transdermal clonidine in the treatment of severe hyperemesis. a pilot randomised control trial:...

Transdermal clonidine in the treatment of severehyperemesis. A pilot randomised control trial:CLONEMESI*†

A Maina,a M Arrotta,a L Cicogna,a V Donvito,a M Mischinelli,b T Todros,b S Rivoloc

a Dipartimento di Medicina, Servizio di Medicina Interna, Ospedale Sant’Anna, AOU Citt�a della Salute e della Scienza, Turin b Divisione di

Medicina Materno-Fetale, Dipartimento di Ostetricia e Ginecologia, Universit�a di Torino, Turin, Italy c Division of Imaging Sciences and

Biomedical Engineering, Department of Biomedical Engineering, King’s College London, St. Thomas’ Hospital, London, UK

Correspondence: Dr A Maina, Dipartimento di Medicina, Servizio di Medicina Interna, Ospedale Sant’Anna, AOU Citt�a della Salute e della

Scienza, 10126 Turin, Italy. Email [email protected], [email protected]

Accepted 8 December 2013. Published Online 1 April 2014.

Objective To study the efficacy of transdermal clonidine in the

treatment of severe refractory hyperemesis gravidarum (HG), the

most severe illness of pregnancy.

Design The study had a randomised, double -blind,

placebo-controlled, cross-over design (RCT).

Setting Single tertiary referral hospital after admission of patients.

Sample Twelve women of gestational age 6–12 weeks and a major

grade of HG clinical severity who were unresponsive to standard

antiemetic treatment.

Methods The patients were randomly treated with and without

the active drug (5 mg patch) for two consecutive periods of

5 days. The patients were allocated to a random list to receive

first placebo and then active drug or the other way round. Other

antiemetic drugs were administered on a scheduled or as-needed

basis. All patients received intravenous hydration and thiamine

supplementation.

Main outcome measures Pregnancy Unique Quantification of

Emesis (PUQE) and visual analog scale (VAS) clinical scores,

positive morning urine ketonuria, number of doses of standard

antiemetic drugs required, and number of days off intravenous

therapy were compared in the two periods.

Results Transdermal clonidine led to a significantly greater

improvement compared with placebo of the primary (PUQE score

P = 0.026 CI 0.43–3.24; VAS score P = 0.010 CI 2.17–12.83) andsecondary outcome measures. A reduction of blood pressure was

reported for systolic 6 mmHg P = 0.01 and diastolic 3 mmHg

P = 0.055.

Conclusions This preliminary RCT demonstrates the efficacy of

transdermal clonidine in the treatment of severe HG, leading to a

significant reduction of symptoms and reducing the need for

other supportive measures and medications.

Keywords Hyperemesis gravidarum, randomised control trial,

transdermal clonidine, treatment.

Linked article This article is commented on by Stephansson O

et al., pp. 1563 in this issue. To view this mini commentary visit

http://dx.doi.org/10.1111/1471-0528.12761.

Please cite this paper as: 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;121:1556–1563.

Introduction

The most severe form of nausea and vomiting, referred to

as hyperemesis gravidarum (HG), affects 1% of pregnant

women. It is associated with high circulating hCG levels

and its treatment usually requires hospital admission, rehy-

dration and antiemetic drugs.1–4

Drug treatment is based on a range of different mole-

cules active as antiemetics, which includes anticholinergics,

antihistamines (H1 receptor antagonists), dopamine agon-

ists such as metoclopramide and domperidone, selective

5-hydroxytryptamine receptor antagonist (ondansetron) or

any combination of these agents. Proton pump inhibitors

and H2 blockers may also be used as useful adjunctive

treatments in women with frequent vomiting or retching.

*CLONEMESI, an academic independent trial, was devised to assess the

effect of TD clonidine in improving the symptoms of severe HG affecting

women in their 6th–12th week of pregnancy. The trial was registered at

ClinicalTrials.gov with the ID number NCT01559012. (http://clinicaltri-

als.gov/ct2/show/NCT01559012?term=clonidine+hyperemesis&rank=1).†ID number NCT01559012

