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Validating the Effect og Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum (VOMIT)

Primary Purpose

Hyperemesis Gravidarum, Nausea Gravidarum, Vomiting of Pregnancy

Status

Terminated

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Mirtazapine

Ondansetron

Placebo

About this trial

This is an interventional treatment trial for Hyperemesis Gravidarum focused on measuring Hyperemesis Gravidarum (HG), Mirtazapine, Ondansetron, Pregnancy, Nausea and Vomiting of Pregnancy (NVP), Randomized Controlled Trial (RCT)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

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 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 and/or
2. hospitalisation due to nausea and vomiting of pregnancy
Singleton pregnancy
The subject must be willing and able to comply with trial protocol

Exclusion Criteria:

Mola pregnancy, multiple gestation or non-vital pregnancy
Nausea and vomiting of other aetiology than NVP
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>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

Sites / Locations

Department of Gynaecology and Obstetrics, Aarhus University Hospital
Department of Gynaecology and Obstetrics, Rigshospitalet
Department of Gynaecology and Obstetrics, Herlev Hospital
Department of Gynaecology and Obstetrics, Nordsjællands Hospital
Department of Gynaecology and Obstetrics, Hvidovre Hospital
Department of Gynaecology and Obstetrics, Kolding Sygehus
Department of Gynaecology and Obstetrics, Odense University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Mirtazapine

Ondansetron

Placebo

Arm Description

Mirtazapine 15 mg oral tablet (incapsulated in gelatine to provide blinding) will be administered once daily (bedtime) for 7 days. Placebo (empty gelatine capsule) will be administered once daily (morning). On Day 7 dosage increase is optional. If desired, mirtazapine 30 mg oral tablet (incapsulated in gelatine) will be administered once daily (bedtime) for 7 days. Placebo (empty gelatine capsule) will be administered three times daily (morning, noon and late afternoon). In case dosage increase is not desired, the subject will continue the initial treatment for an additional 7 days.

Ondansetron 8 mg oral tablet (incapsulated in gelatine) will be administered twice daily (morning and bedtime) for 7 days. On Day 7 dosage increase is optional. If desired, ondansetron 8 mg oral tablet (incapsulated in gelatine) will be administered four times daily (morning, noon, late afternoon and bedtime) for 7 days. In case dosage increase is not desired, the subject will continue the initial treatment for an additional 7 days.

Placebo oral tablet (empty gelatine capsule) will be administered twice daily (morning and bedtime) for 7 days. On Day 7 dosage increase is optional. If desired, placebo oral tablet (empty gelatine capsule) will be administered four times daily (morning, noon, late afternoon and bedtime) for 7 days. In case dosage increase is not desired, the subject will continue the initial treatment for an additional 7 days.

Outcomes

Primary Outcome Measures

Change in nausea and vomiting from baseline to Day 2 (short term) in the mirtazapine group versus the placebo group.

Change in Pregnancy Unique Quantification of Emesis 24 score (PUQE-24 score) (patient reported) from baseline to Day 2 (short term) in the mirtazapine group versus the placebo group. PUQE-24 score ranges 3-15 with 3 being better and 15 being worse.

Change in nausea and vomiting from baseline to Day 2 (short term) in the ondansetron group versus the placebo group.

Change in PUQE-24 score (patient reported) from baseline to Day 2 (short term) in the ondansetron group versus the placebo group.

Change in nausea and vomiting from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus the placebo group.

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-) (long term) in the mirtazapine group versus the placebo group. Only tested if outcome 1 is significant.

Change in nausea and vomiting from baseline to Day 14(+/-1) (long term) in the ondansetron group versus the placebo group.

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-) (long term) in the ondansetron group versus the placebo group. Only tested if outcome 2 is significant.

Change in nausea and vomiting from baseline to Day 2 (short term) in the mirtazapine group versus the ondansetron group.

Change in PUQE-24 score (patient reported) from baseline to Day 2 (short term) in the mirtazapine group versus the ondansetron group. Only tested if outcome 1 is significant.

Secondary Outcome Measures

Change in nausea and vomiting from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group.

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group.

Overall nausea and vomiting during the intervention in the three different groups.

Area under the curve for PUQE-24 score (patient reported) during the intervention in the three different groups.

Change in well-being during the intervention in the three different groups.

Change in PUQE well-being score (patient reported) during the intervention in the three different groups.

