, the ‘Morning’ medication will contain placebo and the ‘Bedtime’ medication will contain 
mirtazapine 15 mg. 
In the ondansetron group both the ‘Morning’ and the ‘Bedtime’ medication will contain ondansetron 8 mg. 
In the placebo group both the ‘Morning’ and the ‘Bedtime’ medication will contain placebo. 
All subjects will be allowed to take metoclopramide as rescue medication, and IMP dosage increase will be 
possible on Day 7(+/-1) in case of insufficient effect 
Trial schedule: 
Planned first subject first visit: 
 
February 2019 
 
Planned last subject randomised: 
 
February 2021 
 
Planned last subject last visit: 
 
February 2021 
 
End of trial:  
 
 
 
October 2021 
 
 

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2. 
Trial Schedule 
 
 
 
 
Screening 
Day -2-0 
 
 
Visit 1 
Randomisation 
Day 0 
 
Online 
questionnaire  
Day 1-14 
 
Visit 2 
Day 7(+/-1) 
 
Visit 3 
Day 14(+/-1) 
 
 
Day 15-20 
 
 
Postpartum 
Informed Consent 
x 
 
 
 
 
 
 
In- and Exclusion criteria 
x 
x 
 
x 
x 
 
 
Demography 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Previous and concomitant medication 
x 
 
 
 
 
 
 
Changes in concomitant medication 
 
x 
 
x 
x 
 
 
Vital signs (Height1, weight, BP and pulse) 
x 
x 
 
x 
x 
 
 
Physical examination 
x 
 
 
 
 
 
 
Ultrasound 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PUQE 24-score 
x 
x 
x 
x 
x 
 
 
Nausea VAS, daily vomiting episodes 
 
x 
x 
x 
x 
 
 
Rescue medication 
 
 
x 
x 
x 
 
 
NVPQOL, HELP, EQ-5D, modified PSQI 
 
x 
 
x 
x 
 
 
Patient consideration of termination of pregnancy 
 
x 
 
x 
x 
 
 
Patient satisfaction with treatment VAS 
 
 
 
x 
x 
 
 
Sick leave 
 
 
 
x 
x 
 
 
Hospitalization 
 
 
 
x 
x 
 
 
I.v. fluids 
 
 
 
x 
x 
 
 
Dosage increase 
 
 
 
x 
 
 
 
Continuation of trial medication 
 
 
 
 
x 
 
 
Side effects, adverse events 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Blood samples 
x 
x 
 
x 
x 
 
 
Urine sample 
x 
 
 
 
 
 
 
ECG 
x 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
 
Dispense of trial medication 
 
x 
 
x 
 
 
 
Drug accountability 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy Outcome 
 
 
 
 
 
 
x 
1) 
Height only at screening 

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3. 
Background / Rationale 
3.1 
Disease background and current treatment modalities 
Nausea and vomiting in pregnancy (NVP) is a common condition. However, in about 1,5% of pregnancies the 
symptoms are so severe that hospitalisation is required(1). The most severe cases are diagnosed hyperemesis 
gravidarum (HG). However, there is not international consensus on the diagnostic criteria of HG which might 
include weight loss, hospitalisation, ketonuria, etc(2). In the guideline from the Danish Society of Obstetrics and 
Gynaecology, HG is defined as a ‘condition with severe nausea and vomiting (PUQE-score ≥13) that starts in 
early pregnancy and is accompanied by dehydration, electrolyte imbalance and nutrition deficits’(3). PUQE 
(Pregnancy-Unique Quantification of Emesis and Nausea) is a validated scoring system used to grade the 
severity of NVP within the last 24 hours. Total score ranges from 3 to 15 (see appendix 1)(4). 
The condition is so physically, psychologically and socially invalidating that 27% of pregnant women with HG 
consider ending the pregnancy and 75% do not wish to become pregnant again(5). 
Furthermore, HG can cause long term complications for mother and child. Maternal complications include deep 
vein thrombosis, Mallory Weiss syndrome, Wernicke’s encephalopathy, rhabdomyolysis, lower quality of life, 
depression in pregnancy and post-partum anxiety and post-traumatic stress symptoms(5–10). In case of 
insufficient maternal weight gain (<7 kg) there is increased risk of adverse infant outcome including low birth 
weight, 5-minute APGAR <7, preterm delivery and perinatal death(11).  
The frequency of hospitalisations caused by HG has been increasing in England(1) and the condition is 
associated with considerable socioeconomic loss because of sick leave and treatment costs. The weekly cost 
per woman with HG was estimated to C$ 653 (2005) in Canada(12), equivalent of DKK 4.000 (2017).  
The aetiology of NVP is poorly understood, but there seems to be consensus that the condition is multifactorial.  
 
The current treatment for NVP is divided into non-pharmacological and pharmacological initiatives. There are 
few clinical studies of good quality that examine the pharmacological treatment, and overall the quality of 
evidence is low(13–15). 
The current guideline from the Danish Society of Obstetrics and Gynaecology recommends pyridoxine (vitamin 
B6), if necessary in combination with cyclizine (a sedating antihistamine), for mild cases where pharmacological 
treatment is indicated. In severe cases, where this has not had sufficient effect, metoclopramide or 
promethazine can be tried. As a third line of treatment the guideline recommends ondansetron or in rare cases 
after the 10th week of pregnancy glucocorticoids (3). 
 
The use of ondansetron for NVP has been increasing. According to the Mini Sentinel Distributed Database from 
the USA, which covered 1,949,201 pregnant women and 2,432,489 live birth pregnancies, oral ondansetron use 
increased from 3.1% of pregnancies in 2006 to 19.7% in 2014(16). Extrapolated to all of the USA that is more 
than 750,000 pregnant women per year(17). In spite of the large number of exposed pregnant women it is still 
unclear if ondansetron poses a risk of congenital heart defects. Two studies have found a higher incidence of 
congenital heart defects in offspring of women who had been exposed to ondansetron in pregnancy, while three 
studies have not(18). 
Another important consideration is that ondansetron has not been approved as treatment for NVP. Alarmingly, 
oral ondansetron has not been tested as treatment for NVP in one single placebo-controlled trial and there have 
only been two double-blinded randomised trials with active comparators.  
In the first study 83 patients with NVP were randomised to treatment with either ondansetron 4 mg or 
metoclopramide 10 mg for two weeks. The first week the ondansetron and metoclopramide were administered 3 
times daily. The second week of treatment administration was reduced to twice daily for 3 days and once daily 
for 4 days. The ondansetron group had a slightly lower VAS score on both nausea and vomiting compared to 
the metoclopramide group, but the difference was only statistically significant on day 3-4 for nausea and day 2-8 
for vomiting(19). 
The other study included 36 patients with NVP who were randomised to ondansetron 4 mg three times daily or 
doxylamine 12,5 mg and pyridoxine 25 mg daily three times daily for 5 days. The study found that ondansetron 
significantly reduced nausea with a median reduction of 51 on a VAS scale compared to a reduction of 20 for 
doxylamine-pyridoxine (p=0.02). Likewise the vomiting was reduced more with ondansetron than with 
doxylamine-pyridoxine (VAS scale reduction of 41 vs 17)(20).  
 
In spite of the common use of the above-mentioned treatment modalities it is often not possible to reduce 
symptoms sufficiently. Consequently it is relevant to examine the effect of alternative treatment options(21). A 
promising candidate for pharmacologic treatment for HG is mirtazapine. It is primarily an antidepressant, but it 
also known to have antiemetic and appetite stimulating effects(22).  
There are case reports on 23 pregnant women where mirtazapine has been effective on treatment resistant 
HG(see appendix 2)(21,23), but there has never been a clinical controlled trial with mirtazapine for NVP or HG. 

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There have, however,  been clinical controlled trials where mirtazapine has been showed to prevent 
postoperative nausea(24,25), as well as case reports describing effect on other conditions associated with 
nausea and vomiting(26–31). 
 
Mirtazapine is primarily an adrenergic alpha2-receptor antagonist that increases the release of noradrenalin. 
This leads to increased stimulation of the serotonergic neurons causing increased serotonin release. However, 
a closer look at the pharmacologic profile of mirtazapine reveals mechanisms of action similar to those of other 
drugs used to treat HG and NVP. Like ondansetron and metoclopramide, it is an antagonist on the serotonin 
5HT3-receptor in the chemoreceptor trigger zone. This action contributes to the antiemetic effect. It also acts as 
an antagonist on the 5HT2A- and 5HT2C-receptors and on the histamine H1-receptor (as do promethazine and 
cyclizine).  Thus, the antiemetic and appetite stimulating effects of mirtazapine are pharmacologically well 
explained. 
A Danish register-study on 614 mirtazapine exposed pregnant women did not find an association between 1st 
trimester exposure and major congenital malformations(32). This is in accordance with a systematic review from 
2016 including 390 women exposed to mirtazapine in pregnancy and/or lactation, which did not find an increase 
in major malformations(33).  
According to janusinfo.se Swedish data on 602 mirtazapine exposed pregnant women found 16 cases of 
malformations where 12-13 cases were expected(34). Thus, they expected an incidence of malformations of 
1,99- 2,16%. This background incidence of major congenital malformations is remarkably lower than the 3.49% 
found in the Danish study based on 966,372 births(32). Thus, the Swedish study might underestimate the 
background incidence of congenital malformations. Disregarding this, janusinfo.se concludes that the incidence 
of malformations in the mirtazapine exposed pregnancies was not alarmingly high and that no specific group of 
malformations was overrepresented(34).  
A European study with a cohort of 357 mirtazapine exposed pregnant women found a (non-statistically 
significant) higher incidence of congenital malformations when compared to non-exposed pregnancies. 
However, the incidence in the mirtazapine exposed pregnancies was similar to that of SSRI exposed 
pregnancies(35). This increased incidence has been explained by underlying disease (confounding by indication 
(likely depression or anxiety)) in a Danish study(36).  
Data on other pregnancy outcomes such as pregnancy loss, preterm birth and neonatal symptoms is 
inconclusive, but show risks similar to those of SSRI-exposed(33,35). Again, this might be explained by 
confounding by indication. 
In summary, there is data on 1963 mirtazapine exposed pregnant women worldwide suggesting that 
mirtazapine is safe in pregnancy. However it is not officially recommended due to insufficient data(37). 
3.2 
Trial rationale 
The existing treatment options for NVP and HG are not profoundly evidence based and in Denmark no drugs 
are approved as treatment on these indications. Furthermore, the current treatment options are often not 
sufficiently effective. Thus, a trial investigating the effect of pharmacologic treatment for NVP and HG is 
warranted. 
 
