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

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

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).

Study Overview

• Status: Terminated
• Conditions: Hyperemesis Gravidarum; Nausea Gravidarum; Vomiting of Pregnancy
• Intervention / Treatment: Drug: Mirtazapine; Drug: Ondansetron; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Anne Ostenfeld, MD; Phone Number: +4520779758; Email: anne.ostenfeld.02@regionh.dk
• Study Contact Backup: Name: Ellen CL Løkkegaard, Prof,MD,PhD; Phone Number: +4548296249; Email: eloe0002@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Department of Gynaecology and Obstetrics, Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Department of Gynaecology and Obstetrics, Rigshospitalet
  • Herlev, Denmark, 2730
    • Department of Gynaecology and Obstetrics, Herlev Hospital
  • Hillerød, Denmark, 3400
    • Department of Gynaecology and Obstetrics, Nordsjællands Hospital
  • Hvidovre, Denmark, 2650
    • Department of Gynaecology and Obstetrics, Hvidovre Hospital
  • Kolding, Denmark, 6000
    • Department of Gynaecology and Obstetrics, Kolding Sygehus
  • Odense, Denmark, 5000
    • Department of Gynaecology and Obstetrics, Odense University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mirtazapine; 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.	Drug: Mirtazapine; 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.; Other Names: KRKA Mirtazapine Oral Tablet
Experimental: Ondansetron; 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.	Drug: Ondansetron; 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.; Other Names: Bluefish Ondansetron Oral Tablet
Placebo Comparator: Placebo; 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.	Drug: Placebo; 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.; Other Names: Placebo Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	2 days
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.	2 days
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.	14 days
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.	14 days
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.	2 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	14 days
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.	14 days
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.	14 days
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.	14 days
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.	14 days
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.	19 days
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.	14 days
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.	14 days
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.	14 days
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.	14 days
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.	14 days
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.	14 days
Request for dosage increase in the three different groups.	Frequency of request for dosage increase in the three different groups.	14 days
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.	14 days
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.	14 days
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	14 days
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.	14 days
Need of hospitalisation during the intervention in the three different groups.	Number of days of hospitalisations during the intervention in the three different groups.	14 days
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.	14 days
Pregnancy outcome: Live birth, loss or termination of pregnancy	Live birth, loss or termination of pregnancy.	8 months
Delivery outcome: Mode of delivery	Mode of delivery: Vaginal, cesarian, vacuum extraction.	8 months
Delivery outcome: Delivery complications	Eg. postpartum hemorrhage, shoulder dystocia, sphincter rupture	8 months
Live birth outcome: birth weight.	Birth weight in g.	8 months
Live birth outcome: gestational age at birth.	Gestational age at birth in weeks plus days.	8 months
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.	8 months
Live birth outcome: umbilical cord pH.	Umbilical cord pH at birth.	8 months
Live birth outcome: placenta weight.	placenta weight in g.	8 months
Live birth outcome: sex.	offsprings sex.	8 months
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.	9 months
Live birth outcome: congenital malformations (depending on gestational age also registered on early ended pregnancies).	Congenital malformations.	8 months
Occurrence of treatment failure in the three different groups.	Frequency of and time to treatment failure in the three different groups.	14 days

Collaborators and Investigators

• Sponsor: Nordsjaellands Hospital
• Collaborators: Odense University Hospital; Aarhus University Hospital; Rigshospitalet, Denmark; Hvidovre University Hospital; Bispebjerg Hospital; Herlev and Gentofte Hospital; Kolding Sygehus; Regionernes Medicinpulje
• Investigators: Principal Investigator: Anne Ostenfeld, MD, Department of Obstetrics and gynecology, Nordsjællands Hospital Hillerød

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 26, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Pregnancy; Ondansetron; Mirtazapine; Hyperemesis Gravidarum (HG); Nausea and Vomiting of Pregnancy (NVP); Randomized Controlled Trial (RCT)
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Pregnancy Complications; Morning Sickness; Nausea; Vomiting; Hyperemesis Gravidarum; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Antidepressive Agents; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Anti-Anxiety Agents; Serotonin 5-HT3 Receptor Antagonists; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Adrenergic alpha-Antagonists; Adrenergic alpha-2 Receptor Antagonists; Mirtazapine; Ondansetron
• Other Study ID Numbers: VOMIT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No