Change in nausea during the intervention in the three different groups.

Change in daily nausea visual analog scale (VAS) (patient reported) during the intervention in the three different groups. VAS score ranges 0-100 with 0 being better and 100 being worse. Numbers are not visible to subjects.

Change in vomiting during the intervention in the three different groups.

Change in number of daily vomiting episodes (patient reported) during the intervention in the three different groups.

Occurrence of side effects in the three different groups.

Occurrence of side effects (patient reported and registered by trial personnel) during and until 5 days after the intervention in the three different groups.

Change in 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 Health-Related Quality of Life for Nausea and Vomiting during Pregnancy (NVPQOL) score (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. NVPQOL score ranges 30-210 with 30 being better and 210 being worse.

Change in severity of hyperemesis gravidarum from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Change in HyperEmesis Level Prediction (HELP) score (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. HELP score ranges 0-50 with 0 being better and 50 being worse.

Change in health-related quality of life from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Change in health status (EQ-5D-5L) (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Change in sleep quality from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Change in modified Pittsburg Sleep Quality Index (PSQI) (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.Modified PSQI score ranges 0-12 with 0 being better and 12 being worse.

Patient satisfaction with treatment Day 7(+/-1) and Day 14(+/-1) in the three different groups.

Patient satisfaction with treatment VAS (patient reported) on Day 7(+/-1) and Day 14(+/-1) in the three different groups. VAS score ranges 0-100 with 0 being better and 100 being worse. Numbers are not visible to subjects.

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.

Change in patient consideration of termination of pregnancy (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Request for dosage increase in the three different groups.

Frequency of request for dosage increase in the three different groups.

Request for continuation of trial medication after end of intervention in the three different groups.

Frequency of request for continuation of trial medication after end of intervention in the three different groups.

Use of rescue medication during the intervention in the three different groups.

Use of rescue medication during (patient reported) the intervention in the three different groups.

Number of days on sick leave during the intervention in the three different groups

Number of days on sick leave (patient reported) during the intervention in the three different groups

Necessity of i.v.-fluids during the intervention in the three different groups.

Amount of treatments with i.v.-fluids during the intervention in the three different groups.

Need of hospitalisation during the intervention in the three different groups.

Number of days of hospitalisations during the intervention in the three different groups.

Weight change from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) 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.

Pregnancy outcome: Live birth, loss or termination of pregnancy

Live birth, loss or termination of pregnancy.

Delivery outcome: Mode of delivery

Mode of delivery: Vaginal, cesarian, vacuum extraction.

Delivery outcome: Delivery complications

Eg. postpartum hemorrhage, shoulder dystocia, sphincter rupture

Live birth outcome: birth weight.

Birth weight in g.

Live birth outcome: gestational age at birth.

Gestational age at birth in weeks plus days.

Live birth outcome: APGAR score.

APGAR score at 1, 5 and 10 minutes after birth. APGAR score ranges 0-10 with 0 being worse and 10 being better.

Live birth outcome: umbilical cord pH.

Umbilical cord pH at birth.

Live birth outcome: placenta weight.

placenta weight in g.

Live birth outcome: sex.

offsprings sex.

Live birth outcome: hospitalizations on neonatal ward during the first month post-partum.

Hospitalizations of the offspring in neonatal ward during the first month post-partum.

Live birth outcome: congenital malformations (depending on gestational age also registered on early ended pregnancies).

Congenital malformations.

Occurrence of treatment failure in the three different groups.

Frequency of and time to treatment failure in the three different groups.

Full Information

NCT ID

NCT03785691

First Posted

November 13, 2018

Last Updated

January 26, 2023

Sponsor

Nordsjaellands Hospital

Collaborators

Bispebjerg Hospital, Aarhus University Hospital, Herlev and Gentofte Hospital, Hvidovre University Hospital, Odense University Hospital, Rigshospitalet, Denmark, Regionernes Medicinpulje, Kolding Sygehus

1. Study Identification

Unique Protocol Identification Number

NCT03785691

Brief Title

Validating the Effect og Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum

Acronym

VOMIT

Official Title

Validating the Effect of Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum: A Double-Blind Randomised Placebo-Controlled Multicentre Trial

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Terminated

Why Stopped

Recruiting difficulties

Study Start Date

March 1, 2019 (Actual)

Primary Completion Date

July 31, 2022 (Actual)

Study Completion Date

July 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Nordsjaellands Hospital