There is a need for a clinical placebo-controlled trial to clarify the effect of mirtazapine, primarily, and 
secondarily ondansetron as treatment for HG. To date there have been no placebo-controlled trials with 
mirtazapine or oral ondansetron as treatment for HG, even though a considerable placebo-effect is reported in 
the few existing placebo-controlled trials with other treatment modalities for NVP(38–40).  
Currently there are no planned or ongoing placebo-controlled trials with mirtazapine or ondansetron 
investigating the effect of these drugs on HG(41,42). The data on ondansetron gained from a such trial will 
make it possible to include ondansetron as comparator to mirtazapine in a possible future confirmatory phase 
three trial with mirtazapine as treatment for HG. 
Due to the category of patients, i.e. pregnant women that do not usually participate in clinical trials, and 
mirtazapine and ondansetron being older drugs that are no longer protected by patents, it is unlikely at trial will 
be sponsored by the pharmaceutical industry. 
3.3 
Benefit-risk assessments and ethical considerations 
The individual subjects may not necessarily benefit from participation in the trial, but the trial medication might 
alleviate NVP symptoms. The information gained from the trial may affect future recommendations on treatment 
for HG and NVP and thus help patients in the future.  
Pregnant women are not regularly included in medical trials and our main concern has been an assessment on 
whether the trial medications are safe to use in early pregnancy. Neither mirtazapine or ondansetron use in 

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early pregnancy pose a significantly increased risk for the mother or unborn child. Based on the number of 
exposed pregnant women for both trial medications, we think that they can be used in early pregnancy(43).  
Despite the absence of placebo-controlled trials, ondansetron is currently being used for NVP in Denmark and 
many other countries. It is often used in the most severe cases and is recommended as third line treatment in 
the current Danish national guideline for hyperemesis. It is most likely the medication to be offered to our patient 
population were they not to participate in the trial. We find it substantially less concerning to enroll patients in a 
clinically controlled trial where efficacy and side effects are collected systematically, than to continue treating 
patients with the current treatment options without availability of such data. 
Another ethical consideration has been randomizing patients to ineffective treatment. By making the trial three-
armed we ‘spare’ a placebo-group and as a consequence only one third, as opposed to half, of the patient 
population will receive ineffective treatment. It should be noted, that the placebo-group will not be treated with 
ineffective medication alone, as all groups will be allowed to use metoclopramide as rescue medication. 
 
 
4. 
Hypothesis 
 
The hypothesis is that both mirtazapine and ondansetron reduce nausea and vomiting more than placebo in 
patients with hyperemesis gravidarum. 
 
 
5. 
Objectives 
5.1 
 Primary objective 
The primary objective is to compare the efficacy of mirtazapine versus placebo on nausea and vomiting in 
patients with HG. 
5.2 
Secondary objectives 
The secondary objectives are to compare the efficacy of ondansetron versus placebo and of mirtazapine versus 
ondansetron on nausea and vomiting in patients with HG. 
5.3 
Primary endpoints 
The coprimary endpoints are:  
• 
Change in PUQE-24 score from baseline to Day 2 (short term) in the mirtazapine group versus the 
placebo group.  
• 
Change in PUQE-24 score from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus 
the placebo group.  
The change in PUQE-24 score is calculated as baseline score minus Day 2 score and baseline score minus 
Day 14(+/-1) score, respectively. Baseline values will be recorded at randomisation. 
The null hypothesis will be rejected if we find a difference of 2 or more on either short or long term or both. 
 
PUQE-score (Pregnancy-Unique Quantification of Emesis and Nausea) is a validated scoring system used to 
grade the severity of NVP. PUQE-24 consists of three elements:  
1) number of hours with nausea within the last 24 hours (from none at all to more than 6 hours),  
2) number of vomiting episodes in the last 24 hours (from 0 to >6 times), and 
3) number of retching episodes without vomiting within the last 24 hours (from 0 to >6 times).   
Each element gives a sub-score of 1 to 5 points and the total score is calculated by adding the three sub-scores 
giving a total score ranging from 3 to 15.  
The condition is graded as mild if the score is 3-6, moderate with a score of 7-12 and severe if the score is 13-
15(3). See Appendix 1. 
5.4 
Secondary endpoints 
• 
Change in PUQE-24 score from baseline to Day 2 in the ondansetron group versus the placebo group. 
• 
Change in PUQE-24 score from baseline to Day 14(+/-1) in the ondansetron group versus the placebo 
group. 
• 
Change in PUQE-24 score from baseline to Day 2 in the mirtazapine group versus the ondansetron 
group. 

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• 
Change in PUQE-24 score from baseline to Day 14(+/-1) in the mirtazapine group versus the 
ondansetron group. 
• 
Area under the curve for PUQE-24 score during the intervention in the three different groups. 
• 
Change in PUQE well-being score during the intervention in the three different groups. 
• 
Change in daily nausea VAS during the intervention in the three different groups.  
• 
Change in number of daily vomiting episodes during the intervention in the three different groups. 
• 
Change in NVPQOL (health-related quality of life for nausea and vomiting during pregnancy) from 
baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. 
• 
Change in HELP score (hyperemesis level prediction) from baseline to Day 7(+/-1) and baseline to Day 
14(+/-1) in the three different groups. 
• 
Change in EQ-5D-5L (health-related quality of life) from baseline to Day 7(+/-1) and baseline to Day 
14(+/-1) in the three different groups. 
• 
Change in modified PSQI (Pittsburg Sleep Quality Index) from baseline to Day 7(+/-1) and baseline to 
Day 14(+/-1) in the three different groups. 
• 
Patient satisfaction with treatment VAS on Day 7(+/-1) and Day 14(+/-1) in the three different groups. 
• 
Change in patient consideration of termination of pregnancy from baseline to Day 7(+/-1) and baseline 
to Day 14(+/-1) in the three different groups. 
• 
Frequency of and time to treatment failure in the three different groups. 
• 
Frequency of request for dosage increase in the three different groups. 
• 
Use of rescue medication during the intervention in the three different groups. 
• 
Number of days of sick leave during the intervention in the three different groups. 
• 
Amount of treatments with i.v.-fluids during the intervention in the three different groups. 
• 
Number of days of hospitalisations during the intervention in the three different groups. 
• 
Weight change in kg from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different 
groups. 
• 
Frequency of request for continuation of trial medication after end of intervention in the three different 
groups. 
• 
Pregnancy outcome (birth weight, gestational age, APGAR, umbilical cord pH, placenta weight, sex, 
hospitalizations on neonatal ward during the first month post-partum, congenital malformations, 
loss/termination of pregnancy). This endpoint will not be double blind on all patients since patients can 
be unblinded after end of the intervention. The statistician will remain blinded. 
 
 
6. 
Trial design 
6.1 
Summary of trial design 
A double-blinded randomised placebo-controlled multi-centre trial.  
 
180 subjects will be randomised 1:1:1 to receive treatment with either  
a) Mirtazapine oral tablet 15 mg at bedtime and placebo oral tablet morning, 
b) Ondansetron oral tablet 8 mg morning and at bedtime, or 
c) Placebo oral tablet morning and at bedtime. 
 
The trial subjects will receive treatment for 14 days. 
 
A dosage increase will be optional on Day 7(+/-1). If dosage increase is desired, the subject will then receive 
treatment with either 
a) Mirtazapine oral tablet 30 mg at bedtime and placebo oral tablet morning, noon and late afternoon 
b) Ondansetron oral tablet 8 mg morning, noon, late afternoon and at bedtime 
c) Placebo oral tablet morning, noon, late afternoon and at bedtime 
If dosage increase is not desired the treatment from Day 0-7 will remain unchanged until Day 14. 
 
Data for the primary endpoint PUQE-24 score will be collected by the subjects completing online questionnaires 
related to their symptoms. 

