Hyperemesis Gravidarum
Conditions
Keywords
Hyperemesis Gravidarum, treatment, transdermal clonidine
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.
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 .
Interventions
DRUGClonidine
transdermal clonidine patch 5 mg q. 5 days
Sponsors
A.O.U. Città della Salute e della Scienza
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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 |
| Systolic Blood Pressure | 10 days | Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days) |
| Diastolic Blood Pressure | 10 days | Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle |
| 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. |
| 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. |
Countries
Italy
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 6 |
| 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 | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo First - Clonidine Second | Clonidine First - Placebo Second | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Continuous | 32.3 years STANDARD_DEVIATION 5.99 | 31.8 years STANDARD_DEVIATION 5.46 | 32.1 years STANDARD_DEVIATION 5.51 |
| Region of Enrollment Italy | 7 participants | 6 participants | 13 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 1 / 7 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 |
Outcome results
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.
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.
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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | PUQE Score for Assessment of Severity in Hyperemesis Gravidarum | 6.3 units on a scale |
| Placebo | PUQE Score for Assessment of Severity in Hyperemesis Gravidarum | 8.5 units on a scale |
Comparison: 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.p-value: 0.00195% CI: [1.05, 3.32]Wilcoxon (Mann-Whitney)
Comparison: 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).p-value: <0.0295% CI: [0.43, 3.24]Wilcoxon (Mann-Whitney)
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.
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clonidine | VAS Score for Assessment of Severity in Hyperemesis Gravidarum | 22 units on a scale | — |
| Placebo | VAS Score for Assessment of Severity in Hyperemesis Gravidarum | 29 units on a scale | 95% Confidence Interval 2.58 |
Comparison: 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. .p-value: 0.00995% CI: [1.78, 11.5]Wilcoxon (Mann-Whitney)
Comparison: 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.p-value: <0.0195% CI: [2.17, 12.83]Wilcoxon (Mann-Whitney)
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.
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. | 1.5 daily doses of antiemetics |
| Placebo | Daily Doses of Standard Antiemetic Drugs Required in the Two Different Periods. | 2.3 daily doses of antiemetics |
Comparison: 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. .p-value: 0.01395% CI: [0.13, 1.57]Wilcoxon (Mann-Whitney)
Secondary
Diastolic Blood Pressure
Diastolic BP was recorded every day during clonidine (5 days) and placebo (5 days) cycle
Time frame: 10 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Diastolic Blood Pressure | 58 mmHg |
| Placebo | Diastolic Blood Pressure | 61 mmHg |
p-value: 0.05595% CI: [0.3, 6.3]Wilcoxon (Mann-Whitney)
Secondary
Morning Urine Ketonuria
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Morning Urine Ketonuria | 0.06 Proportion of person-days |
| Placebo | Morning Urine Ketonuria | 0.36 Proportion of person-days |
Comparison: All patients were treated with TD clonidine for 5 days and switched to placebo for 5 days, or the other way round~Allocation order randomizedp-value: 095% CI: [0.04, 0.47]Wilcoxon (Mann-Whitney)
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.
Time frame: at 1 minute and at 5 minutes after delivery
Population: APGAR score of newborns at 1 minute and at 5 minutes
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Newborn Outcome Measure: APGAR Score. | 9 units on a scale |
| Placebo | Newborn Outcome Measure: APGAR Score. | 9 units on a scale |
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.
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only | 0.40 Proportion of person-days |
| Placebo | Number of Days Off i.v. Therapy, the TD System (Clonidine/Placebo) Being Applied Only | 0.20 Proportion of person-days |
Comparison: 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. .p-value: 0.051Wilcoxon (Mann-Whitney)
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
Time frame: at 10 days since start of treatment
Population: no determination of sample size
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clonidine | Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. | 9 participants |
| Placebo | Number of Patients Choosing Active Treatment for Off-label, Compassionate Use. | 3 participants |
p-value: 0.0089Fisher Exact
Secondary
Pregnancy Outcome Measures: Birth Weight.
Birth weight adjusted for gestational age at delivery is a measure of pregnancy outcome after treatment of HG.
Time frame: at delivery
Population: no determination of sample size Recording for safety issue
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Pregnancy Outcome Measures: Birth Weight. | 3312 grams |
Secondary
Systolic Blood Pressure
Systolic BP was measured every day during the clonidine treatment (5 days) and placebo (5 days)
Time frame: 10 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Systolic Blood Pressure | 91 mmHg |
| Placebo | Systolic Blood Pressure | 97 mmHg |
p-value: 0.0195% CI: [0.9, 10.9]Wilcoxon (Mann-Whitney)