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The aim is to investigate the efficacy of mirtazapine and ondansetron as treatment for hyperemesis gravidarum(HG). The setup is a double-blind multicenter trial where patients suffering from HG will be randomized to treatment with either mirtazapine, ondansetron or placebo (1:1:1).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyperemesis Gravidarum, Nausea Gravidarum, Vomiting of Pregnancy

Keywords

Hyperemesis Gravidarum (HG), Mirtazapine, Ondansetron, Pregnancy, Nausea and Vomiting of Pregnancy (NVP), Randomized Controlled Trial (RCT)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Randomized placebo controlled multicenter trial testing already marketed drugs on a new indication.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

All oral tablets will be encapsulated in gelatine to ensure identical look, smell and taste.

Allocation

Randomized

Enrollment

58 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Mirtazapine

Arm Type

Experimental

Arm Description

Arm Title

Ondansetron

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Mirtazapine

Other Intervention Name(s)

KRKA Mirtazapine Oral Tablet

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Ondansetron

Other Intervention Name(s)

Bluefish Ondansetron Oral Tablet

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Placebo Oral Tablet

Intervention Description

Primary Outcome Measure Information:

Title

Change in nausea and vomiting from baseline to Day 2 (short term) in the mirtazapine group versus the placebo group.

Description

Time Frame

2 days

Title

Change in nausea and vomiting from baseline to Day 2 (short term) in the ondansetron group versus the placebo group.

Description

Change in PUQE-24 score (patient reported) from baseline to Day 2 (short term) in the ondansetron group versus the placebo group.

Time Frame

2 days

Title

Change in nausea and vomiting from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus the placebo group.

Description

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-) (long term) in the mirtazapine group versus the placebo group. Only tested if outcome 1 is significant.

Time Frame

14 days

Title

Change in nausea and vomiting from baseline to Day 14(+/-1) (long term) in the ondansetron group versus the placebo group.

Description

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-) (long term) in the ondansetron group versus the placebo group. Only tested if outcome 2 is significant.

Time Frame

14 days

Title

Change in nausea and vomiting from baseline to Day 2 (short term) in the mirtazapine group versus the ondansetron group.

Description

Change in PUQE-24 score (patient reported) from baseline to Day 2 (short term) in the mirtazapine group versus the ondansetron group. Only tested if outcome 1 is significant.

Time Frame

2 days

Secondary Outcome Measure Information:

Title

Change in nausea and vomiting from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group.

Description

Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group.

Time Frame

14 days

Title

Overall nausea and vomiting during the intervention in the three different groups.

Description

Area under the curve for PUQE-24 score (patient reported) during the intervention in the three different groups.

Time Frame

14 days

Title

Change in well-being during the intervention in the three different groups.

Description

Change in PUQE well-being score (patient reported) during the intervention in the three different groups.

Time Frame

14 days

Title

Change in nausea during the intervention in the three different groups.

Description

Time Frame

14 days

Title

Change in vomiting during the intervention in the three different groups.

Description

Change in number of daily vomiting episodes (patient reported) during the intervention in the three different groups.

Time Frame

14 days

Title

Occurrence of side effects in the three different groups.

Description

Occurrence of side effects (patient reported and registered by trial personnel) during and until 5 days after the intervention in the three different groups.

Time Frame

19 days

Title

Change in 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.

Description

Time Frame

14 days

Title

Change in severity of hyperemesis gravidarum from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Description

Time Frame

14 days

Title

Change in health-related quality of life from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Description

Change in health status (EQ-5D-5L) (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Time Frame

14 days

Title

Change in sleep quality from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Description

Time Frame

14 days

Title

Patient satisfaction with treatment Day 7(+/-1) and Day 14(+/-1) in the three different groups.

Description

Time Frame

14 days

Title

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.

Description

Change in patient consideration of termination of pregnancy (patient reported) from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Time Frame

14 days

Title

Request for dosage increase in the three different groups.

Description

Frequency of request for dosage increase in the three different groups.

Time Frame

14 days

Title

Request for continuation of trial medication after end of intervention in the three different groups.

Description

Frequency of request for continuation of trial medication after end of intervention in the three different groups.

Time Frame

14 days

Title

Use of rescue medication during the intervention in the three different groups.

Description

Use of rescue medication during (patient reported) the intervention in the three different groups.