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Figure 1 - Trial design 
 
6.2 
Discussion of Design 
The existing clinical studies on treatment for NVP generally have two arms; an IMP is tested against placebo or 
an active comparator. In designing this study with three arms, we can compare both mirtazapine and 
ondansetron to placebo and thus spare a placebo group. Furthermore, we can gain data on mirtazapine 
compared to an active comparator (ondansetron). 
The intervention will last 14 days which is also seen in other clinical trials on treatment of NVP(39). This is 
estimated to be sufficient time to observe the effect of the intervention. An effect is expected within days after 
initiating treatment, thus at the visit on Day 7 a potential effect will have reached a stable level. If the treatment 
is not sufficiently effective it will be possible to increase the dosage of the IMPs. 
In the national guideline on HG ondansetron 8 mg is to be administered twice daily with optional increase to a 
maximum total dosage of 32 mg per day. By allowing an increase in administration to exactly that our 
intervention will reflect current practice.  
In most of the case reports on mirtazapine as treatment for HG, dosages of up to 15 mg daily have been 
effective. However, in a few cases the patients were started on mirtazapine 30 mg daily. Thus, to not disregard 
a possible effect due to inadequate dosage, we consider it relevant to make dosage increase to 30 mg daily 
optional. 
The option of dosage increase might also ensure that the subjects stay in the trial even if they do not experience 
the desired symptom relief during the first week. However, there is still a concern that due to drop-outs and 
missing data the dataset may be incomplete at the end of the trial. As a consequence, we risk that a potential 
clinically significant effect of an IMP might not be shown as statistically significant. To minimize this risk, we will 
have two primary endpoints: a change in PUQE-score from baseline to Day 2 and from baseline to Day 14(+/-
1). In this manner, we will be able to show a potential effect on Day 2, even if we do not have sufficient data to 
show it at the end of the intervention (Day 14). Furthermore, we have added ‘treatment failure’ as a secondary 
outcome, and subjects will be prompted to indicate if insufficient symptom relief was the reason for drop-out. 
According to the Danish guideline, diagnosis of HG requires a PUQE-24 score ≥13. However, patients with a 
PUQE-24 score ≥13 are often not able to tolerate oral tablets and would therefore not be able to participate in 
this trial. Thus, subjects can be included in the trial with PUQE-24 score <13. The inclusion criterion on severity 
of NVP is PUQE-24 score ≥13 OR PUQE-24 score ≥7 AND weight loss >5% of pre-pregnancy weight and/or 
 
 
 
 
 
 
 
 
 
                  
 
 
 
 
 
 
 
 
                                   
 
 
 
 
 
 
 
 
 
                    
 
 
 
 
 
 
 
 
 
 
    Day 0-7 
 
         Day 7-14 
Mirtazapine 15 mg x1, 
placebo x1, N=60 
Randomization 
N=180 
Hospitalized or 
out-patient 
with NVP 
Ondansetron 8 mg x2, 
N=60 
Placebo x2, N=60 
 
Mirtazapine 15 mg x1, 
placebo x1 
Mirtazapine 30 mg x1, 
placebo x3 
Ondansetron 8 mg x2 
 
Ondansetron 8 mg x4  
 
Placebo x4 
Placebo x2 
 

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hospitalisation due to nausea and vomiting of pregnancy. This is in accordance with other randomised 
controlled trials on HG where weight loss and hospitalisation often are seen as definition items(2). 
6.3 
Patient Involvement  
Development of the study protocol and the final trial design has been supported by patient representatives as 
well as leading HG researches from Amsterdam. Patient representatives from the Danish and English patient 
organisations have provided valuable input to the protocol, specifically on outcome measures, feasibility of the 
study and ethical considerations.  
6.4 
Trial Schedule 
Planned first subject first visit  
February 2019 
 
Planned last subject randomised 
February 2021 
 
Planned last subject last visit: 
February 2021 
 
End of trial  
 
 
October 2021 
 
 
7. 
Trial population  
 
The trial population will consist of pregnant women with HG both out-patient and hospitalised patients.  
If a patient at the time of referral to hospital is in a condition where treatment with intravenous antiemetics 
(ondansetron or other) is indicated, such treatment will be initiated. If and when the patient’s clinical condition 
improves sufficiently for a transfer to orally administered antiemetics, the patient can then be enrolled in the trial. 
Subjects meeting all of the inclusion criteria listed and none of the exclusion criteria will be considered eligible 
for the trial. 
7.1 
Inclusion criteria 
• 
Written informed consent obtained before any trial related procedures are performed 
 
• 
Female age >18 years 
 
• 
Pregnant woman with gestational age between 5+0 and 11+6 
 
• 
Nausea and vomiting without other obvious reason 
 
• 
PUQE-24 score ≥13 OR  
 
PUQE-24 score ≥7 AND  
1. weight loss >5% of pre-pregnancy weight and/or 
2. hospitalisation due to nausea and vomiting of pregnancy  
 
Compliance with this criterion on any given day within 3 days prior to screening (possibly not compliant with 
this criterion on day of randomization) 
 
• 
Singleton pregnancy 
 
• 
The subject must be willing and able to comply with trial protocol 
7.2 
Exclusion criteria 
• 
Mola pregnancy, multiple gestation or non-vital pregnancy 
 
• 
Nausea and vomiting of other aetiology than NVP 

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• 
Allergic to selective 5-HT3-receptor antagonists 
 
• 
Ongoing treatment with antidepressant medication 
 
• 
Pre-existing diagnosis of chronic kidney disease, diabetes type 1 or 2, significant cardiac disease (incl. 
long QT syndrome), epilepsy, HIV. In case of other pre-existing conditions subjects might be excluded 
based on individual assessment by an MD 
 
• 
Elevated liver enzymes (ALAT/ASAT >150 U/l) 
 
• 
Elevated creatinine (>100 µmol/l) 
 
• 
ECG showing long QT-syndrome (QTc >460msek) 
 
• 
Weekly alcohol intake >2 units of alcohol 
 
• 
Not able to take medicine orally 
 
• 
Not able to understand spoken and/or written Danish 
 
• 
Participation in another investigational drug trial within current pregnancy 
7.3 
Recruiting 
Eligible subjects, either out-patient or hospitalised, will be identified by medical professionals (MD, nurse or 
midwife) involved in their treatment. The subjects will be asked if they are interested in hearing more about the 
trial. If they accept they will be informed about the trial by either that same medical professional or specific trial 
personnel. Consent from an eligible subject must be obtained before any transfer of information on the subject 
from a medical professional involved in the treatment to trial personnel. 
7.4 
Discontinuation 
Subjects will be informed about the possibility of discontinuing the trial at any time. We will encourage the 
subjects to inform the investigator as soon as they have decided to discontinue the trial and last administration 
of trial medication will be registered. In case of discontinuation we will ask the subject to indicate a reason for 
the discontinuation which will be registered. If the reason for discontinuation is treatment failure, time of 
treatment failure will be registered. 
Subjects will be discontinued from the trial in case of icterus or mania or if they comply with an exclusion 
criterion. 
Subjects may be unblinded at discontinuation if this is necessary to make clinical decisions about their future 
treatment. Subjects will be encouraged to fill out daily online questionnaires on possible side effects until three 
days after last administration of trial medication.  
Birth outcome will be registered on all subjects including dropouts unless subjects withdraw consent.  
Data on treatment effect (NVP symptoms) collected before discontinuation will be evaluated and dropouts will 
not be replaced by new subjects. 
All discontinued subjects will have to return the trial medication.  
 
8. 
Randomisation, treatment blinding / unblinding and sample size 
8.1 
Randomisation 
Subjects will be randomised in a 1:1:1 ratio and stratified by site. 
Randomisation will be performed using REDCap to create a numbered randomisation list. After identification of 
an eligible patient, the subject will be assigned a randomisation number and will subsequently receive trial 
medication corresponding to the randomisation number. 

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8.2 
Blinding 
A double-blind set-up will be used. Mirtazapine, ondansetron and placebo will be similar in appearance, smell 
and taste and will be packaged identically to maintain the treatment blind. 
Information on type of trial medication corresponding to each randomisation number will be kept by Glostrup 
Apotek and thus will not be accessible to trial personnel involved in the conduct of the trial during the 
intervention. Neither the sponsor, the subject, nor the investigational site staff will know which treatment the 
subject is receiving. 
If a subject desires to continue the IMP after the intervention, the randomisation code for that particular subject 
can be broken. Thus, for unblinded subjects data collected after unblinding (side effects and AEs 0-3 days after 
the intervention and birth outcome) will not be blinded for the subjects or the clinicians, but the statistician will 
remain blinded. 
The randomisation code for a particular subject can be broken during the intervention in a medical emergency 
or if knowledge of the IMP is necessary for the optimal treatment of the subject. 
To break the randomisation code the investigational staff must call Glostrup Apotek which is available at all 
times of day and night. 
Whenever a randomisation code is broken, the person breaking the randomisation code must record the time, 
date and reason as well as his/her initials in the source documents. The sponsor and investigator must be 
notified immediately after randomisation code break if this happens because of an emergency during the 
intervention. No matter the reason for unblinding, the subject must be discontinued from the trial (side effects 
and AEs 0-3 days after the intervention and birth outcome will still be collected). 
8.3 
Sample Size 
The trial is dimensioned to find a difference of 2 in PUQE-24 score change from baseline to Day 2 (short term) 
and/or from baseline to Day 14(+/-1)(long term) between the mirtazapine group and the placebo group with 80% 
power based on a standard deviation (SD) of change of PUQE-24 score of 3, a type 1 error rate of 2,5% and 
25% drop-out. The reason for the 2,5% type 1 error rate is that we want to test 2 hypotheses; effect of 
mirtazapine versus placebo short and long term on HG. 
Thus, we will have to include 57 subjects in each of the 3 groups, which we round up to 60 subjects, equivalent 
of 180 subjects all together. 
An SD of 3 is a conservative estimate based on the placebo-controlled trial with doxylamine-pyridoxine(39). 
 
 
9. 
Trial Products 
9.1 
Administration of Trial Products 
Each subject will be randomly assigned to receive mirtazapine (IMP1), ondansetron (IMP2) or placebo. Please 
refer to figure 1 on page 17 for a visual on the trial design. 
Trial medication will be provided by Glostrup Apotek in accordance with GMP. IMP1, IMP2 and placebo will be 
similar in appearance, smell and taste due to the IMPs being encapsulated in gelatine. In the placebo group the 
medication will be an empty gelatine capsule. 
 
At Visit 1 on Day 0 each subject will receive two containers with sufficient medication for 10 days. One container 
will be labelled ‘Morning’ and one will be labelled ‘Bedtime’ to be administered orally in the morning and at 
bedtime for the first week (until Visit 2 on Day 7(+/-1)). Administration will start at bedtime of Day 0. 
Thus, during the first week of intervention there will be two administrations of trial medication daily. 
At Visit 2, two new containers with sufficient medication for 10 days will be administered. If dosage increase is 
not desired administration will proceed unchanged. 
If a dosage increase is desired the number of daily administrations will go from two to four. One container will 
then be labelled ‘Morning, noon and afternoon’ and will be administered orally in the morning, at noon and late 
afternoon or early evening. The other container labelled ‘Bedtime’ will be administered only at bedtime. 
 
