CLONEMESI: Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum

• Sponsor: Azienda Ospedaliera Città della Salute e della Scienza di Torino (Other)
• Overall Status: Completed
• CT.gov ID: NCT01559012
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 10
• Patients Per Site Per Month: 1.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hyperemesis Gravidarum	Drug: Clonidine	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The CLONEMESI Study: a Randomized Placebo-controlled Study With Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum.
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. PUQE Score for Assessment of Severity in Hyperemesis Gravidarum [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.]

   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.

2. VAS Score for Assessment of Severity in Hyperemesis Gravidarum [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.

Secondary Outcome Measures

1. Morning Urine Ketonuria [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

2. Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. [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.

3. Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only [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.

4. Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. [at 10 days since start of treatment]

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

5. Pregnancy Outcome Measures: Birth Weight. [at delivery]

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

6. Newborn Outcome Measure: APGAR Score. [at 1 minute and at 5 minutes after delivery]

   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.

7. Systolic Blood Pressure [10 days]

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

8. Diastolic Blood Pressure [10 days]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale Sant'Anna. Dipartimento di Ostetricia e Neonatologia. Servizio di Medicina Interna	Torino		Italy	10126

Sponsors and Collaborators

• 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.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Aldo Maina, M.D. Unit of Obstetric Medicine. Principal Investigator, Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
• ClinicalTrials.gov Identifier: NCT01559012
• Other Study ID Numbers: Registro CE 409 det. 163/2012
• First Posted: Mar 20, 2012
• Last Update Posted: Apr 30, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Aldo Maina, M.D. Unit of Obstetric Medicine. Principal Investigator, Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna: Hyperemesis Gravidarum; treatment; transdermal clonidine
• Additional relevant MeSH terms: Hyperemesis Gravidarum; Clonidine

Study Results

Participant Flow

Recruitment Details	Patients admitted to hospital for severe hyperemesis (HG) March - December 2012
Pre-assignment Detail	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.

Arm/Group Title	Clonidine First - Placebo Second	Placebo First - Clonidine Second
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	6	7
COMPLETED	6	6
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Clonidine First - Placebo Second	Placebo First - Clonidine Second	Total
Arm/Group Description	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	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 of all reporting groups
Overall Participants	6	7	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	7 100%	13 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.8 (5.46)	32.3 (5.99)	32.1 (5.51)
Sex: Female, Male (Count of Participants)
Female	6 100%	7 100%	13 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Italy	6 100%	7 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	PUQE Score for Assessment of Severity in Hyperemesis Gravidarum
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	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	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
Measure Participants	12	12
Mean (95% Confidence Interval) [units on a scale]	6.3 (5.5-7.11)	8.5 (7.3-9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	This is an analysis between groups of intervention clonidine versus placebo. Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean + SD.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	A sample size modeling (MGH Mallinckrodt General Clinical Research Center) 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.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Statistical significance was assessed by the use of Mann-Whitney U test. P < 0.05 was defined as statistically significant
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; 1.05 to 3.32
	Parameter Dispersion	Type: Standard Deviation; Value: 2.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	This is a within patient variation between clonidine and placebo. Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean +/- Standard Deviation (SD).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A sample size modeling (MGH Mallinckrodt General Clinical Research Center) 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
Statistical Test of Hypothesis	p-Value	<0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	within patient variation
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 0.43 to 3.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	VAS Score for Assessment of Severity in Hyperemesis Gravidarum
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	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	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
Measure Participants	12	12
Mean (95% Confidence Interval) [units on a scale]	22	29 (2.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	Analysis within groups clonidine versus placebo. Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean + SD. .
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7
	Confidence Interval	(2-Sided) 95%; 1.78 to 11.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	Analysis within-patient. Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean + SD.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A sample size modeling for crossover studies (MGH Mallinckrodt General Clinical Research Center) 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
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	within patient variation
	Estimated Value	7.5
	Confidence Interval	(2-Sided) 95%; 2.17 to 12.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Morning Urine Ketonuria
Description	Morning urine ketonuria is a simple direct marker of starving associated to nausea and vomiting
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round Allocation order randomized	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round Allocation order randomized
Measure Participants	12	12
Mean (95% Confidence Interval) [Proportion of person-days]	0.06	0.36

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round Allocation order randomized
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	difference of percentage of positivity
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods.
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round Clonidine : transdermal clonidine patch 5 mg q. 5 days
Measure Participants	12	12
Mean (95% Confidence Interval) [daily doses of antiemetics]	1.5	2.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean + SD. .
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	mean values
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.13 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only
Description	if the symptoms improve the patient and her doctors may decide to stop parenteral drugs continuing the TD system therapy.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round.	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round
Measure Participants	12	12
Mean (95% Confidence Interval) [Proportion of person-days]	0.40	0.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments	Statistical significance was assessed by the use of Mann-Whitney U test P < 0.05 was defined as statistically significant . Data are presented as mean + SD. .
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.051
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	days off-therapy %
	Estimated Value	29
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Patients Choosing Active Treatment for Off-label, Compassionate Use.
Description	the patients were asked to choose between two transdermal systems (active drug versus placebo) as the most effective
Time Frame	at 10 days since start of treatment

Outcome Measure Data

Analysis Population Description

no determination of sample size

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round
Measure Participants	12	12
Number [participants]	9 150%	3 42.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	proportion
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Pregnancy Outcome Measures: Birth Weight.
Description	Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG.
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

no determination of sample size Recording for safety issue

Arm/Group Title	Mean Birth Weight of 12 Patients
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round Allocation order randomized
Measure Participants	12
Mean (Full Range) [grams]	3312

8. Secondary Outcome

Title	Newborn Outcome Measure: APGAR Score.
Description	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.
Time Frame	at 1 minute and at 5 minutes after delivery

Outcome Measure Data

Analysis Population Description

APGAR score of newborns at 1 minute and at 5 minutes

Arm/Group Title	APGAR Score at 1'	APGAR Score at 5'
Arm/Group Description	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round	All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round
Measure Participants	12	12
Mean (Full Range) [units on a scale]	9	9

9. Secondary Outcome

Title	Systolic Blood Pressure
Description	Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days)
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	systolic blood pressure was recorded during clonidine treatment cycle	systolic blood pressure was recorded during placebo cycle
Measure Participants	12	12
Mean (95% Confidence Interval) [mmHg]	91	97

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; 0.9 to 10.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Diastolic Blood Pressure
Description	Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Clonidine	Placebo
Arm/Group Description	diastolic blood pressure was recorded every day during clonidine treatment cycle	diastolic blood pressure was recorded every day during placebo cycle
Measure Participants	12	12
Mean (95% Confidence Interval) [mmHg]	58	61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Clonidine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3
	Confidence Interval	(2-Sided) 95%; 0.3 to 6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	10 days of hospital stay
Adverse Event Reporting Description	For 5 days the patient received TD clonidine, the other 5 days received placebo.
Arm/Group Title	Clonidine		Placebo
Arm/Group Description	patients are treated with transdermal clonidine patch 5 mg for 5 days		patients are treated with placebo (sham patch) for 5 days
All Cause Mortality
	Clonidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clonidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Clonidine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Itching	0/6 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

Efficacy and safety issues are represented by maternal exposure in a critical period for organogenesis and hypotensive effect of the drug. Findings based on a very limited number of women limit the reliability of results

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.