Clinical Trials Register

Summary
EudraCT Number:	2018-002285-39
Sponsor's Protocol Code Number:	VOMIT
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2018-09-25
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2018-002285-39

A.3

Full title of the trial

Validating the Effect of Ondansetron and Mirtazapine In Treating Hyperemesis Gravidarum.
A Double-blind Randomized Placebo-Controlled Multicentre Trial.

Validering af effekten af ondansetron og mirtazapin som behandling af hyperemesis gravidarum.
Et dobbelt-blindet randomiseret placebokontrolleret multicenter studie.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Investigation of the effect of ondansetron and mirtazapine as treatment for severe nausea and vomiting of pregnancy.

Undersøgelse af virkningen af ondansetron og mirtazapin som behandling af svær graviditetskvalme og -opkastninger.

A.3.2

Name or abbreviated title of the trial where available

VOMIT

A.4.1

Sponsor's protocol code number

VOMIT

A.5.4

Other Identifiers

Name:

Danish Data Protection Agency

Number:

P-2019-75

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Department of Gynaecology and Obstetrics Nordsjællands Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Regionernes Medicinpulje
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Nordsjællands Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Gynaecology and Obstetrics Nordsjællands Hospital
B.5.2	Functional name of contact point	anne.ostenfeld.02@regionh.dk
B.5.3	Address:
B.5.3.1	Street Address	Dyrehavevej 29
B.5.3.2	Town/ city	Hillerød
B.5.3.3	Post code	3400
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4520779758
B.5.6	E-mail	anne.ostenfeld.02@regionh.dk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mirtazapin KRKA 15 mg tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA Sverige AB
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ondansetron Bluefish filmovertrukne tabletter 8 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Bluefish Pharmaceuticals AB
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mirtazapin KRKA 30 mg tablet
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA Sverige AB
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hyperemesis gravidarum

Svær graviditetskvalme og -opkastninger.

E.1.1.1

Medical condition in easily understood language

Severe nausea and vomiting of pregnancy

Svær graviditetskvalme og -opkastninger.

E.1.1.2

Therapeutic area

Body processes [G] - Reproductive physiologi cal processes [G08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10020614
E.1.2	Term	Hyperemesis gravidarum
E.1.2	System Organ Class	10036585 - Pregnancy, puerperium and perinatal conditions

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to compare the efficacy of mirtazapine versus placebo on nausea and vomiting in patients with hyperemesis gravidarum.
The secondary objective is to compare the efficacy of ondansetron versus placebo and mirtazapine versus ondansetron on nausea and vomiting in patients with hyperemesis gravidarum.

E.2.2

Secondary objectives of the trial

The secondary objective is to compare the efficacy of ondansetron versus placebo and mirtazapine versus ondansetron on nausea and vomiting in patients with hyperemesis gravidarum.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Pregnant with gestational age between 5+0 and 19+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

E.4

Principal 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

E.5 End points

E.5.1

Primary end point(s)

The co-primary 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 2 (short term) in the ondansetron group versus the placebo group (this will be tested only if mirtazapine versus placebo on day 2 is significant).
• change in PUQE-24 score from baseline to day 2 (short term) in the mirtazapine group versus the ondansetron group (this will be tested only if ondansetron versus placebo on day 2 is significant).

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be evaluated daily during the intervention.

E.5.2

Secondary end point(s)

Secondary endpoints include:
• change in PUQE-24 score from baseline to day 14(+/-) (long term) in the mirtazapine group versus the placebo group (this will be tested only if mirtazapine versus placebo on day 2 is significant).
• change in PUQE-24 score from baseline to day 14(+/-) (long term) in the ondansetron group versus the placebo group (this will be tested only if ondansetron versus placebo on day 2 is significant).
• Change in PUQE-24 score on long term in the mirtazapine group versus the ondansetron group.
• Area under the curve for PUQE-24 score during the intervention.
• PUQE well-being score.
• Number of daily vomiting episodes.
• Nausea VAS.
• Side effects.
• 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.
• Request for dosage increase.
• Request for continuation of trial medication after end of intervention.
• Use of rescue medication.
• Days on sick leave.
• Amount of treatments with i.v.-fluids.
• Days of hospitalisation.
• Weight change.
• Pregnancy outcome (birth weight, gestational age, APGAR, umbilical cord pH, placenta weight, sex, mode of delivery, delivery complications, hospitalisations on neonatal ward during the first month, congenital malformations, loss/termination of pregnancy).
• Occurrence of treatment failure.

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to section E.5.2 for specification of time of evaluation of secondary endpoints.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End of trial will be approximately one month after the last subject has given birth. Thus, end of trial is not the last visit. This is in order to allow registration of birth outcome and possible hospitalisation of the newborn within the first month after delivery.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

180

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

180

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

If subjects desire, continuation of trial medication after end of intervention is possible. In this case, subjects will, obviously, be unblinded.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-03-18

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