In case a subject vomits within 45 minutes after administration of trial medication the subject will have to 
administer a new dosage as described in the folder ‘Praktisk information om forsøgsmedicinen’. 
If a subject runs out of trial medication before the next visit due to extra administrations because of vomiting, the 
subject must contact the investigator as described in the folder ‘Praktisk information om forsøgsmedicinen’. 
 
The folder ‘Praktisk information om forsøgsmedicinen’ will be handed out with the trial medication. Patients are 
encouraged to register time of administration and possible vomiting episodes within 45 minutes after 
administration in the folder. 

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9.2 
Mirtazapine: IMP1 
In the mirtazapine group, the ‘Morning’ medication will contain placebo and the ‘Bedtime’ medication dispensed 
at Visit 1 will contain mirtazapine 15 mg. Thus, the subjects in this group will initially receive treatment with 
 
Placebo oral tablet in the morning and  
Mirtazapine 15 mg oral tablet at bedtime. 
The medication dispensed at Visit 2 on day 7(+/-1) will be the same and administration will remain unchanged in 
week 2 if dosage increase is not desired. 
If dosage increase is desired at Visit 2 the ‘Morning, noon and afternoon/evening’ medication will be unchanged 
and still contain placebo. However, the ‘Bedtime’ medication dispensed will contain mirtazapine 30 mg as 
opposed to 15 mg in week 1. Thus, the treatment in the second week will be 
 
Placebo oral tablet in the morning, at noon and late afternoon/early evening and  
Mirtazapine 30 mg oral tablet at bedtime. 
 
Mirtazapine is an antidepressant known to have antiemetic and appetite-stimulating effect. It is an alfa2-receptor 
antagonist, an antagonist on several serotonin-receptors (5HT2A, 5HT2C and 5HT3) and on one histamine-
receptor (H1). 
Recommended dosage is 15-30 mg daily initially and 15-45 mg daily as maintenance dosage, preferably 
administered once daily before bedtime.  
Peak plasma-concentration is reached within 2 hours after oral administration. Elimination half-life is 20-40hours 
and time to reach steady state is 3-4 days. 
 
Side effects:  
>10% : 
Increased appetite, weight gain, dry mouth, headache, sedation and somnolence. 
1-10%: 
Diarrhea, obstipation, vomiting, orthostatic hypotension, peripheral edema, arthralgia, myalgia, 
back pain, abnormal dreams, anxiety, drowsiness, confusion, dizziness, tremor and rash. 
0,1-1%: 
Hypotension, agitation, hallucinations, mania, motoric unrest, paresthesia, syncope.  
0,01-0,1%: 
Pancreatitis, aggressiveness, myoclonia. 
Not known: 
Edema, eosinophilia, bone marrow depression, hyponatremia, rhabdomyolysis, dysarthria, oral 
paresthesia, serotonin syndrome, suicidal thoughts or behavior, bullous dermatitis, erythema 
multiforme, Stevens-Johnsons syndrome, toxic epidermal necrolysis, urine-retention.(37)  
 
There is data on 1963 mirtazapine-exposed pregnant women without higher incidence of congenital 
malformations(32–35). 
9.3 
Ondansetron: IMP2 
In the ondansetron group both the ‘Morning’ and the ‘Bedtime’ medication dispensed at Visit 1 on Day 0 will 
contain ondansetron 8 mg. Consequentially the subjects in this group will initially receive 
 
Ondansetron 8 mg oral tablet in the morning and at bedtime. 
If dosage increase is desired on at Visit 2 on Day 7(+/-1) the medication dosage in the dispensed medication 
will remain unchanged, but with the two added administrations the treatment regimen will be 
 
Ondansetron 8 mg oral tablet in the morning, at noon, in late afternoon/early evening and at 
bedtime.  
 
Ondansetron is an antiemetic. It works as a serotonin antagonist by binding selectively to the 5HT3-receptors in 
the chemo-receptors of the trigger zone thus reducing nausea and vomiting. 
Recommended dosage depends is 8 mg every 12 hours. 
Peak plasma-concentration is reached within 1,5 hours after oral administration, and elimination half-life is about 
3 hours. 
 
Side effects: 
>10%: 
Headache. 
1-10%: 
Blushing, sensation of heat, obstipation. 
0,1-1%: 
Affected liver, arrhythmia, bradycardia, hypotension, extrapyramidal symptoms. 
0,01-0,1%: 
QT-interval prolongation, allergic reactions, anaphylactic reaction, visual disturbances (primarily 
seen in i.v. administration) 
<0,01%: 
Toxic epidermal necrolysis, passing blindness (primarily seen in i.v. administration).(45) 
 
Obstipation is a common side effect to ondansetron and this will be emphasised at randomisation and in the 
folder ‘Praktisk information om forsøgsmedicinen’. Patients will be encouraged to administer a laxative (we 
recommend magnesium) if they experience any signs of constipation. 

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In spite of the large number of ondansetron-exposed pregnant women it is still unclear whether ondansetron 
caused a higher incidence of congenital heart defects. Two studies have found a higher incidence of congenital 
heart defects, while three studies have not(18). However, ondansetron is frequently used for HG in Denmark 
and other countries. 
9.4 
Placebo 
In the placebo group both the ‘Morning’ and the ‘Bedtime’ medication dispensed at Visit 1 on Day 0 will contain 
placebo. Consequentially the subjects in this group will initially receive 
 
Placebo oral tablet in the morning and at bedtime. 
If dosage increase is desired on at Visit 2 on Day 7(+/-1) the medication will still be placebo, but with the added 
administrations the treatment regimen will be 
 
Placebo oral tablet in the morning, at noon, in late afternoon/early evening and at bedtime.  
9.5 
Rescue Medication: Metoclopramide 
All three groups will receive metoclopramide which they are allowed to use as rescue medication. In case of 
insufficient symptom relief, subjects are allowed to administer 
Metoclopramide 10 mg oral tablet or i.v. max x 3 daily. 
Subjects will be asked to register administered rescue medication in the daily online questionnaires. 
 
Metoclopramide is an antiemetic that increases gastrointestinal motility. It is a competitive dopamine(D2)-
receptor antagonist and in high concentrations it also works as a 5HT3-receptor antagonist. Furthermore, it 
inhibits the chemo-receptors of the trigger zone and thus reduces nausea and vomiting. 
Recommended dosage is 10 mg max x3 daily. 
Peak plasma-concentration is reached within 1 hour after oral administration, and elimination half-life is 3-5 
hours. 
 
Side effects: 
>10%: 
Drowsiness. 
1-10%: 
Weakness, diarrhea, dry mouth, hypotension, akathisia, depression, extrapyramidal symptoms, 
parkinsonism. 
0,1-1%: 
Bradycardia, hyperprolactinemia, loss of consciousness, dyskinesia, dystonia, hallucinations, 
hypersensitivity, amenorrhea.  
0,01-0,1%: 
Confusion, cramps. 
Not Known: 
AV-bloc, QT-interval prolongation, cardiac arrest, hypertension, vascular collapse, 
methemoglobinemia, gynecomastia, malignant neuroleptica syndrome, suicidal behavior, 
syncope, tardive dyskinesia, allergic reactions.(46)  
 
Subjects will be thoroughly instructed to stop administrations of metoclopramide if they experience 
extrapyramidal symptoms. 
9.6 
Thiamine 
All subjects will receive treatment with thiamine during the trial as to minimize the risk of developing Wernicke’s 
encephalopathy. If the subject is hospitalised thiamine 100 mg i.v. will be administered daily. Out-patient 
participants will take 1 oral tablet Apovit B-combin stærk daily which contains B1 15 mg, B2 15 mg and B6 15 
mg. 
9.7 
IMP Management and accountability 
At each study site, there will be an IMP accountability log that will contain  
• 
Amount received at the study site 
• 
Date of delivery 
• 
Expiration date 
• 
Amount accessible at the study site 
• 
Date and initials of the person updating the log 
 
There will be an accountability log on subject level to ensure traceability and compliance. This log will contain 
• 
Subject ID 

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• 
Expiration date 
• 
Amount dispensed 
• 
Dispensed by: date and initials 
• 
Amount returned by subject 
• 
Excess medication received by 
 
The subjects will be instructed to keep a log of administered IMP and rescue medication as described in the 
folder ‘Praktisk information om forsøgsmedicinen’. They will be asked to return any unused medication. 
The local investigators are responsible for keeping the accountability log up to date at centre level as well as on 
subject level. 
 
IMP management and accountability will be monitored by the GCP-unit throughout the trial. 
 
 
10. Procedures 
10.1 Visit Schedule 
 
Visit ID 
Procedures to be performed at the visit 
Screening Visit 
Day -2-0 
 
Obtain written informed consent for the trial before any other trial procedures are 
performed 
Assess compliance with inclusion and exclusion criteria 
Obtain demographic data 
Record medical history  
Record use of relevant previous medications and concomitant medication 
Record PUQE-24 score 
Record pre-pregnancy weight 
Measure weight 
Measure height 
Measure vital signs 
Perform physical examination 
Perform ultrasound scan to confirm gestational age and singleton pregnancy, if there is 
no record of such in the medical journal from within 4 four weeks prior to visit 
Collect blood samples 
Record ECG to rule out long QT-syndrome 
Schedule date for next visit. 
 
