| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Nausea and Vomiting in pregnancy
Hyperemesis gravidarum |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe nausea and vomiting in pregnancy. |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Reproductive physiologi cal processes [G08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether, in addition to IV rehydration, ondansetron vs placebo ondansetron and metoclopramide vs placebo metoclopramide reduces the rate of treatment failure up to 10 days after initiation. |
|
| E.2.2 | Secondary objectives of the trial |
The inclusion criteria for the EMPOWER study are as follows:
• Pregnant women suffering from severe NVP
• Gestation ≤16 6/7 weeks (16 weeks 6 days)
• Taken first line antiemetic treatment (cyclize, chlorpromazine, promethazine or prochlorperazine as recommended by the RCOG [10]), as prescribed i.e. full course taken by participant in the current pregnancy with no sustained improvement in symptoms (over a minimum of 24 hours use)
• Age ≥18 years
• Able to give informed consent
• Able to read/understand written English
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The exclusion criteria for the EMPOWER study are as follows:
• Allergy/hypersensitivity to any of the study drugs
• Prior treatment with the study drugs in this pregnancy
• Pre-existing diagnosis of medical condition: type 1 and 2 diabetes, chronic kidney disease (CKD) stage 3-5, Graves’ disease, significant cardiac disease (including long QT syndrome), phaeochromocytoma, epilepsy (or other seizure disorder).
• Moderate renal impairment (known CKD 3b/4/5 or Cr > 100 in pregnancy)
• Severe liver impairment (ALT / AST > 150)
• Severe diarrhoea (definition >10 loose, watery stools in a day (24 hours))*
• Hypokalaemia**
• Vomiting caused by another underlying condition/infection
• Concomitant use of apomorphine, serotonergic drugs (e.g. selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium)
*If a woman who has severe diarrhoea (as defined above) meets other inclusion criteria and is subsequently found to have a serum potassium > 3 mmol/L and has not yet been prescribed an antiemetic it would be reasonable to offer participation in EMPOWER.
**all women with severe NVP will have routine assessment of 'Urea & Electrolytes' - in the absence of severe diarrhoea women can be approached, consented and given study treatments before results are available. If the serum potassium is subsequently found to be low (<3 mmol/L) they should not be withdrawn from the trial but the hypokalaemia corrected quickly with intravenous supplementation.
|
|
| E.4 | Principal exclusion criteria |
The exclusion criteria for the EMPOWER study are as follows:
• Allergy/hypersensitivity to any of the study drugs
• Prior treatment with the study drugs in this pregnancy
• Pre-existing diagnosis of medical condition: type 1 and 2 diabetes, Chronic kidney disease (CKD) stage 3-5, Graves’ disease, significant cardiac disease (including long QT syndrome), phaeochromocytoma, epilepsy (or other seizure disorder).
• Moderate renal impairment (known CKD 3b/4/5 or Cr > 100 in pregnancy)
• Severe liver impairment (ALT / AST > 150)
• Severe diarrhoea (definition >10 loose, watery stools in a day (24 hours))*
• Hypokalaemia**
• Vomiting caused by another underlying condition/infection
• Concomitant use of apomorphine, serotonergic drugs (e.g. selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium)
*If a woman who has severe diarrhoea (as defined above) meets other inclusion criteria and is subsequently found to have a serum potassium > 3 mmol/L and has not yet been prescribed an antiemetic it would be reasonable to offer participation in EMPOWER.
**all women with severe NVP will have routine assessment of 'Urea & Electrolytes' - in the absence of severe diarrhoea women can be approached, consented and given study treatments before results are available. If the serum potassium is subsequently found to be low (<3 mmol/L) they should not be withdrawn from the trial but the hypokalaemia corrected quickly with intravenous supplementation.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the number of participants experiencing a treatment failure. Treatment failure is defined as the need for further treatment as a participant’s symptoms have worsened between 12 hours and 10 days post treatment initiation. If further treatment is required a participant should be placed on a third line antiemetic treatment i.e. high dose ondansetron or corticosteroids. Participants cannot be given metoclopramide or low dose ondansetron as third line antiemetic treatment initiation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoints of this evaluation are between 12 hours and 10 days post treatment. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for the EMPOWER study are as follows:
Participant reported symptom severity: The PUQE score will be used to assess severity of symptoms. The scale quantifies the amount of nausea, vomiting and retching experienced over the previous 24 hours. The PUQE score will be collected at baseline, 48 hours, 5 days and 10 days post treatment commencing.
