Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum (CLONEMESI)

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

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.

Study Overview

• Status: Completed
• Conditions: Hyperemesis Gravidarum
• Intervention / Treatment: Drug: Clonidine

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 .

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Torino, Italy, 10126
    • Ospedale Sant'Anna. Dipartimento di Ostetricia e Neonatologia. Servizio di Medicina Interna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Città della Salute e della Scienza di Torino
• Investigators: Principal Investigator: Aldo Maina, M.D., Dipartimento di Ostetricia e Neonatologia. Servizio di Medicina Interna. Ospedale Sant'Anna Torino; Study Chair: Tullia Todros, M.D., Head . Dipartimento di Ostetricia e Neonatologia. Università di Torino.

Publications and helpful links

General Publications

• Maina A, Arrotta M, Cicogna L, Donvito V, Mischinelli M, Todros T, Rivolo S. Transdermal clonidine in the treatment of severe hyperemesis. A pilot randomised control trial: CLONEMESI. BJOG. 2014 Nov;121(12):1556-62. doi: 10.1111/1471-0528.12757. Epub 2014 Apr 1.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: March 12, 2012
• First Submitted That Met QC Criteria: March 18, 2012
• First Posted (Estimate): March 20, 2012

Study Record Updates

• Last Update Posted (Estimate): April 30, 2014
• Last Update Submitted That Met QC Criteria: March 31, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Keywords: treatment; Hyperemesis Gravidarum; transdermal clonidine
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Pregnancy Complications; Morning Sickness; Vomiting; Hyperemesis Gravidarum; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympatholytics; Clonidine
• Other Study ID Numbers: Registro CE 409 det. 163/2012