Visit 1 
(Randomisation) 
Day 0 
Baseline values 
recorded  
Re-assess compliance with inclusion and exclusion criteria 
Record changes to concomitant medication 
Record PUQE-24 score 
Record nausea VAS 
Record number of daily vomiting 
Record EQ-5D, NVPQOL, HELP and modified PSQI 
Record possible patient consideration of termination of pregnancy 
Measure weight  
Measure vital signs 
Collect blood samples 
Randomise the subject 
Instruct the subject on how to use the IMP 
Dispense IMP, rescue medication and B-kombin to the subject (sufficient medication for 
10 days) 
Schedule date for next visit 
 
Visit 2 
Day 7  
 
Re-assess compliance with inclusion and exclusion criteria 
Record changes to concomitant medication and including rescue medication  
Record PUQE-24 score 
Record nausea VAS 
Record number of daily vomiting 
Record EQ-5D, NVPQOL, HELP and modified PSQI 

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Visit ID 
Procedures to be performed at the visit 
Record patient satisfaction with treatment VAS 
Record possible patient consideration of termination of pregnancy 
Record sick leave 
Record possible hospitalization 
Record possible administration of i.v. fluids 
Record side effects 
Assess AEs occurring since the last visit 
Record use of rescue medication 
Record desire for dosage increase 
Measure weight  
Measure vital signs 
Record ECG 
Collect blood samples 
Collect used IMP and rescue medication and perform drug accountability and 
compliance check 
Dispense IMP, rescue medication and B-kombin to the subject (sufficient medication for 
10 days) 
Schedule date for next visit  
 
Visit 3 
Day 14 
 
Re-assess compliance with inclusion and exclusion criteria 
Record changes to concomitant medication including rescue medication 
Record PUQE-24 score 
Record nausea VAS 
Record number of daily vomiting 
Record EQ-5D, NVPQOL, HELP and modified PSQI 
Record patient satisfaction with treatment VAS 
Record possible patient consideration of termination of pregnancy 
Record sick leave 
Record possible hospitalization 
Record possible administration of i.v. fluids 
Record side effects 
Assess AEs occurring since the last visit 
Record use of rescue medication 
Record desire to continue trial medication 
Measure weight  
Measure vital signs 
Record ECG 
Collect blood samples 
Collect used IMP and rescue medication and perform drug accountability and 
compliance check 
If continuous treatment is desired the subject will be unblinded 
 
Pregnancy 
Outcome 
 obtained from 
Medical Journal 
Record gestational age at birth or loss/termination of pregnancy 
Record APGAR 
Record gender 
Record birth weight 
Record umbilical cord pH 
Record placenta weight 
Record possible congenital malformations and hospitalization at neonatal ward during 
the first month post-partum 
 
 
 
10.2 Trial Procedures 
This section outlines the trial procedures that will be performed during the trial. For further details on the specific 
timing of the procedures please refer to the visit schedule in above. 
The tasks listed below must be performed by a physician or an appropriately trained nurse or midwife to whom 
the local investigator has delegated the tasks: 

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• 
Obtainment of informed consent 
• 
Evaluation of in- and exclusion criteria 
• 
Physical examination 
• 
Assessment of AEs/SAEs 
• 
Assessment of ECG and other laboratory results 
• 
Decision to break the randomisation code for individual subjects (See 7.3 Discontinuation and 8.2 
Blinding) 
10.3 Informed Consent 
The written informed consent must be obtained (i.e. signed and dated by the subject) before any trial activities 
are performed. 
Each subject must be informed that participation in the trial is voluntary and that he/she may withdraw from the 
trial at any time during the course of the trial and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician. 
Subjects meeting the inclusion criteria for the trial will be given thorough verbal and written information about the 
trial. This information will be given by a trial authorized physician, nurse or midwife directly affiliated with the 
trial. Information must take place in an undisturbed room. The subject will be given time to ask questions and 
allowed sufficient time (minimum 24 hours) to consider the trial before deciding whether to participate. 
If subjects so desire, they may make a later appointment with the site investigator after having reviewed the 
written information about the trial, at which they can meet and discuss participation in the trial. Such a meeting 
must take place in an undisturbed room and the subject may bring a family member or friend to aid the decision-
making. After this meeting, the subject may deliberate on trial participation for up to seven days. 
The subjects will be informed of any potential risks associated with the trial. 
It is the responsibility of the principal investigator or a sub-investigator to obtain the written informed consent 
from the subject. 
After completion of trial, all participating subjects will be informed of the overall results. Information of individual 
data and the interpretation hereof will be provided by the investigator. The individual subject’s right not to know 
of own data will be respected. 
10.4 Future contact 
When subjects are asked to consent to participation in the trial, they will be asked specifically if they can accept 
possible future contact for the purpose of further research regarding HG. The answer to this question will be 
recorded on the informed consent form as well as on the e-CRF. Subjects will be able to participate in the trial 
without giving consent to future contact and they can withdraw their consent at any time. 
10.5 Consent for long-term storage of blood samples in a biobank  
Subjects will also be asked specifically if they can accept the storage of their samples within a biobank. The 
answer to this question will be recorded on the informed consent form as well as on the e-CRF. Subjects will be 
able to participate in the trial without giving consent to long-term storage of blood samples. Subjects may 
withdraw this consent at any time, and any samples stored in the biobank will then be destroyed. 
10.6 Access the offspring’s medical journal 
In order to register possible congenital malformations and/or hospitalizations of the offspring during the first 
month after delivery we will ask consent from both parents (forældremyndighedsindehaver(e)) to access the 
offspring’s medical journal. Access to the offspring’s medical journal is solely a safety measure and there will be 
no intervention on the newborn. 
If the co-parent is present at screening or trial visits he/she will be informed verbally and in writing then and 
there. If the co-parent is not present, the trial subject will be asked if there is a future co-parent and if 
confirmatory, written information on the trial may be given to the trial subject who can pass it on to the co-
parent. The co-parent will be offered to make an appointment with the site investigator after having reviewed the 
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verbal information on the trial may be given over the phone. The co-parent will be given time to ask questions 
and allowed sufficient time (minimum 24 hours) to consider whether to consent. 
The co-parent may sign the consent form at home and it may be brought to the trial personnel by the trial 
subject. 
10.7 Subject ID number  
All subjects enrolled must be identifiable throughout the trial. This will be done by using subject number 
allocated to the subject at Visit 1 (the screening visit). 
10.8 Demography 
The following data will be recorded directly in REDCap: 
• 
Date of birth 
• 
Phone number 
• 
E-mail address 
• 
Occupation 
• 
Pre-pregnancy weight 
• 
Gestational age 
• 
Parity 
• 
Possible previous NVP or HG 
• 
Date of initiation of current hospital contact 
• 
PUQE-24 score leading up to current hospital contact 
10.9 Medical history and concomitant disease 
Medical history is a medical event that the subject has experienced in the past. Only medical history considered 
relevant by the Investigator should be reported. 
Concomitant disease is any illness that is present at the start of the trial (i.e. at the screening visit or found as a 
result of the screening procedure) 
This will be recorded directly in the e-CRF. 
10.10 Concomitant and previous medication 
All medication taken during current pregnancy will be recorded, as will concomitant medication. Concomitant 
medication is any medication, other than trial products, which is taken after signing the Informed Consent.  
At each visit the Investigator or delegate should ask the subject about use of concomitant medication including 
rescue medication. All concomitant medication and changes hereto must be documented in the subject’s 
medical records and directly in the e-CRF.  
10.11 Vital signs and weight 
Blood pressure (BP) and pulse will be measured after 10 minutes sitting rest twice on the left arm with an 
automatic device. 
Weight and height will be measured according to local procedures.  
This will be recorded directly in the e-CRF. 
10.12 Physical Examination 
A physical examination will be performed by the investigator or a delegate according to local procedures. 
 

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Significant findings that are present at screening must be recorded as medical history in the e-CRF. Significant 
findings found at the following visits, which meet the definition of an AE, must be recorded on an AE page in the 
e-CRF. 
10.13 Ultrasound scan 
An ultrasound scan will be performed by the investigator or a delegate trained to do so. The purpose of the 
ultrasound scan is to determine gestational age and confirm singleton pregnancy. 
If the medical journal holds records that an ultrasound scan has been performed within 4 weeks prior to 
screening visit, a confirmatory ultrasound is not necessary. The ultrasound confirmed gestational age will be 
recorded in the e-CRF. It will also be recorded whether the it was obtained from the medical journal or recorded 
directly in the e-CRF based on an ultrasound scan performed by the investigator or a delegate. 
10.14 ECG 
An ECG will be recorded according to local procedures with the purpose of identifying possible subjects with 
long QT-syndrome and potential QT prolongation during the study. Subjects with long QT syndrome cannot be 
enrolled in the trial. In case of QT prolongation onset during the trial subjects must be discontinued, QT, QTc 
and pulse will be recorded in the e-CRF. 
10.15 Laboratory Tests 
Blood samples will be taken using standard venepuncture techniques. Altogether approximately 25 ml blood will 
be drawn from each subject. 
The following laboratory variables will be measured: 
Haematology: 
Erythrocytes, haemoglobin, haematocrit, leukocytes, neutrophils, eosinophils, basophils, lymphocytes, and 
monocytes. 
Blood chemistry: 
Creatinine, urea, sodium, potassium, calcium, alanine aminotransferase (ALAT), albumin, bilirubin, alkaline 
phosphatase, lactate dehydrogenase (LDH), C-reactive protein (CRP), thyroid stimulation hormone (TSH), T3 
and T4. 
The clinical laboratory values will be reported to the investigator or a delegate by the laboratory and he/she 
must review them for significance. 
These blood samples are taken as standard part of monitoring patients suffering from HG in order to identify 
possible electrolyte derangement or other conditions causing symptoms similar to HG. Specifically relevant to 
this trial are ALAT, ASAT and creatinine since subjects might be excluded from the trial if these are elevated.  
Plasma-mirtazapine and -ondansetron will be measured in the mirtazapine- and ondansetron-groups, after the 
last subject has been unblinded. The purpose of this analysis is explorative. 
Biobank: 
Blood samples will be stored at – 800 C, so that subsequent analysis of newly discovered relevant markers can 
be performed without further discomfort to the patient. The blood samples will be stored for 10 years and will 
then be destroyed. 
10.16 Questionnaires  
Questionnaires on PUQE-24 score, nausea VAS, number of daily vomiting episodes, EQ-5D-5L (health related 
quality of life), NVPQOL (nausea and vomiting of pregnancy quality of life), HELP (hyperemesis level 
prediction), modified PSQI (Pittsburg sleep quality index), patient satisfaction with treatment VAS, possible 
patient consideration of termination of pregnancy and possible side effects and AEs, sick leave, hospitalisation 
and amount of i.v. fluids will be filled out online directly in the e-CRF by subjects at Visit 1, 2 and 3.  
Subjects will daily fill out online questionnaires directly in the e-CRF on PUQE-24 score, nausea VAS, number 
of daily vomiting episodes, time of IMP-administration (and possible re-administration) use of rescue medication 
as well as possible side effects and AEs during the trial. 
Subjects will be prompted to continue daily online registration of possible side effects and AEs until five days 
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10.17 Treatment failure 
Treatment failure will be registered if a subject decides to discontinue the trial because of insufficient symptom 
relief. Time of treatment failure will be registered directly in the e-CRF by the investigator or a delegate. 
10.18 Electronic medical record  
The electronic medical record will be viewed in the process of recruiting subjects and assessing compliance with 
in- and exclusion criteria. The subjects will have to confirm compliance with these criteria prior to starting the 
trial. Furthermore the medical record will be accessed to obtain pregnancy outcome. 
 
