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

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ClinicalTrials.gov Identifier: NCT03785691
Recruitment Status : Recruiting
First Posted : December 24, 2018
Last Update Posted : June 24, 2019
Sponsor:
Collaborators:
Bispebjerg Hospital
Aalborg University Hospital
Aarhus University Hospital
Herlev and Gentofte Hospital
Hvidovre University Hospital
Odense University Hospital
Rigshospitalet, Denmark
Regionernes Medicinpulje
Information provided by (Responsible Party):
Anne Ostenfeld, Nordsjaellands Hospital

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).


Condition or disease Intervention/treatment Phase
Hyperemesis Gravidarum Nausea Gravidarum Vomiting of Pregnancy Drug: Mirtazapine Drug: Ondansetron Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized placebo controlled multicenter trial testing already marketed drugs on a new indication.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: All oral tablets will be encapsulated in gelatine to ensure identical look, smell and taste.
Primary Purpose: Treatment
Official Title: Validating the Effect of Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum. A Double-Blind Randomised Placebo-Controlled Multicentre Trial
Actual Study Start Date : March 1, 2019
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : October 1, 2021

Resource links provided by the National Library of Medicine


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 Name: 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 Name: 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 Name: Placebo Oral Tablet




Primary Outcome Measures :
  1. Change in nausea and vomiting from baseline to Day 2 (short term) in the mirtazapine group versus the placebo group. [ Time Frame: 2 days ]
    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. Change in nausea and vomiting from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus the placebo group. [ Time Frame: 14 days ]
    Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-1) (long term) in the mirtazapine group versus the placebo group.


Secondary Outcome Measures :
  1. Change in nausea and vomiting from baseline to Day 2 in the ondansetron group versus the placebo group. [ Time Frame: 2 days ]
    Change in PUQE-24 score (patient reported) from baseline to Day 2 in the ondansetron group versus the placebo group.

  2. Change in nausea and vomiting from baseline to Day 14(+/-1) in the ondansetron group versus the placebo group. [ Time Frame: 14 days ]
    Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-1) in the ondansetron group versus the placebo group.

  3. Change in nausea and vomiting from baseline to Day 2 in the mirtazapine group versus the ondansetron group. [ Time Frame: 2 days ]
    Change in PUQE-24 score (patient reported) from baseline to Day 2 in the mirtazapine group versus the ondansetron group.

  4. Change in nausea and vomiting from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group. [ Time Frame: 14 days ]
    Change in PUQE-24 score (patient reported) from baseline to Day 14(+/-1) in the mirtazapine group versus the ondansetron group.

  5. Overall nausea and vomiting during the intervention in the three different groups. [ Time Frame: 14 days ]
    Area under the curve for PUQE-24 score (patient reported) during the intervention in the three different groups.

  6. Change in well-being during the intervention in the three different groups. [ Time Frame: 14 days ]
    Change in PUQE well-being score (patient reported) during the intervention in the three different groups.

  7. Change in nausea during the intervention in the three different groups. [ Time Frame: 14 days ]
    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.

  8. Change in vomiting during the intervention in the three different groups. [ Time Frame: 14 days ]
    Change in number of daily vomiting episodes (patient reported) during the intervention in the three different groups.

  9. 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. [ Time Frame: 14 days ]
    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.

  10. Change in severity of hyperemesis gravidarum from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. [ Time Frame: 14 days ]
    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.

  11. Change in health-related quality of life from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. [ Time Frame: 14 days ]
    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.

  12. Change in sleep quality from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. [ Time Frame: 14 days ]
    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.

  13. Patient satisfaction with treatment Day 7(+/-1) and Day 14(+/-1) in the three different groups. [ Time Frame: 14 days ]
    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. 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. [ Time Frame: 14 days ]
    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.

  15. Occurrence of treatment failure in the three different groups. [ Time Frame: 14 days ]
    Frequency of and time to treatment failure in the three different groups.

  16. Request for dosage increase in the three different groups. [ Time Frame: 14 days ]
    Frequency of request for dosage increase in the three different groups.

  17. Use of rescue medication during the intervention in the three different groups. [ Time Frame: 14 days ]
    Use of rescue medication during (patient reported) the intervention in the three different groups.

  18. Number of days on sick leave during the intervention in the three different groups [ Time Frame: 14 days ]
    Number of days on sick leave (patient reported) during the intervention in the three different groups

  19. Necessity of i.v.-fluids during the intervention in the three different groups. [ Time Frame: 14 days ]
    Amount of treatments with i.v.-fluids during the intervention in the three different groups.

  20. Need of hospitalisation during the intervention in the three different groups. [ Time Frame: 14 days ]
    Number of days of hospitalisations during the intervention in the three different groups.

