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Trial record 11 of 326 for:    clonidine

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

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ClinicalTrials.gov Identifier: NCT01559012
Recruitment Status : Completed
First Posted : March 20, 2012
Results First Posted : April 30, 2014
Last Update Posted : April 30, 2014
Sponsor:
Information provided by (Responsible Party):
Aldo Maina, Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hyperemesis Gravidarum
Intervention Drug: Clonidine
Enrollment 13
Recruitment Details Patients admitted to hospital for severe hyperemesis (HG) March - December 2012
Pre-assignment Details

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
Hide 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 [1]
Completed 6 6 [2]
Not Completed 0 1
Reason Not Completed
Withdrawal by Subject             0             1
[1]
1 more patient added to randomization list to reach the pre-assignment number of treated patients
[2]
Patient N. 2 withdrew from study for alleged side effects at day 1 of placebo cycle.
Arm/Group Title Clonidine First - Placebo Second Placebo First - Clonidine Second Total
Hide 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 Number of Baseline Participants 6 7 13
Hide Baseline Analysis Population Description
Baseline biophysical and demographic data were reported: age, race, ethnicity, parity, HG in previous pregnancy, smoking, BMI, weight loss, concurrent diseases, concurrent treatment,gestational age at start of symptoms, gestational age at enrollment, PUQE score at enrollment
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 7 participants 13 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
6
 100.0%
7
 100.0%
13
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 7 participants 13 participants
31.8  (5.46) 32.3  (5.99) 32.1  (5.51)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 7 participants 13 participants
Female
6
 100.0%
7
 100.0%
13
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Italy Number Analyzed 6 participants 7 participants 13 participants
6 7 13
1.Primary Outcome
Title PUQE Score for Assessment of Severity in Hyperemesis Gravidarum
Hide 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.
Hide Outcome Measure Data
Hide 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
Hide 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

Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
6.3
(5.5 to 7.1)
8.5
(7.7 to 9.3)
Show Statistical Analysis 1 Hide 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 [Not Specified]
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 [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter within patient variation
Estimated Value 1.83
Confidence Interval (2-Sided) 95%
0.43 to 3.24
Estimation Comments [Not Specified]
2.Primary Outcome
Title VAS Score for Assessment of Severity in Hyperemesis Gravidarum
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide 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

Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
22
(19 to 26)
29
(25 to 32)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7
Confidence Interval (2-Sided) 95%
1.78 to 11.5
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide 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 [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter within patient variation
Estimated Value 7.5
Confidence Interval (2-Sided) 95%
2.17 to 12.83
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Morning Urine Ketonuria
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide 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

Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: Proportion of person-days
0.06
(0.04 to 0.18)
0.36
(0.24 to 0.47)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.000
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter difference of percentage of positivity
Estimated Value 0.30
Confidence Interval (2-Sided) 95%
0.04 to 0.47
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide 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

Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: daily doses of antiemetics
1.5
(1.1 to 2.9)
2.3
(1.9 to 3.0)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter mean values
Estimated Value 0.8
Confidence Interval (2-Sided) 95%
0.13 to 1.57
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide 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
Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: Proportion of person-days
0.40
(0.28 to 0.54)
0.20
(0.09 to 0.36)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.051
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter days off-therapy %
Estimated Value 29
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Patients Choosing Active Treatment for Off-label, Compassionate Use.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
no determination of sample size
Arm/Group Title Clonidine Placebo
Hide 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
Overall Number of Participants Analyzed 12 12
Measure Type: Number
Unit of Measure: participants
9 3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clonidine, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0089
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter proportion
Estimated Value 0
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Pregnancy Outcome Measures: Birth Weight.
Hide Description Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG.
Time Frame at delivery
Hide Outcome Measure Data
Hide Analysis Population Description
no determination of sample size Recording for safety issue
Arm/Group Title Mean Birth Weight of 12 Patients
Hide 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

Overall Number of Participants Analyzed 12
Mean (Full Range)
Unit of Measure: grams
3312
(2510 to 4180)
8.Secondary Outcome
Title Newborn Outcome Measure: APGAR Score.
Hide 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
Hide Outcome Measure Data
Hide 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'
Hide 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
Overall Number of Participants Analyzed 12 12
Mean (Full Range)
Unit of Measure: units on a scale
9
(9 to 9)
9
(9 to 9)
9.Secondary Outcome
Title Systolic Blood Pressure
Hide Description Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days)
Time Frame 10 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide Arm/Group Description:
systolic blood pressure was recorded during clonidine treatment cycle
systolic blood pressure was recorded during placebo cycle
Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: mmHg
91
(87 to 94)
97
(93 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clonidine, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 6
Confidence Interval (2-Sided) 95%
0.9 to 10.9
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Diastolic Blood Pressure
Hide Description Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle
Time Frame 10 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Clonidine Placebo
Hide Arm/Group Description:
diastolic blood pressure was recorded every day during clonidine treatment cycle
diastolic blood pressure was recorded every day during placebo cycle
Overall Number of Participants Analyzed 12 12
Mean (95% Confidence Interval)
Unit of Measure: mmHg
58
(55 to 60)
61
(59 to 63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clonidine, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.055
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3
Confidence Interval (2-Sided) 95%
0.3 to 6.3
Estimation Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Clonidine Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/6 (0.00%)      0/7 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Clonidine Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/6 (0.00%)      1/7 (14.29%)    
Skin and subcutaneous tissue disorders     
Itching * [1]  0/6 (0.00%)  0 1/7 (14.29%)  1
*
Indicates events were collected by non-systematic assessment
[1]
Itching was reported at day 1 on site of application of sham patch

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

Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Aldo Maina M.D. Obstetric Medicine
Organization: Città della Salute e della Scienza Ospedale Sant'Anna. Servizio di Medicina Interna
Phone: 0039011313 ext 5735
EMail: amaina@cittadellasalute.to.it
Layout table for additonal information
Responsible Party: Aldo Maina, Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
ClinicalTrials.gov Identifier: NCT01559012     History of Changes
Other Study ID Numbers: Registro CE 409 det. 163/2012
First Submitted: March 12, 2012
First Posted: March 20, 2012
Results First Submitted: February 12, 2014
Results First Posted: April 30, 2014
Last Update Posted: April 30, 2014