The following data will be obtained from the subject’s electronic medical record and entered in the e-CRF: 
Prior to enrolment: 
• 
Record of possible ultrasound to confirm gestational age and singleton pregnancy 
• 
Record of PUQE-24 score 
• 
5HT3-receptor allergy  
• 
Pre-existing diagnosis of cronic disease 
Postpartum: 
• 
Pregnancy outcome: gestational age at birth or loss/termination of pregnancy, APGAR, gender, birth 
weight, placenta weight, umbilical cord pH, mode of delivery. Pregnancy outcome is a safety measure 
to ensure the identification of any serious adverse events. 
 
Record of possible congenital malformations or hospitalization of the new-born at neonatal ward during the first 
month post-partum will be obtained from offspring’s electronic medical record and entered in the e-CRF. This 
outcome is a safety measure to ensure the identification of any serious adverse events. 
 
 
 
11. Assessment of Safety 
 
Information about Adverse Events (AEs), whether reported by the subject, discovered by the investigator by 
reviewing dialy records, detected through physical examination, laboratory test or other means, must be 
collected and recorded on the AE form and followed up as appropriate.  
Evaluation of AEs including severity, causality, outcome and seriousness assessments must be performed by a 
physician. 
Any AE occurring from the time the informed consent was signed by the subject and until five days after Visit 3 
must be recorded and reported on an AE page in the e-CRF. 
Standardised report forms for AEs and SAEs will be provided as part of the e-CRF. 
11.1   Definitions – Adverse Event (AE) 
An AE is any untoward medical occurrence in a subject administered a medicinal product/device even if it does 
not necessarily have a causal relationship with this treatment. 
The following events should not be recorded as AEs: 
• A pre-planned procedure, e.g. a surgical intervention, unless the condition for which the procedure was 
planned has worsened since the informed consent form was signed.   
• Pre-existing conditions documented as medical history. Any worsening in severity or frequency of a pre-
existing condition during the clinical trial period must be regarded as an AE. 
11.2 Definitions – Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) 
A serious adverse event/reaction is an experience that at any dose results in any of the following: 
 
• 
Results in death 
• 
Is life-threatening - this refers to an event in which the subject was at risk of death at the time of the 
event 
• 
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
• 
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• 
Is a congenital anomaly or birth defect 
• 
Is judged medical important (this refers to an event that may not be immediately life-threatening or 
result in death or hospitalisation, but may jeopardise the subject or may require intervention to prevent 
one of the other outcomes listed above) 
 
11.3 Assessments of AEs and SAEs 
Assessment: 
 
When assessing AEs and SAEs the investigator will refer to the product resumes 4.8. 
 
Severity: 
 
The severity of an AE/SAE is a clinical observation assessed by the investigator using the following definitions: 
• 
Mild: Transient symptoms, no interference with the subject’s daily activities 
• 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
• 
Severe: Considerable interference with the subject’s daily activities, unacceptable 
Potential AEs/SAEs will be treated according to standard practice and if relevant follow-ups will be scheduled 
with relevant specialist. 
 
Causality / Causal Relationship to IMP: 
 
The following terms and definitions are used when assessing the relationship between an AE/SAE and the 
relevant trial product (IMP): 
 
• 
Probable: good reason for sufficient documentation to assume a causal relationship 
• 
Possible: a causal relationship is conceivable and cannot be dismissed 
• 
Unlikely: the event is most likely related to aetiology other than the trial product 
 
Final outcome: 
 
The outcome of an AE/SAE is assessed by the sponsor using the following definitions: 
 
• 
Recovered/resolved: Fully recovered or has returned to baseline 
• 
Recovered with sequelae: As a result of the AE the subject suffered persistent and significant 
disability/incapacity 
• 
Not recovered: The condition has not returned to baseline, however symptoms may have improved 
• 
Fatal: Event that results in death – An AE with fatal outcome must be reported as an SAE 
• 
Unknown: The outcome is unknown. This term should only be used when no other definition is possible 
e.g. the subject is lost to follow-up 
11.4 Reporting 
SAE reporting will be performed in the e-CRF and reviewed by the sponsor. In case of IT breakdown, printed 
versions of the SAE form will be available at all study sites. 
Both the sponsor and the primary investigator must be notified via e-mail or phone within 24 hours: 
 
Sponsor: 
Email address: 
Primary investigator: 
Ellen Christine Leth Løkkegaard 
Eloe0002@regionh.dk 
Anne Ostenfeld 
Email address: 
Anne.ostenfeld.02@regionh.dk 
Emergency phone: 
Not yet available 
 
Serious Adverse Events:  

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SAEs must be reported to the above-mentioned persons immediately (within 24 hours of awareness). Any 
follow-up data must be detailed in a subsequent SAE form in due time. 
 
The initial SAE report must contain as much information as possible including relevant information from the e-
CRF (e.g. medical history, concomitant medication) and must be provided via the e-CRF system. If the reporter 
does not have access to the e-CRF, e-mail may be used.  
 
The SAE report will remain open as long as new relevant data on the event may emerge. The report will be 
finalised when all relevant information is collected. 
 
Suspected unexpected serious adverse reaction (SUSAR): 
 
An unexpected serious adverse reaction where source or severity is not consistent with information in the 
current Summary of Product Characteristics (SmPC). 
 
It is the responsibility of the Sponsor to determine whether a reported SAE is a SAR and whether a SAR is a 
SUSAR. A SUSAR resulting in death or life threatening must be reported within 7 days after the Sponsor 
becomes aware of the reaction. Within 8 days after reporting, the sponsor must notify the Danish Health and 
Medicines Authority and the Committee System on Biomedical Research Ethics of all relevant information 
concerning follow-up of the reaction. Any other SUSAR must be reported to the above-mentioned agencies 
within 15 days after the Sponsor becomes aware the reaction. SUSARs must also be reported to all local 
investigators on all study sites. 
11.5 Annual reporting 
The Sponsor is responsible for annually reporting SARs and SUSARs to the Danish Health and Medicines 
Authority and the Committee System on Biomedical Research Ethics and all local investigators on the involved 
study sites. 
 
 
12. Data handling / Data Management 
 
Data will be handled according to the law on handling personal data(persondataforordningen).  
The trial has been reported to ‘Datatilsynet’ in Region Hovedstaden and approval has been granted (VD-2018-
144, I-suite: 6385). The trial will be reported to all involved regions ahead of initiating the trial in each region.  
Data will be stored for 10 years, after which they will be transferred to “Dansk Data Arkiv” or deleted or 
anonymised. 
12.1 CRF 
An electronic CRF (REDCap) is provided and all data related to the trial will be recorded here and provide the 
basis for a central database. 
Data on ultrasound scan and birth outcome may be collected from the subject’s medical journal and registered 
in the e-CRF. The new-born’s medical journal will be assessed and possible data on congenital malformations 
and hospitalization during the first month will be registered in the e-CRF.   
The e-CRF is to be completed by the investigator or a delegate at the time of the subject’s visit to the clinic so 
that it always reflects the latest observations on the subject. 
At the subject’s final visit, the e-CRF should be verified and signed off by the responsible investigator or 
delegate at the site. 
12.2 Laboratory Data 
Values from blood and urine samples and ECG will obtained from the medical journal and be entered manually 
into the e-CRF.  
 
 

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13. Statistical evaluation 
 
The primary analysis will consist of a linear mixed effects model taking the full longitudinal design into account. 
The model will be adjusted for site (categorical variable) due to the stratified design. Subjects will be included in 
the analysis irrespectively of their adherence to the protocol. The treatment effect for the primary outcome will 
be presented as the average difference between the mirtazapine and placebo groups in changes in PUQE-24 
score from baseline to Day 2 and from baseline to Day 14. These comparisons will be based on the standard 
errors from the linear mixed model. Sensitivity analyses will be performed using multiple imputation where the 
imputation model will include all available baseline variables. 
 
Before the randomisation code will be added to the cleaned dataset, a prespecified statistical analysis plan 
(SAP) will be elaborated and accepted by the statistician and investigators. 
 
All data will be described including data-incompleteness as well as reasons for data-incompleteness. Data will 
be analysed blinded by the statistician. Any changes to the statistical analysis plan will be described in any 
future publications. 
 
For further information on the final analysis refer to the SAP. 
 
 
14. End of trial 
 
Within 90 days after the trial completion the sponsor must inform the Danish Health Authorities and Ethics 
Committee about the completion. The result of the trial must be submitted within 12 months. 
14.1 Early termination of the trial 
The sponsor reserves the right to terminate the trial under the following conditions: 
- 
Safety concerns  
- 
If an interim statistical analysis shows that the trial has no scientific value or too low power 
If the trial is prematurely terminated or suspended, the investigator should promptly inform the subjects and 
ensure appropriate therapy and follow-up. Furthermore, the investigator and/or Sponsor should promptly inform 
the pertinent ethics committee and regulatory authorities.  
14.2 Subject Discontinuation 
The subject will be advised in the informed consent form that he/she has the right to withdraw from the trial at 
any time without prejudice. Where discontinuation from the trial is initiated by the subject, the investigator is to 
ascertain the primary reason for discontinuation from the list below: 
 
• 
An AE for which the investigator did not consider discontinuation from the trial necessary 
• 
Co-existing disease 
• 
Withdrawal of consent 
• 
Other reasons including treatment failure 
 
The subject may at any time be discontinued from the trial at the discretion of the investigator. 
 