  21. Weight change from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups. [ Time Frame: 14 days ]
    Weight change in kg from baseline to Day 7(+/-1) and baseline to Day 14(+/-1) in the three different groups.

  22. Request for continuation of trial medication after end of intervention in the three different groups. [ Time Frame: 14 days ]
    Frequency of request for continuation of trial medication after end of intervention in the three different groups.

  23. Pregnancy outcome: Live birth, loss or termination of pregnancy [ Time Frame: 8 months ]
    Live birth, loss or termination of pregnancy.

  24. Delivery outcome: Mode of delivery [ Time Frame: 8 months ]
    Mode of delivery: Vaginal, cesarian, vacuum extraction.

  25. Delivery outcome: Delivery complications [ Time Frame: 8 months ]
    Eg. postpartum hemorrhage, shoulder dystocia, sphincter rupture

  26. Live birth outcome: birth weight. [ Time Frame: 8 months ]
    Birth weight in g.

  27. Live birth outcome: gestational age at birth. [ Time Frame: 8 months ]
    Gestational age at birth in weeks plus days.

  28. Live birth outcome: APGAR score. [ Time Frame: 8 months ]
    APGAR score at 1, 5 and 10 minutes after birth. APGAR score ranges 0-10 with 0 being worse and 10 being better.

  29. Live birth outcome: umbilical cord pH. [ Time Frame: 8 months ]
    Umbilical cord pH at birth.

  30. Live birth outcome: placenta weight. [ Time Frame: 8 months ]
    placenta weight in g.

  31. Live birth outcome: sex. [ Time Frame: 8 months ]
    offsprings sex.

  32. Live birth outcome: hospitalizations on neonatal ward during the first month post-partum. [ Time Frame: 9 months ]
    Hospitalizations of the offspring in neonatal ward during the first month post-partum.

  33. Live birth outcome: congenital malformations (depending on gestational age also registered on early ended pregnancies). [ Time Frame: 8 months ]
    Congenital malformations.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

    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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03785691


Contacts
Layout table for location contacts
Contact: Anne Ostenfeld, MD +4520779758 anne.ostenfeld.02@regionh.dk
Contact: Ellen CL Løkkegaard, Prof,MD,PhD +4548296249 eloe0002@regionh.dk

Locations
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Denmark
Department of Gynaecology and Obstetrics, Herlev Hospital Recruiting
Herlev, Denmark, 2730
Contact: Tina B Futtrup, MD         
Contact: Line M Lindgren, MD         
Principal Investigator: Tina B Futtrup, MD         
Principal Investigator: Line M Lindgren, MD         
Department of Gynaecology and Obstetrics, Nordsjællands Hospital Recruiting
Hillerød, Denmark, 3400
Contact: Anne Ostenfeld, MD    +4520779758    anne.ostenfeld.02@regionh.dk   
Contact: Ellen C Løkkegaard, MD, Professor    +4548296249    eloe0002@regionh.dk   
Principal Investigator: Anne Ostenfeld, MD         
Department of Gynaecology and Obstetrics, Hvidovre Hospital Recruiting
Hvidovre, Denmark, 2650
Contact: Kamille Fogh, MD       kamille.fogh@regionh.dk   
Contact: Benny Kirschner       benny.kirschner@regionh.dk   
Principal Investigator: Kamille Fogh, MD         
Sponsors and Collaborators
Nordsjaellands Hospital
Bispebjerg Hospital
Aalborg University Hospital
Aarhus University Hospital
Herlev and Gentofte Hospital
Hvidovre University Hospital
Odense University Hospital
Rigshospitalet, Denmark
Regionernes Medicinpulje
Investigators
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Principal Investigator: Anne Ostenfeld, MD Department of Obstetrics and gynecology, Nordsjællands Hospital Hillerød

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Responsible Party: Anne Ostenfeld, MD, PhD student, Nordsjaellands Hospital
ClinicalTrials.gov Identifier: NCT03785691     History of Changes
Other Study ID Numbers: VOMIT
First Posted: December 24, 2018    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by Anne Ostenfeld, Nordsjaellands Hospital:
Hyperemesis Gravidarum (HG)
Mirtazapine
Ondansetron
Pregnancy
Nausea and Vomiting of Pregnancy (NVP)
Randomized Controlled Trial (RCT)

Additional relevant MeSH terms:
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Nausea
Vomiting
Hyperemesis Gravidarum
Pregnancy Complications
Signs and Symptoms, Digestive
Signs and Symptoms
Morning Sickness
Ondansetron
Mirtazapine
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipruritics
Dermatologic Agents
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Anti-Anxiety Agents
Antidepressive Agents
Histamine H1 Antagonists
Histamine Antagonists
Histamine Agents
Adrenergic alpha-2 Receptor Antagonists