Time Frame

14 days

Title

Number of days on sick leave during the intervention in the three different groups

Description

Number of days on sick leave (patient reported) during the intervention in the three different groups

Time Frame

14 days

Title

Necessity of i.v.-fluids during the intervention in the three different groups.

Description

Amount of treatments with i.v.-fluids during the intervention in the three different groups.

Time Frame

14 days

Title

Need of hospitalisation during the intervention in the three different groups.

Description

Number of days of hospitalisations during the intervention in the three different groups.

Time Frame

14 days

Title

Weight change from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Description

Weight change in kg from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

Time Frame

14 days

Title

Pregnancy outcome: Live birth, loss or termination of pregnancy

Description

Live birth, loss or termination of pregnancy.

Time Frame

8 months

Title

Delivery outcome: Mode of delivery

Description

Mode of delivery: Vaginal, cesarian, vacuum extraction.

Time Frame

8 months

Title

Delivery outcome: Delivery complications

Description

Eg. postpartum hemorrhage, shoulder dystocia, sphincter rupture

Time Frame

8 months

Title

Live birth outcome: birth weight.

Description

Birth weight in g.

Time Frame

8 months

Title

Live birth outcome: gestational age at birth.

Description

Gestational age at birth in weeks plus days.

Time Frame

8 months

Title

Live birth outcome: APGAR score.

Description

APGAR score at 1, 5 and 10 minutes after birth. APGAR score ranges 0-10 with 0 being worse and 10 being better.

Time Frame

8 months

Title

Live birth outcome: umbilical cord pH.

Description

Umbilical cord pH at birth.

Time Frame

8 months

Title

Live birth outcome: placenta weight.

Description

placenta weight in g.

Time Frame

8 months

Title

Live birth outcome: sex.

Description

offsprings sex.

Time Frame

8 months

Title

Live birth outcome: hospitalizations on neonatal ward during the first month post-partum.

Description

Hospitalizations of the offspring in neonatal ward during the first month post-partum.

Time Frame

9 months

Title

Live birth outcome: congenital malformations (depending on gestational age also registered on early ended pregnancies).

Description

Congenital malformations.

Time Frame

8 months

Title

Occurrence of treatment failure in the three different groups.

Description

Frequency of and time to treatment failure in the three different groups.

Time Frame

14 days

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 19+6 Nausea and vomiting without other obvious reason PUQE-24 score ≥13 OR PUQE-24 score ≥7 AND weight loss >5% of pre-pregnancy weight and/or hospitalisation due to nausea and vomiting of pregnancy Singleton pregnancy The subject must be willing and able to comply with trial protocol Exclusion Criteria: Mola pregnancy, multiple gestation or non-vital pregnancy Nausea and vomiting of other aetiology than NVP 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>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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Anne Ostenfeld, MD

Organizational Affiliation

Department of Obstetrics and gynecology, Nordsjællands Hospital Hillerød

Official's Role

Principal Investigator

Facility Information:

Facility Name

Department of Gynaecology and Obstetrics, Aarhus University Hospital

City

Aarhus

ZIP/Postal Code

8200

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Rigshospitalet

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Herlev Hospital

City

Herlev

ZIP/Postal Code

2730

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Nordsjællands Hospital

City

Hillerød

ZIP/Postal Code

3400

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Hvidovre Hospital

City

Hvidovre

ZIP/Postal Code

2650

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Kolding Sygehus

City

Kolding

ZIP/Postal Code

6000

Country

Denmark

Facility Name

Department of Gynaecology and Obstetrics, Odense University Hospital

City

Odense

ZIP/Postal Code

5000

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Access to patient level data and supporting clinical documents may be requested. Requests will be reviewed on the basis of methodological proposal. Patient data will be de-identified to protect the privacy of trial patients in line with applicable laws and regulations.

IPD Sharing Time Frame

Following publication, no end date.

Citations:

PubMed Identifier

32209630

Citation

Ostenfeld A, Petersen TS, Futtrup TB, Andersen JT, Jensen AK, Westergaard HB, Pedersen LH, Lokkegaard ECL. Validating the effect of Ondansetron and Mirtazapine In Treating hyperemesis gravidarum (VOMIT): protocol for a randomised placebo-controlled trial. BMJ Open. 2020 Mar 24;10(3):e034712. doi: 10.1136/bmjopen-2019-034712.

Results Reference

derived

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Validating the Effect og Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum

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