Subjects must be discontinued from the trial under the following circumstances: 
 
• 
If a criterion equivalent to an exclusion criterion occurs 
• 
If, in the investigator’s opinion, continuation in the trial would be detrimental to the subject’s well-being 
• 
Occurrence of intolerable AE(s) as determined by the investigator and/or subject 
• 
Subject lost to follow-up 
• 
If the randomisation code is broken 
• 
If informed consent is withdrawn 
 
In all cases, the primary reason for discontinuation must be recorded in the e-CRF and in the subject’s medical 
records. Follow-up on the subject is necessary to establish whether the reason was an AE. If so, this must be 
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As far as possible, all examinations scheduled for the final visit must be performed on subjects who receive the 
IMP but do not complete the trial according to the protocol.  
Data obtained until discontinuation will be entered in the clinical database and used for statistical analyses. 
 
15. Administrative procedures 
15.1 Source data and subject data protection 
Source data will be registered in patient records or on source data sheets or directly in the e-CRF. 
 
Prior to start of data recording from subjects, the investigator will prepare a Source Data Location Agreement to 
document where the first recording of data is done.  
As a minimum requirement, the following data must be source data-verifiable in source documentation other 
than the e-CRF: 
§ Subjects informed consent 
§ Date of informed consent 
§ List of randomised subjects 
 
A common e-CRF will be constructed and provide the basis for a central database. Data will in the central 
database be stored in coded form according to the rules of the Danish Data Protection Agency (Datatilsynet) 
with whom the trial is registered.  
 
In accordance with the Danish Data Protection Agency data processing will be completed by 01.06.2028. 
Afterwards data in paper form will be destroyed and electronic data will be transferred and stored at the Danish 
Data Archives (Statens Arkiver). 
Anne Ostenfeld will be responsible for data collection and processing. 
In addition, Ellen Løkkegaard, Tonny Studsgaard Petersen, Lars Henning Pedersen, Hanne Brix Westergaard, 
Jon Thor Trærup Andersen and Andreas Emil Kryger Jensen will be involved in data processing. 
 
The investigator will have direct access to source data and documents in case of monitoring, auditing or 
inspection from health authorities (Lægemiddelstyrelsen, Videnskabsetisk komité, GCP-enhederne). 
15.2 Quality control and assurance 
The trial will be carried out according to the protocol, ICH-GCP and current law and it will follow the Declaration 
of Helsinki.  
Quality control and assurance will be carried out in accordance with ICH-GCP and standard procedures will be 
followed including monitoring, auditing or inspection from health authorities (Lægemiddelstyrelsen, 
Videnskabsetisk komité, GCP-enhederne). 
15.3 Monitoring 
Regular monitoring visits will be performed according to ICH-GCP. Data will be evaluated for compliance with 
the protocol and accuracy in relation to source documents. The monitor will verify that the clinical trial is 
conducted and data are generated, documented and reported in compliance with the protocol, GCP and the 
applicable regulatory requirements. 
The regional GCP units will conduct the monitoring of sites, regulatory compliance, and review of e-CRFs to 
source documents. The monitoring will be coordinated from the GCP-unit at Bispebjerg University Hospital, 
Copenhagen, Denmark. It is the responsibility of the Sponsor that the trial is monitored. 
15.4 Research Biobank 
During the trial blood samples will be stored at -800C in a research biobank at Nordsjællands Hospital in pseudo 
anonymized form. After end of trial and unblinding plasma-mirtazapine and plasma-ondansetron will be 
analyzed in the respective groups and any left-over material in this research biobank will be kept in a biobank 
for future research if the subjects have concented to this, or be destroyed in case the subjects have not 
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15.5 Biobank 
A biobank for possible future research will be established at Nordsjællands Hospital. 
The biobank will store blood in pseudo anonymized form at -80 0C for possible later analysis of biomarkers. 
Samples in the biobank will be stored for 10 years provided subjects acceptance; hereafter the material will be 
destroyed. 
Additional analysis will only be performed after approval by the Committee System on Biomedical Research 
Ethics. All project related data and samples that can be referred directly to an individual subject will be 
destroyed immediately or by the closure of the trial. 
15.6 Financing 
The initiative for this trial was taken by the sponsor, investigator and advisors, none of whom have any financial 
interest in the trial. 
Financial support for the conduct of this study has so far been given to sponsor’s research account at 
Nordsjællands Hospital from Regionernes Medicinpulje who supported the trial with 1,685,096 DKK. This will 
cover the majority of the trial expenses; salaries (VIP and TAP), laboratory costs, transportation costs for trial 
subjects and investigator, trial medication, IT-equipment and open access publication. Sponsor, investigator and 
advisors have no financial links to Regionernes Medicinpulje. 
Furthermore, The Research Foundation at Nordsjællands Hospital has supported the trial with 75,000 DKK to 
cover part of VIP salary. 
We are currently applying to other funds for further financing. 
15.7 Financial compensation to subjects 
The trials subjects will be financially compensated for any documented costs caused by their participation in the 
trial. 
15.8 Insurance 
Patients will be covered according to current regulations. Trials in the Danish regions are covered by the 
patient-insurance (Patienterstatningen). 
15.9 Ethical Considerations 
Irrespective of the outcome of the trial it will provide useful information on treatment of HG. 
The result of the trial will thereby provide physicians and patients with new relevant information guiding their 
choice of treatment. Currently the treatment offered for severe NVP is not profoundly evidence based and it is 
often not sufficiently effective, thus 27% of this patient population consider ending the pregnancy and 75% do 
not wish to become pregnant again. 
Based on the number of women exposed to mirtazapine and ondansetron in pregnancy we consider both 
treatments safe to use in early pregnancy.  
All three groups will be allowed to use metoclopramide as rescue medication so no subjects are completely 
excluded from effective treatment. 
 
 
16. Publication 
 
The trial is investigator-initiated and data are owned by Region Hovedstaden. Both positive, negative and in-
conclusive study results will be published via www.clinicaltrials.gov and in an international peer-reviewed 
scientific journal by the investigators of the study group. Anne Ostenfeld will draft the first manuscript. 
 
 
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Appendix 1  
PUQE-score (Pregnancy Unique Quantification of Emesis and Nausea- score)  
 
Marker det svar, der bedst beskriver dine symptomer de sidste 24 timer 
1. Hvor lang tid har du følt dig forkvalmet, i løbet af de sidste 24 timer? 
Slet ikke 
≤ 1 time 
2-3 timer 
4-6 timer 
> 6 timer 
(1) 
(2) 
(3) 
(4) 
(5) 
 
2. Hvor mange gange har du kastet op, i løbet af de sidste 24 timer? 
Ingen opkastninger 
1-2 gange 
3-4 gange 
5-6 gange 
≥ 7 gange 
(1) 
(2) 
(3) 
(4) 
(5) 
 
3. Har du haft opkastningsbevægelser (uden at der kommer noget med op), i løbet af de sidste 24 timer? 
Nej 
1-2 gange 
3-4 gange 
5-6 gange 
≥ 7 gange 
(1) 
(2) 
(3) 
(4) 
(5) 
PUQE-24 score: Mild ≤ 6, Moderat = 7-12, Svær = 13-15. 
 
På en skala fra 0 til 10 hvordan vil du vurdere dit generelle velbefindende? ____ 
0 (værst tænkelig), 10 (så godt, som du havde det før, du blev gravid) 
 
Dansk oversættelse af: Ebrahimi et al. Nausea and Vomiting of Pregnancy: Using the 24-hour Pregnancy-
Unique Quantification of Emesis (PUQE-24) Scale.  J Obstet Gynaecol Can. September 2009;31(9):803-7 (3) 
 
 
Appendix 2 
Schematic overview of case-reports where NVP/HG has been treated with mirtazapine 
 
Case
and 
refer-
ence 
Symptoms 
Treatment 
prior to 
mirtazapine 
Mirtazapine dosage 
Effect 
Gestation
-al age at 
initiation 
of mirta-
zapine 
treatment 
Pregnancy  
outcome 
Case
1(23) 
 
Severe NVP 
and panic 
attacks. 
Wanted 
pregnancy 
termination. 
Not specified. 15 mg daily until 17 
weeks, then 7,5 mg 
daily until delivery. 
When trying dosage 
reduction symptoms 
reoccurred 
immediately. 
Significant 
reduction in NVP. 
The abortion was 
cancelled. 
Between 
week 5 
and 17. 
Not 
specified. 
Healthy infant 
delivered at 36 
weeks by c-
section. Normal 
development. 