Participant reported severity of nausea: We will use a visual analogue score (VAS) for nausea alongside the PUQE symptoms severity score to examine more subtle changes in nausea. The VAS asks participants to rate, on a scale of 0-10 where 10 is the worst possible nausea you could feel, how bad their nausea is now. The VAS score will be collected at baseline, 48 hours, 5 days and 10 days post treatment commencing.
NVPQOL: The Health-Related Quality of Life for Nausea and Vomiting during Pregnancy (NVPQOL) provides a total score and those in 4 domains (physical symptoms and aggravating factors; fatigue; emotions; limitations). The NVPQOL will be collected at baseline and 10 days post treatment commencing. Of primary interest will be the total NVPQOL score.
Anxiety, depression and social support: These parameters will be measured using the following scales which are validated for use in pregnancy:
Edinburgh Post-natal Depression Scale (EPDS).
State Trait Anxiety Inventory [STAI]:
Maternity Social Support scale:
Data will be collected as the total EPDS score (depression) and total STAI score (anxiety) at baseline and 10 days. The total maternal social support scale score will be reported at baseline.
Clinical indicators of anti-emetic effectiveness
(a) The number of participants experiencing a treatment failure (as per primary endpoint) at 48 hours
(b) Relapse rate at 5 and 10 days (defined as a PUQE score of ≤ 6 at 48 hours followed by an increase to > 12 at 5 / 10 days)
(c) Remission rate at 10 days (defined as a PUQE score of ≤ 6 at 48 hours with return to persistent symptoms [PUQE score 7-12] at 10 days)
(d) Readmission rates (the number of participants readmitted with NVP within 10 days of recruitment and between 10 days of recruitment and 20 weeks of pregnancy)
(e) Total in-patient days related to NVP between recruitment and 20 weeks of pregnancy and between 20 weeks of pregnancy and delivery
(f) Additional antiemetic use
Side effects and adverse events: Participants will be asked about the occurrence of the most common side effects of each drug identified from previous research. Those indicating the presence of a specific side effect will be asked to grade severity using the Common Terminology Criteria for Adverse Events (CTCAE). Participants will also be asked about any other suspected adverse events. Adverse events will be reported by grade (including no occurrence for pre-specified side effects) at 48 hours, 5 days and 10 days and as the worst grade reported over the 10 day period.
Pregnancy and neonatal outcomes: The number of women reporting miscarriage, termination of pregnancy and stillbirth will be reported. For each infant born, the mode of delivery, gestational age at delivery, birth weight and number of infants born small for gestational age (SGA) will also be reported. SGA refers to an infant born with a birth weight less than the 10th centile, customised for maternal characteristics (maternal height, weight, parity and ethnic group) as well as gestational age at delivery and infant sex. Information on congenital anomalies detected prior to discharge will be collected by the research teams at site via review of participant medical records and provided to the UK Teratology Information Service (UKTIS). In the case of multiple births, this information will be collected for each infant. Participants will also be asked if they would be willing to provide information directly to UKTIS via their Bumps website online reporting tool however this is not mandatory. The participant will use their unique participant trial identifier to provide information and no identifiable data will be collected via the online tool.
Key economic outcomes (detailed in Economic Analysis section) include: (a) Costs to the NHS, women and their families; (b) Willingness to pay for the benefits of antiemetic treatment; (c) Incremental cost per additional successful treatment and incremental net-benefit.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timepoints of this evaluation are between baseline and post birth. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| As follow-up data will be collected after the participant has delivered end of trial is defined as the date the last infant born is discharged from hospital. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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