Trial Outcomes & Findings for Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum (NCT NCT01559012)

NCT ID: NCT01559012

Last Updated: 2014-04-30

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 13 participants
• Primary outcome timeframe: 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.
• Results posted on: 2014-04-30

Participant Flow

Patients admitted to hospital for severe hyperemesis (HG) March - December 2012

The crossover study design allows to compare in the same patient the response to different treatment schedules. The assumption is that the condition treated is not changing over the time of observation. The reported evidence in literature is that severe HG does not spontaneously improve till 14th week.

Participant milestones

Measure	Clonidine First - Placebo Second in this group patients are treated with TD clonidine first for 5 days then switch to placebo for 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days	Placebo First - Clonidine Second in this group patients are treated with placebo first for 5 days then with TD clonidine for next 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days
Overall Study STARTED	6	7
Overall Study COMPLETED	6	6
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Measure	Clonidine First - Placebo Second in this group patients are treated with TD clonidine first for 5 days then switch to placebo for 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days	Placebo First - Clonidine Second in this group patients are treated with placebo first for 5 days then with TD clonidine for next 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum

Baseline characteristics by cohort

Measure	Clonidine First - Placebo Second n=6 Participants in this group patients are treated with TD clonidine first for 5 days then switch to placebo for 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days	Placebo First - Clonidine Second n=7 Participants in this group patients are treated with placebo first for 5 days then with TD clonidine for next 5 days Clonidine : transdermal clonidine patch 5 mg q. 5 days	Total n=13 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	31.8 years STANDARD_DEVIATION 5.46 • n=5 Participants	32.3 years STANDARD_DEVIATION 5.99 • n=7 Participants	32.1 years STANDARD_DEVIATION 5.51 • n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Italy	6 participants n=5 Participants	7 participants n=7 Participants	13 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Population: A sample size calculation for crossover studies using a model available on line (MGH Mallinckrodt General Clinical Research Center - Harvard Medical School) showed that a total of 12 patients were needed in order to detect a difference of 2 points of PUQE score between the two groups at P \< 0.01 and a beta \> 0.90.

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.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
PUQE Score for Assessment of Severity in Hyperemesis Gravidarum	6.3 units on a scale 95% Confidence Interval 5.5-7.11 • Interval 5.5 to 7.1	8.5 units on a scale 95% Confidence Interval 7.3-9.3 • Interval 7.7 to 9.3

PRIMARY outcome

Timeframe: 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 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.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
VAS Score for Assessment of Severity in Hyperemesis Gravidarum	22 units on a scale Interval 19.0 to 26.0	29 units on a scale 95% Confidence Interval 2.58 • Interval 25.0 to 32.0

SECONDARY outcome

Timeframe: 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

Morning urine ketonuria is a simple direct marker of starving associated to nausea and vomiting

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Morning Urine Ketonuria	0.06 Proportion of person-days Interval 0.04 to 0.18	0.36 Proportion of person-days Interval 0.24 to 0.47

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods.	1.5 daily doses of antiemetics Interval 1.1 to 2.9	2.3 daily doses of antiemetics Interval 1.9 to 3.0

SECONDARY outcome

Timeframe: 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

if the symptoms improve the patient and her doctors may decide to stop parenteral drugs continuing the TD system therapy.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only	0.40 Proportion of person-days Interval 0.28 to 0.54	0.20 Proportion of person-days Interval 0.09 to 0.36

SECONDARY outcome

Timeframe: at 10 days since start of treatment

Population: no determination of sample size

the patients were asked to choose between two transdermal systems (active drug versus placebo) as the most effective

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Number of Patients Choosing Active Treatment for Off-label, Compassionate Use.	9 participants	3 participants

SECONDARY outcome

Timeframe: at delivery

Population: no determination of sample size Recording for safety issue

Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Pregnancy Outcome Measures: Birth Weight.	3312 grams Interval 2510.0 to 4180.0	—

SECONDARY outcome

Timeframe: at 1 minute and at 5 minutes after delivery

Population: APGAR score of newborns at 1 minute and at 5 minutes

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.

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Newborn Outcome Measure: APGAR Score.	9 units on a scale Interval 9.0 to 9.0	9 units on a scale Interval 9.0 to 9.0

SECONDARY outcome

Timeframe: 10 days

Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days)

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Systolic Blood Pressure	91 mmHg Interval 87.0 to 94.0	97 mmHg Interval 93.0 to 100.0

SECONDARY outcome

Timeframe: 10 days

Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle

Outcome measures

Measure	Clonidine n=12 Participants Six patients are treated with TD clonidine first for 5 days then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized. Every patient is the comparison as to herself	Placebo n=12 Participants Six patients are treated with TD clonidine first,for 5 days, then switch to placebo for next 5 days Other six patients are treated with placebo first, for 5 days, then are switched to TD clonidine for next 5 days. The allocation order for every patient is randomized Every patient is the comparison as to herself
Diastolic Blood Pressure	58 mmHg Interval 55.0 to 60.0	61 mmHg Interval 59.0 to 63.0

Adverse Events

Clonidine

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Clonidine n=6 participants at risk patients are treated with transdermal clonidine patch 5 mg for 5 days	Placebo n=7 participants at risk patients are treated with placebo (sham patch) for 5 days
Skin and subcutaneous tissue disorders Itching	0.00% 0/6 • 10 days of hospital stay For 5 days the patient received TD clonidine, the other 5 days received placebo.	14.3% 1/7 • Number of events 1 • 10 days of hospital stay For 5 days the patient received TD clonidine, the other 5 days received placebo.

Additional Information

Dr. Aldo Maina M.D. Obstetric Medicine

Città della Salute e della Scienza Ospedale Sant'Anna. Servizio di Medicina Interna

Phone: 0039011313

Email: amaina@cittadellasalute.to.it

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place