Validating the Effect og Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum

Study Overview
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Brief Summary
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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).

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

Conditions
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Hyperemesis Gravidarum, Nausea Gravidarum, Vomiting of Pregnancy

Intervention / Treatment
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* Drug: Mirtazapine
* Drug: Ondansetron
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized placebo controlled multicenter trial testing already marketed drugs on a new indication.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirtazapine<br>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<br>* 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.<br>* Other names: KRKA Mirtazapine Oral Tablet;|
| Experimental: Ondansetron<br>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<br>* 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.<br>* Other names: Bluefish Ondansetron Oral Tablet;|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>* Other names: Placebo Oral Tablet;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperemesis Gravidarum (HG), Mirtazapine, Ondansetron, Pregnancy, Nausea and Vomiting of Pregnancy (NVP), Randomized Controlled Trial (RCT)