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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.
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 .
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| clonidine first - placebo second | Other | in this group patients are treated with transdermal clonidine first for 5 days then switch to placebo for 5 days |
|
| placebo first - clonidine second | Other | in this group patients are treated with placebo first for 5 days then with transdermal clonidine for next 5 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clonidine | Drug | transdermal clonidine patch 5 mg q. 5 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| PUQE Score for Assessment of Severity in Hyperemesis Gravidarum | PUQE in an acronym for Pregnancy Unique Quantification of Emesis, a validated clinical score for assessment of severity of emesis in pregnancy. It is composed of three items; every item has a score from 1 (best) to 5 (worst). The sum range varies from 3 (best) to 15 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | Mean values of first period of five days are compared with mean values of second period of five days. Change is reported as baseline value - value at day 5 or at day 10. |
| VAS Score for Assessment of Severity in Hyperemesis Gravidarum | VAS is a Visual Analogic Scale formulated in 5 items. Every item has a score from 0 (best) to 10 (worst). The sum range swings from 0 (best ) to 50 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | Mean values of first period of five days are compared with mean values of second period of five days. Change is reported as baseline value - value at day 5 or at day 10. |
| Measure | Description | Time Frame |
|---|---|---|
| Morning Urine Ketonuria | Morning urine ketonuria is a simple direct marker of starving associated to nausea and vomiting | participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days |
| Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Aldo Maina, M.D. | Dipartimento di Ostetricia e Neonatologia. Servizio di Medicina Interna. Ospedale Sant'Anna Torino | Principal Investigator |
| Tullia Todros, M.D. | Head . Dipartimento di Ostetricia e Neonatologia. Università di Torino. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ospedale Sant'Anna. Dipartimento di Ostetricia e Neonatologia. Servizio di Medicina Interna | Torino | 10126 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24684734 | Derived | Maina A, Arrotta M, Cicogna L, Donvito V, Mischinelli M, Todros T, Rivolo S. Transdermal clonidine in the treatment of severe hyperemesis. A pilot randomised control trial: CLONEMESI. BJOG. 2014 Nov;121(12):1556-62. doi: 10.1111/1471-0528.12757. Epub 2014 Apr 1. |
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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.
Patients admitted to hospital for severe hyperemesis (HG) March - December 2012
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Placebo First - Clonidine Second |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | PUQE Score for Assessment of Severity in Hyperemesis Gravidarum | PUQE in an acronym for Pregnancy Unique Quantification of Emesis, a validated clinical score for assessment of severity of emesis in pregnancy. It is composed of three items; every item has a score from 1 (best) to 5 (worst). The sum range varies from 3 (best) to 15 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | 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. |
|
10 days of hospital stay
For 5 days the patient received TD clonidine, the other 5 days received placebo.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Clonidine | patients are treated with transdermal clonidine patch 5 mg for 5 days |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Itching | Skin and subcutaneous tissue disorders | Non-systematic Assessment | 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
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Aldo Maina M.D. Obstetric Medicine | Città della Salute e della Scienza Ospedale Sant'Anna. Servizio di Medicina Interna | 0039011313 | 5735 | amaina@cittadellasalute.to.it |
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| ID | Term |
|---|---|
| D006939 | Hyperemesis Gravidarum |
| ID | Term |
|---|---|
| D048968 | Morning Sickness |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D003000 | Clonidine |
| ID | Term |
|---|---|
| D048288 | Imidazolines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
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The patients were randomly treated with and without TD clonidine (5mg patch) for 2 consecutive periods of 5 days , other antiemetic drugs (promethazine, prochlorperazine, metoclopramide, ondansetron) and anti reflux drugs (ranitidine, omeprazole) being administered on a scheduled or as-needed basis. All patients received intravenous hydration and supplementation with thiamine, during both periods. The use of steroids was allowed as a rescue medication in case of further worsening of symptoms. |
| participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days |
| Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only | if the symptoms improve the patient and her doctors may decide to stop parenteral drugs continuing the TD system therapy. | participants are followed for the whole duration of hospital stay (10 days) comparing the first period of 5 days with the second period of 5 days |
| Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. | the patients were asked to choose between two transdermal systems (active drug versus placebo) as the most effective | at 10 days since start of treatment |
| Pregnancy Outcome Measures: Birth Weight. | Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG. | at delivery |
| Newborn Outcome Measure: APGAR Score. | The APGAR score is the most common indicator of neonatal status immediately after delivery. The test is done by a doctor, midwife, or nurse. The health care provider will examine the baby's: Breathing effort Heart rate Muscle tone Reflexes Skin color Each category is scored with 0, 1, or 2, depending on the observed condition. The APGAR rating is based on a total score of 1 to 10. The higher the score, the better the baby is doing after birth. | at 1 minute and at 5 minutes after delivery |
| Systolic Blood Pressure | Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days) | 10 days |
| Diastolic Blood Pressure | Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle | 10 days |
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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Clonidine |
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 |
| OG001 | 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 |
|
|
|
| Primary | VAS Score for Assessment of Severity in Hyperemesis Gravidarum | VAS is a Visual Analogic Scale formulated in 5 items. Every item has a score from 0 (best) to 10 (worst). The sum range swings from 0 (best ) to 50 (worst). Participants are followed for the whole duration of hospital stay (10 days) asking them to score their symptoms daily. | Posted | Mean | 95% Confidence Interval | units on a scale | Mean values of first period of five days are compared with mean values of second period of five days. Change is reported as baseline value - value at day 5 or at day 10. |
|
|
|
|
| Secondary | Morning Urine Ketonuria | Morning urine ketonuria is a simple direct marker of starving associated to nausea and vomiting | Posted | Mean | 95% Confidence Interval | Proportion of person-days | 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 |
|
|
|
|
| Secondary | Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. | The patients were randomly treated with and without TD clonidine (5mg patch) for 2 consecutive periods of 5 days , other antiemetic drugs (promethazine, prochlorperazine, metoclopramide, ondansetron) and anti reflux drugs (ranitidine, omeprazole) being administered on a scheduled or as-needed basis. All patients received intravenous hydration and supplementation with thiamine, during both periods. The use of steroids was allowed as a rescue medication in case of further worsening of symptoms. | Posted | Mean | 95% Confidence Interval | daily doses of antiemetics | 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 |
|
|
|
|
| Secondary | Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only | if the symptoms improve the patient and her doctors may decide to stop parenteral drugs continuing the TD system therapy. | Posted | Mean | 95% Confidence Interval | Proportion of person-days | 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 |
|
|
|
|
| Secondary | Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. | the patients were asked to choose between two transdermal systems (active drug versus placebo) as the most effective | no determination of sample size | Posted | Number | participants | at 10 days since start of treatment |
|
|
|
|
| Secondary | Pregnancy Outcome Measures: Birth Weight. | Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG. | no determination of sample size Recording for safety issue | Posted | Mean | Full Range | grams | at delivery |
|
|
|
| Secondary | Newborn Outcome Measure: APGAR Score. | The APGAR score is the most common indicator of neonatal status immediately after delivery. The test is done by a doctor, midwife, or nurse. The health care provider will examine the baby's: Breathing effort Heart rate Muscle tone Reflexes Skin color Each category is scored with 0, 1, or 2, depending on the observed condition. The APGAR rating is based on a total score of 1 to 10. The higher the score, the better the baby is doing after birth. | APGAR score of newborns at 1 minute and at 5 minutes | Posted | Mean | Full Range | units on a scale | at 1 minute and at 5 minutes after delivery |
|
|
|
| Secondary | Systolic Blood Pressure | Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days) | Posted | Mean | 95% Confidence Interval | mmHg | 10 days |
|
|
|
|
| Secondary | Diastolic Blood Pressure | Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle | Posted | Mean | 95% Confidence Interval | mmHg | 10 days |
|
|
|
|
| 0 |
| 6 |
| 0 |
| 6 |
| EG001 | Placebo | patients are treated with placebo (sham patch) for 5 days | 0 | 7 | 1 | 7 |
|
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| D014839 | Vomiting |
| D012817 | Signs and Symptoms, Digestive |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
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. |
| Wilcoxon (Mann-Whitney) |
| <0.01 |
| within patient variation |
| 7.5 |
| 2-Sided |
| 95 |
| 2.17 |
| 12.83 |
| Yes |
| Non-Inferiority or Equivalence |
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 |