1556 ª 2014 Royal College of Obstetricians and Gynaecologists

DOI: 10.1111/1471-0528.12757

www.bjog.orgMaternal medicine

http://dx.doi.org/10.1111/1471-0528.12761

http://clinicaltrials.gov/ct2/show/NCT01559012?term=clonidine+hyperemesis&rank=1

http://clinicaltrials.gov/ct2/show/NCT01559012?term=clonidine+hyperemesis&rank=1

Due to the inability of the women to take oral medication,

all the drugs should be administered parenterally. The clini-

cal response of the woman to standard therapy is unpre-

dictable and sometimes disappointing; rehydration is the

only consistently effective treatment. In refractory patients,

steroid treatment often results in impressive improvement.5

HG remains a rare condition but it may pose severe risks

to the mother’s and fetus’ health: the findings of a large

study showed a clear relationship between persistent HG in

the second trimester and placental dysfunction disorders.6

The study found that there was a doubled risk of preterm

preeclampsia, a threefold risk of placental abruption, and a

slightly increased risk of a small-for-gestational-age new-

born, indicating an association between abnormal placenta-

tion with raised and persistent hCG levels and HG

manifested in the second trimester. A similar association

was found in former studies.7–9 Moreover, newborns of

mothers who have lost weight in early pregnancy are more

likely to have a birthweight below the 10th percentile at

delivery.10 These consequences cannot be ignored and the

condition should not be left untreated.

Following our preliminary report on a possible helpful

effect of transdermal (TD) clonidine in a series of women

affected by severe refractory HG,11 we present here the results

obtained from a small randomised placebo controlled trial.

Methods

PatientsWomen at 6–12 weeks’ gestation, affected by severe HG,

who were unresponsive to standard antiemetic treatment

(pyridoxine, metoclopramide or ondansetron plus an anti--

reflux medication such as ranitidine or omeprazole), were

considered eligible. Clinical severity was defined by a PUQE

score index ≥13 associated to one or more of the following

conditions: weight loss >5% of pregravid weight, electrolyte

disturbances, dehydration, duration of symptoms >10 days,

inadequate food and drink intake. Language barrier was the

only exclusion criteria.

SettingThe trial was carried out in a single hospital setting (Ospe-

dale Sant’Anna) after admission of patients.

EthicsThe study protocol was reviewed and approved by the

Institutional Review Board (Comitato Etico Interaziendale

Sant’Anna—Mauriziano, dated 20 December 2011, and

Protocol Determination Reference n. 163, dated 21 Febru-

ary 2012) and was conducted according to Italian law and

the Declaration of Helsinki for Medical Research involving

Human Subjects. No pharmaceutical company was

involved in any phase of the trial including protocol

design, study conduction, coordination and monitoring,

data handling and analysis. All women were requested to

sign a written informed consent before enrolment.

Study designThe study had a randomised, double-blind, placebo-con-

trolled, crossover design. Randomisation was performed at

the Department of Obstetrics and Neonatology using a

computer-generated randomisation number sequence:

patients were allocated to a balanced random list to receive

first placebo and then TD clonidine (n = 6) or the other

way round (n = 6). The principal investigator, physicians,

nurses and statistician were unaware of the treatment

assignments. The randomisation code was broken after

completion of the study and analysis of the data.

StatisticsThe analysis of results was limited to days 2–5 of both

cycles, according to the pharmacodynamic features of TD

clonidine and to the study design, in order to allow a

washout period and minimise any carryover effect. A sam-

ple size calculation using a model available on line (MGH

Mallinckrodt General Clinical Research Center—Harvard

Medical School) showed that in a cross-over study design,

12 patients were needed to detect a difference of two points

of the PUQE score between the two groups at an alpha

level of 0.01 and a power of 0.90. The calculation was

based on pre-trial data.

Data analysis was performed using a customised software

package designed using MATLAB (Matlab R2011a; Math-

works, Inc., Natick, MA, USA) and statistical significance

was assessed by the Mann–Whitney U-test. When appropri-

ate, the chi-square test and Fisher’s test were used for dis-

continuous variables. A within-person comparison for

continuous variables representing the primary efficacy end-

points was also performed: this analysis will produce a

smaller standard deviation because it will, by design, allow

between-person differences and this will affect the level of

statistical significance and the confidence interval. All data

were analysed before the study code was broken, according

to the linear model of Kenward and Jones.12

TreatmentEnrolled women were randomly treated with and without

TD clonidine (5 mg clonidine patch or sham patch) for

two consecutive periods of 5 days, other antiemetic drugs

(promethazine, prochlorperazine, metoclopramide, ondan-

setron) and anti-reflux drugs (ranitidine, omeprazole)

being administered on a scheduled or as-needed basis.

All women received intravenous hydration and supple-

mentation with thiamine during both periods. The use of

steroids was allowed as a rescue medication in the case of

further worsening of symptoms.

1557ª 2014 Royal College of Obstetricians and Gynaecologists

Transdermal clonidine in severe hyperemesis gravidarum

BlindingThe randomisation list was deposited at the Department

office and was not accessible to care providers. Ran-

domisation and allocation order (placebo-clonidine or

clonidine-placebo) were assigned by phone. Only one

investigator had access to the randomisation list and she

was involved only in patch positioning or removal, having

no role in clinical assessment, care provision or data

collection.

