Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum

Study Overview
=================
Brief Summary
-----------------
CLONEMESI is an academic, independent, randomized placebo-controlled trial to assess the effect of transdermal (TD) clonidine in improving the symptoms of severe Hyperemesis Gravidarum(HG) affecting women in their 6th-12th week of pregnancy. The study has a crossover design.

Detailed Description
-----------------
Setting. The trial is performed at a single hospital setting after admission of patients. Ethics. The study has been approved by our local Ethics Committee and women are requested to sign an informed consent. No pharmaceutical company is involved in any phases of the trial including protocol design, study conduction, coordination and monitoring, data handling and analysis. Randomization. The patients are allocated to a random list to receive first placebo and then TD clonidine or the other way round. Blinding. Neither the patients nor their attending caregivers know the order of administration . The outcome assessors are blinded as well. Treatment.The patients are randomly treated with and without TD clonidine for 2 consecutive periods of 5 days , other antiemetic drugs (promethazine, metoclopramide, ondansetron) and anti- reflux drugs (ranitidine, omeprazole) being administered on a scheduled or as-needed basis. All patients receive intravenous hydration and supplementation with thiamine. Assessment. Physical condition of patients are assessed daily: blood pressure (lying and standing), body weight, morning ketonuria. Two different clinical self administered scores as PUQE (Pregnancy Unique Quantification of Emesis) and VAS (Visual Analogue Scale) are employed to check daily the intensity of symptoms and the sense of wellbeing. The consumption of antiemetic and anti-reflux drugs administered in the two periods is monitored .

Official Title
-----------------
The CLONEMESI Study: a Randomized Placebo-controlled Study With Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum.

Conditions
-----------------
Hyperemesis Gravidarum

Intervention / Treatment
-----------------
* Drug: Clonidine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Gestational age 6-12 weeks and a major grade of HG clinical severity defined as follows: a PUQE score index ≥ 13 associated to one or more of the following conditions: weight loss > 5% of pregravidic weight, electrolyte disturbances, dehydration, duration of symptoms > 10 days , inadequate food and drink intake Exclusion Criteria: Language barrier.
Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: clonidine first - placebo second<br>in this group patients are treated with transdermal clonidine first for 5 days then switch to placebo for 5 days | Drug: Clonidine<br>* transdermal clonidine patch 5 mg q. 5 days<br>* Other names: Catapresan TTS 2 transdermal patch;|
| Other: placebo first - clonidine second<br>in this group patients are treated with placebo first for 5 days then with transdermal clonidine for next 5 days | Drug: Clonidine<br>* transdermal clonidine patch 5 mg q. 5 days<br>* Other names: Catapresan TTS 2 transdermal patch;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PUQE Score for Assessment of Severity in Hyperemesis Gravidarum | PUQE in an acronym for Pregnancy Unique Quantification of Emesis, a validated clinical score for assessment of severity of emesis in pregnancy. It is composed of three items; every item has a score from 1 (best) to 5 (worst). The sum range varies from 3 (best) to 15 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | Mean values of first period of five days are compared with mean values of second period of five days. Change is reported as baseline value - value at day 5 or at day 10. | 
| VAS Score for Assessment of Severity in Hyperemesis Gravidarum | VAS is a Visual Analogic Scale formulated in 5 items. Every item has a score from 0 (best) to 10 (worst). The sum range swings from 0 (best ) to 50 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | Mean values of first period of five days are compared with mean values of second period of five days. Change is reported as baseline value - value at day 5 or at day 10. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morning Urine Ketonuria | Morning urine ketonuria is a simple direct marker of starving associated to nausea and vomiting | participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days | 
| Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. | The patients were randomly treated with and without TD clonidine (5mg patch) for 2 consecutive periods of 5 days , other antiemetic drugs (promethazine, prochlorperazine, metoclopramide, ondansetron) and anti reflux drugs (ranitidine, omeprazole) being administered on a scheduled or as-needed basis. All patients received intravenous hydration and supplementation with thiamine, during both periods. The use of steroids was allowed as a rescue medication in case of further worsening of symptoms. | participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days | 
| Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only | if the symptoms improve the patient and her doctors may decide to stop parenteral drugs continuing the TD system therapy. | participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days | 
| Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. | the patients were asked to choose between two transdermal systems (active drug versus placebo) as the most effective | at 10 days since start of treatment | 
| Pregnancy Outcome Measures: Birth Weight. | Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG. | at delivery | 
| Newborn Outcome Measure: APGAR Score. | The APGAR score is the most common indicator of neonatal status immediately after delivery. The test is done by a doctor, midwife, or nurse. The health care provider will examine the baby's: Breathing effort Heart rate Muscle tone Reflexes Skin color Each category is scored with 0, 1, or 2, depending on the observed condition. The APGAR rating is based on a total score of 1 to 10. The higher the score, the better the baby is doing after birth. | at 1 minute and at 5 minutes after delivery | 
| Systolic Blood Pressure | Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days) | 10 days | 
| Diastolic Blood Pressure | Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle | 10 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hyperemesis Gravidarum, treatment, transdermal clonidine