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Case
2(23) 
 
Severe NVP. 
Not specified. 7,5 mg daily. Slowly 
tapered off at 
11weeks. 
Symptoms 
subsided 
completely within 
a few days. 
Not 
specified. 
Abortion at 16 
weeks due to 
trisomy 18. 
Case
3(23) 
 
Severe NVP 
and severe 
depression. 
Not specified. 7,5 mg daily. When 
trying dosage 
reduction symptoms 
reoccurred 
immediately. 
Continued 
mirtazapine until late 
2nd trimester. 
NVP subsided 
within a few days. 
Week 15. Healthy infant 
delivered at 38 
weeks. Normal 
development. 
Case
4(23) 
 
Moderate 
NVP. 
Not specified. 3,75 mg daily. 
Discontinued after 
less than one week. 
NVP subsided 
almost 
immediately. NVP 
did not reoccur 
after 
discontinuation. 
Week 9. 
Healthy infant 
delivered at term. 
Normal 
development. 
Case
5(23) 
 
Severe NVP, 
5 kg weight 
loss.  
Oral 
doxylamine, 
i.v. 
chlorpromazin
e, 
ondansetron 
and 
clorazepate. 
15 mg daily without 
effect, however she 
had been vomiting 
the mirtazapine. Then 
administered only 
when not vomiting. 
Dosage increased to 
30 mg daily at 11 
weeks. At 14 weeks 
decreased to 15 mg 
daily until delivery. 
When 
administered only 
when not vomiting 
NVP subsided 
slowly and had 
subsided 
completely after 8 
days. No further 
NVP. 
Between 
week 8 
and 11. 
Not 
specified. 
Healthy infant 
delivered at term. 
Normal 
development. 
Case 
6(47) 
 
Treatment 
resistant HG 
with 30 
vomiting 
episodes 
daily. 12 kg 
weight loss. 
Need of 
parenteral 
nutrition. 
Considered 
pregnancy 
termination. 
I.v. 
dimenhydrinat
e, ranitidine, 
metocloprami
de and 
triflupromazin
e, all without 
effect. 
Lorazepam 
orodisolvable 
tablet. 
6 mg i.v. daily for 3 
days, then 15 mg oral 
tablet daily for 4 
weeks. Then dosage 
decrease to 15 mg 
every other day for 2 
weeks and then 
discontinued. 
Stagnation of 
symptoms after 1 
day. Symptoms 
completely 
subsided after 3 
days. 
Week 16. Healthy infant 
delivered at week 
37. 
Case
7(48) 
 
HG, severe 
weight loss, 
dehydration 
and 
hypokalemia. 
Wanted 
pregnancy 
termination. 
Metocloprami
de and 
promethazine
, insufficient 
effect. 
30 mg daily for 6 
days.  
Responded in 24 
hours and could 
resume diet after 3 
days. 
Week 12. Healthy infant 
delivered at 35 
weeks by c-section 
because of 
preterm premature 
rupture of 
membranes. 
Normal 
development at 1 
year of age. 

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Case
8(48) 
 
HG, 5 kg 
weight loss, 
dehydration. 
Wanted 
pregnancy 
termination.  
I.v. 
metocloprami
de.  
30 mg daily for 10 
days.  
Responded 
promptly and 
could resume diet 
after 4 days. 
Occasional 
vomiting in 2nd and 
3rd trimester.  
Week 10. Healthy infant 
delivered at 39 
weeks. Normal 
development at 1 
year of age. 
Case
9(48) 
 
HG, 2.5 kg 
weight loss. 
Wanted 
termination of 
pregnancy. 
 
Metoclopra-
mide and 
promethazine 
without effect. 
30 mg daily for 7 days Responded 
promptly and 
could resume diet 
after 4 days. 
Week 5. 
Healthy infant 
delivered at 40 
weeks. Normal 
development at 1 
year of age. 
Case
10 
(49) 
Severe NVP 
and stomach 
cramps, 13 kg 
weight loss. 
Wanted 
termination of 
pregnancy. 
Dimenhydrina
te, 
metocloprami
de, 
triflupromazin
e and 
pyridoxine 
with minimal 
effect. 
6 mg i.v. daily for 3 
days, then 30 mg oral 
tablet daily for 2 
weeks. Slowly 
tapered and finally 
discontinued after 4 
weeks. Treatment 
reinstalled in week 27 
due to gastroenteritis. 
Discontinued in week 
33. 
Symptoms 
resolved within 
hours.   
Week 15. Healthy twins 
delivered at 36 
weeks by c-
section. Normal 
development at 6 
months of age. 
Case
11 
(50) 
 
HG, anxiety 
and 
depressive 
symptoms. 
Need of 
parenteral 
nutrition. 
Ondansetron, 
droperidol. 
15 mg daily. Dosage 
increased to 30 mg 
daily at week 19 
because of anxiety. 
Discontinuation tried 
in week 15, which 
lead to reoccurrence 
of symptoms. 
Symptoms 
resolved within 
days. 
Week 13. Healthy infant 
delivered at 40 
weeks by c-section 
because of 
frustran induction. 
Case
12  
(50) 
 
HG, history of 
depression. 
Ondansetron 
without effect. 
From week 
19 
ondansetron 
pump with 
effect. 
15 mg daily, 
increased to 45 mg 
daily at week 23 
because of anxiety 
and depressive 
symptoms. 
No effect of 15 mg 
daily, but 
symptoms 
resolved after the 
dosage increase in 
week 23.  
Week 10. Healthy infant 
delivered at 39 
weeks. 
Case 
13 
(50) 
 
NVP, 
dehydration, 
depression. 
Promethazine 
without effect, 
metocloprami
de.  
15 mg daily for 2 
weeks, then 
discontinued because 
of the price. 
Symptom relief. 
Recurrence of 
symptoms after 
discontinuation. 
Week 17. Healthy infant 
delivered at term.  
Case 
14 
(50) 
 
HG, 
dehydration. 
Need of 
parenteral 
nutrition. 
Metocloprami
de and 
ondansetron 
tried, but 
discontinued 
due to side 
effects.  
Trimetho-
benzamide 
with some 
effect. 
15 mg daily 
throughout 
pregnancy. 
At week 13 only 
some nausea 
persisted.  
Week 11. Healthy infant 
delivered at term. 

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Case 
15  
(50) 
 
HG. Chronic 
depression 
and anxiety. 
Promethazine 
ondansetron. 
7.5 mg daily. Tapered 
off at 28 weeks. 
Symptom relief. 
Week 10. 7-pound infant with 
persistent fetal 
circulation and 
pulmonal 
hypertension, 
needing a 
ventilator. 
Discharged 3 days 
later. 
Case 
16 
(50) 
 
NVP, mild 
depression 
and anxiety. 
Need of 
parenteral 
nutrition. 
 
(Same 
patient as 
case 11, but 
new 
pregnancy) 
 
Ondansetron 
10 mg twice 
daily and 
diphenhydra
mine 
hydrochloride 
and 
famotidine 
with 
insufficient 
effect. 
Droperidol 
tried but 
discontinued 
due to side 
effects.   
15 mg daily 
throughout 
pregnancy. 
Prompt symptom 
relief. Other 
medications 
discontinued. 
Week 12. 7-pound healthy 
infant delivered by 
elective c-section. 
Case 
17 
(50) 
 
Nausea and 
depression. 
None. 
7.5 mg daily 
increased to 15 mg 
daily after 2 weeks, 
remained on this 
dosage throughout 
pregnancy. 
Patient felt better 
after starting 
mirtazapine, and 
symptoms 
subsided 
completely after 
dosage increase.  
Week 10. 7-pound healthy 
infant delivered at 
37 weeks by c-
section because of 
shoulder dystocia. 
Case 
18 
(51) 
 
Treatment 
resistant HG 
since week 
12, 9 kg 
weight loss. 
Type 1 
diabetes. 
Metocloprami
de and 
dimenhydrinat
e with 
insufficient 
effect. 
6 mg i.v. daily. 
Discontinuation lead 
to recurrence of 
symptoms within 
days. Then (week 29) 
started on 45 mg 
daily until delivery.  
Symptoms 
resolved within 
days and subsided 
completely after 3 
days. 
Week 25. Premature infant 
delivered at 34 
weeks by c-section 
due to 
preeclampsia and 
intrauterine growth 
restriction. 
Developed 
withdrawal 
symptoms after 34 
hrs that persisted 
for 36 hrs.  
Case 
19 
(52) 
 
Severe NVP, 
3 kg weight 
loss, 
depressive 
symptoms. 
Metocloprami
de without 
effect. 
7.5 mg daily, 
increased to 15 mg 
daily until week 28. 
Moderate effect of 
7.5 mg daily. 
Symptoms 
subsided 
completely after 
dosage increase. 
Week 14 
Healthy infant 
delivered at 40 
weeks. 
Case 
20 
(52) 
 
Severe NVP, 
weight loss, 
depressive 
symptoms. 
Antiemetics 
(not specified) 
with some 
effect. 
15 mg daily until 
week 34, then 7.5 mg 
daily until delivery. 
Significant effect in 
NVP within days 
and decrease in 
depressive 
symptoms within 2 
weeks. 
Week 18 
Healthy infant 
delivered at 40 
weeks. 

VOMIT 
CONFIDENTIAL 
 
Clinical Trial Protocol 
Version 3 – 05.12.18 
NOH Page  40 of 40 
 
Case 
21 
(53) 
 
Severe 
nausea, 3 kg 
weight loss 
insomnia, 
panic attacks. 
No 
antiemetics. 
Citalopram for 
anxiety 
symptoms 
from week 18. 
7.5 mg daily until 
delivery. 
Discontinuation was 
tried but lead to 
recurrence of 
symptoms.  
Dramatic decrease 
in symptoms.  
Week 22 
Healthy infant 
delivered at 38 
weeks by elective 
c-section. 
Case 
22 
(53) 
 
Nausea, 
decreased 
appetite, 
insomnia, 
depressive 
symptoms. 
Sertraline 50 
mg daily 
started 
simultaneousl
y with 
mirtazapine. 
7.5 mg daily until 
delivery. 
Discontinuation was 
tried but lead to 
recurrence of 
symptoms. 
Significant 
decrease in 
symptoms.  
Week 24. Healthy infant 
delivered at 40 
weeks. 
Case 
23 
(54) 
 
HG, 
dehydration. 
Need of 
parenteral 
nutrition. 
Type 1 
diabetes. 
Dimenhydrina
te, 
metocloprami
de, 
ondansetron, 
haloperidol, 
dexamethaso
ne without 
effect. 
30 mg i.v. daily for 3 
days, then 30 mg 
tablet daily until 
delivery.  
Symptoms 
subsided 
completely within 
48 hrs. 
Week 21. Delivery be c-
section at 35 
weeks.