AssessmentPhysical condition was determined daily by measurement

of blood pressure (lying and standing), body weight and

morning ketonuria. Two different clinical scores, Pregnancy

unique quantification of emesis (PUQE) (range 3–15) and

a visual analog scale (VAS) (range 0–50), were employed to

check daily the intensity of symptoms and the sense of

wellbeing: higher scores indicate worse symptoms.11,13,14

The consumption of antiemetic drugs administered in the

two periods was monitored. A number of outcomes were

considered to assess efficacy of TD clonidine in improving

the women’s symptoms and condition.

Primary efficacy endpointsPUQE and VAS clinical scores were compared in the two

periods.

Secondary efficacy endpointsSeveral outcomes were compared in the two periods: posi-

tive morning urine ketonuria, number of doses of standard

antiemetic drugs required, and number of days off intrave-

nous therapy, with only the TD system being applied.

Women were also asked to choose one of the two differ-

ent systems (active drug or placebo) for off-label compas-

sionate use after discharge, if still symptomatic.

Side effectsSide effects of drug treatment were compared in the two

periods.

Pregnancy outcomesAll women were followed until delivery: complications of

pregnancy, mode of delivery, gestational age, birthweight,

neonatal Apgar score were recorded. All the babies born

underwent a paediatric examination to exclude congenital

anomalies. The live birth of a healthy baby without major

or minor congenital anomalies was considered a secondary

outcome. Side effects of the treatment and possible preg-

nancy complications (miscarriage, termination of preg-

nancy, stillbirth, preeclampsia, preterm delivery, gestational

diabetes, pregnancy hypertension, bleeding and thrombosis)

and birthweight were considered secondary outcomes as

well.

Results

Clinical observation at baselineThe baseline biophysical and demographic data of the

women are reported in Table 1. The two groups were simi-

lar with regard to age, body mass index (BMI), weight loss,

gestational age at the onset of symptoms and at enrolment,

and severity.

Population and enrolment flowchartFrom 23 February to 12 December 2012 we enrolled 13

women affected by severe, unresponsive HG (Figure 1). At

enrolment, all were receiving hydration, eight metoclopra-

mide, five ondansetron, nine ranitidine, four omeprazole,

and two prochlorperazine. All of the women were followed

closely during hospital admission and monthly after dis-

charge until delivery. One women dropped out of the study

after enrolment and randomisation on day 1: she was

receiving placebo and claimed to have side effects of the

TD system (itching, headache). No violation of the study

was recorded, according to patient reports.

EfficacyTD clonidine led to a greater improvement of all the

primary and secondary outcome measures compared with

placebo (Tables 2 and 3). The subjective improvement,

expressed by lower clinical scores and confirmed by the

decline in morning ketonuria, allowed a consequent

Table 1. Baseline biophysical and demographic data

Clonidine first,

n = 6 (range)

Placebo first,

n = 6 (range)

Singleton pregnancy 6 6

Age (years) 31.3 (23–40) 31.8 (24–37)

Race Caucasian 4,

Black African 1,

Mongolian 1

Caucasian 6

Ethnicity European 3,

Indian 1, African 1,

Central Asian 1

European 2,

Arabian 3,

Hispanic 1

Primiparous 2 1

Previous HG 1 4

Smoking 0 0

BMI kg/m2 22.3 (17–28) 24.3 (19–31)

Weight loss, kg 4.83 (1.5–6.5) 5.33 (1–9)

Concurrent disease 2 1

Concurrent treatment 2 0

Gestational age at

start of symptoms

6 (5–7) 6 (5–7)

Gestational age at

enrolment

9.17 (8–12) 9.67 (6–12)

PUQE score at enrolment 13.8 (13–15) 14 (13–15)


Maina et al.

reduction of other parenteral drug doses and intravenous

line dependency.

During the placebo cycle two women needed rescue

medication with parenteral steroids because of the occur-

rence of invalidating symptoms not responsive to other

drugs (Fisher’s exact test P = 0.47).

Nine of 11 women (one did not express her choice)

opted to go on with the active drug patch after discharge

as compassionate treatment (Fisher’s exact test P = 0.009).

Side effectsThe mean lying blood pressure decreased during treatment

by 6 mmHg for systolic and 3 mmHg for diastolic pres-

sure. In the short term, the use of TD clonidine was not

associated to an increase of any adverse effects such as las-

situde, drowsiness, dry mouth, headache, dizziness, fainting

or skin intolerance as compared with placebo group

(paired t-test P = 0.2).

Pregnancy outcomesThe symptoms of HG ceased in late second trimester (eight

women), at delivery (three), or a few days after delivery

(one). Two major pregnancy complications occurred in the

follow-up, a central venous catheter (CVC)-related sepsis

and a postpartum haemorrhage. We did not report any

adverse fetal outcome, defined as miscarriage, stillbirth,

preterm delivery or low birthweight; one baby was small

for gestational age. No major or minor birth defects were

detected. The delivery outcomes and pregnancy complica-

tions are presented in Table 4.

Discussion

Main findingsThe effect of TD clonidine is clear-cut, both on the main out-

comes (subjective assessment measures represented in

Figures 2 and 3) and on the secondary outcomes (objective

assessment measures). When on TD clonidine, women felt

better, reported less nausea and vomiting, and positive

morning ketonuria was less frequent. This improvement led

to a reduction of antiemetic drug doses and to a lesser need

for parenteral intravenous rehydration and drug therapy.

Overall, nine of 12 women showed a significant clinical

benefit during TD clonidine treatment. Moreover, the active

drug was significantly superior to placebo on other outcome

measures, such as the proportion of women wishing to con-

tinue treatment after the trial on a compassionate basis. The

use of TD clonidine was not associated with an increased rate

of any adverse effect as compared with the placebo.

Strengths and limitationsThe strengths of the study lie in the enrolment of severe,

unresponsive cases only, the racial and ethnic heterogeneity,

Table 2. Mean values and 95% confidence intervals for TD clonidine and placebo

Clonidine Placebo Mann–Whitney

U-test (P)

PUQE score 6.3 (5.5–7.1) 8.5 (7.7–9.3) 0.001

VAS score 22 (19–26) 29 (25–32) 0.009

Morning positive ketonuria 0.06 (0.04–0.18) 0.36 (0.24–0.47) 0.000

Parenteral drug daily doses 1.5 (1.1–2.9) 2.3 (1.9–3.0) 0.013

Number of days off-therapy 0.4 (0.28–0.54) 0.2 (0.09–0.36) 0.051

Systolic pressure, mmHg 91 (87–94) 97 (93–100) 0.010

Diastolic pressure, mmHg 58 (55–60) 61 (59–63) 0.055

Enrolment

Allocation

Follow-up

Analysis

Assessed for eligibility n. 13

Randomised n. 13Excluded n. 0

Clonidine first, n = 6Received allocated intervention, n = 6

Didn’t receive allocated intervention, n = 0

Placebo first, n = 7Received allocated intervention, n = 7


Lost at follow-up, n = 0Discontinued intervention, n = 0


(alleged side effects)

Analysed, n = 0 Analysed, n = 0



Placebo second, n = 6Received allocated intervention, n = 6


Clonidine second, n = 6Received allocated intervention, n = 6


Figure 1. Consort statement diagram flow (crossover design).

Table 3. Within–patient variation

Mean SD P-value 95% CI

PUQE score 1.8333 2.4802 0.026 0.43–3.24

VAS score 7.5 9.41 0.018 2.17–12.83



and the blinded placebo-controlled approach. The small

number of enrolled patients, the single hospital setting, the

use of a single fixed dosage, as no dose-response study is

currently available, and the limited period of observation

represent shortcomings of the study.

InterpretationClonidine is a centrally acting, alpha-2 adrenergic agonist

drug mainly used as an antihypertensive. It has been used

to treat hypertension in pregnancy and so far no increase

of birth defects after use in the first trimester has been

reported in international databases and registries. Other

indications, from a reduction in central adrenergic outflow,

are reported in recent literature: it has been effectively used

in the treatment of postoperative pain15, labour and deliv-

ery pain16, abstinence syndromes17, nervous tics and dysto-

nias18, menopausal vasomotor symptoms19 and,

interestingly, for prevention of postoperative nausea and

vomiting.20–22 Moreover, in some experimental animal

models, clonidine and other alpha-2 adrenergic agonists

has been effective in inhibiting the emetic response to

pharmacological stimulation.23 The mechanism underlying

the antiemetic effect is as yet unknown: it may involve a

direct effect on nausea and vomiting trigger zones in the

midbrain24 or a secondary effect with reduction of the level

of noradrenergic activation.25 In this context, the adrener-

gic overstimulation may be evoked in response to stressing

conditions of severe psychological sufferings connected

with the pregnancy (such as separation from family and

native country, inability to work, anger at being unwell,

guilt and resentment about the desire for pregnancy) which

are conveyed to the autonomous nervous system.

Table 4. Pregnancy outcomes

Major pregnancy complications 1 CVC-related sepsis

Fetal losses 0

Prematurity 0

Preeclampsia 0

Major complication at delivery 1 Postpartum

haemorrhage >2000 ml

Caesarean section 4

Mean gestational age at

delivery (weeks)

39.5 Range: 37–41

Mean birthweight (g) 3312 Range: 2510–4180

Number of pregnancies

delivered prematurely

0

Number of babies born

under the 5th percentile

1

Mean Apgar score at 1 minute 9

Mean Apgar score at 5 minutes 9

Major and minor congenital

birth defects

0

Figure 2. Motherisk PUQE scoring system.13,14

Figure 3. VAS score.11


Maina et al.

The study was devised to show the efficacy of TD cloni-

dine over placebo in a specific clinical setting while women

were allowed to receive the standard treatment. The sever-

ity of HG at enrolment was judged using an accepted and

validated index. The drug dose and duration of patch

application were decided on the basis of our preliminary

experience and the pharmacokinetics of the drug in preg-

nancy.26,27 The cross-over design of the study and the

pharmacodynamic features of the drug delivered by the TD

system, with more than 24 hours latency of effect after

positioning of patch and the persistence of effect after

removal, underscore the magnitude of efficacy measures of

20% (conservative assumption). Nevertheless, we describe a

manifest and unambiguous effect of TD clonidine; the

cross-over design of this study allowed successful differenti-

ation of the effect of the drug from that of placebo.

The results of our study may be interpreted taking into

account the effect of clonidine in other stressful conditions

with emetic response, such as postoperative nausea and

vomiting. However, findings based on a very limited num-

ber of women limit the reliability of results both for effi-

cacy and safety issues. There are two safety issues. One

issue is the effect of the drug when administered in the

phase of organogenesis, until the 12th week. This is par-

tially resolved by the fact that no birth defects have been

reported after long-term use of clonidine for treatment of

hypertension in pregnancy. The second issue is whether the

hypotensive action of this drug impacts negatively on fetus

health and growth: this point has been addressed by a work

recently published,28 but that study dealt with hypertensive

women and a different period of exposure.

Conclusions

Our findings indicate that, as used, TD clonidine is an effi-

cacious and well tolerated treatment for severe HG, leading

to a significant reduction of symptoms and reducing the

need of other supportive measures and medications. Apart

from a significant but well tolerated decrease in blood pres-

sure, no relevant side effects either in the mothers or in the

newborns were detected in the period of observation and

in the subsequent follow-up.

With the limitations described above, the Authors want

to make a strong point that the results should not immedi-

ately lead to changes in care and the indications remain

very limited. Caution should be exercised in prescribing the

drug, e.g. in severe and non-responsive cases, and all

patients should be monitored, supervising blood pressure

response and taking pregnancy outcome into account.

This off-label therapeutic indication of TD clonidine

warrants further studies. If the same results are confirmed

in different settings, TD clonidine should be offered as a

possible alternative therapy in severe HG. The efficacy of

clonidine casts a new light on the underlying pathophysiol-

ogy of HG: further studies are necessary to understand

which pathogenic mechanisms are most important with

regard to the antiemetic effects of clonidine in HG.

Disclosure of interestsAll authors declare: no support from any organisation for

the submitted work; no financial relationships with any or-

ganisations that might have an interest in the submitted

work in the previous 3 years. A.M declares that an Italian

patent application relating to the use of clonidine in the

therapeutic treatment of hyperemesis gravidarum is pend-

ing (Patent application No. TO2011A000230).

Contribution to authorshipAM conceived and designed the study, took part to clinical

routine and work up, wrote the draft of the paper. MA,

LC, VD, MM took part to clinical work up and data col-

lecting. TT acted as a guarantor and reviewed the draft. SR

carried out the statistical analysis. All authors approved the

final draft.

Details of ethics approvalComitato Etico Interaziendale Sant’Anna—Mauriziano.

Date of approval: 20 December 2011. Protocol Determina-

tion Reference n. 163, 21 February 2012.

FundingInsurance coverage was provided by a fund devolved to not-

for-profit studies by Azienda Ospedaliera OIRM—Sant’Anna.

AcknowledgementsWe are indebted to the women who participated in the study;

to Ms Marilisa Biolcati, who generated the random list and

assigned allocations; to Paolo Manzoni for helpful sugges-

tions in preparing the manuscript; to Jonathan Bestwick and

Nick Wald for advice on and review of statistical methods.&

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Maina et al.

transdermal clonidine in the treatment of severe hyperemesis. a pilot randomised control trial:...

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