Effectiveness of Acupuncture and Doxylamine/Pyridoxine for Moderate to Severe Nausea and Vomiting in Pregnancy

Study Overview
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Brief Summary
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Nausea and vomiting in pregnancy (NVP) is one of the most common symptoms of pregnancy affecting 50-85% of women during the first half of pregnancy. Maternal morbidity is common and includes psychological effects, financial burden, clinical complications from nutritional deficiencies, gastrointestinal trauma, and in rare cases, neurological damage. As the main means of alternative treatment, economical and easy to obtain; the clinical efficacy of acupuncture treatment of this disease has low level of evidence and needs to be reconfirmed. Doxylamine vitamin B6 sustained release tablets (Diclectin, combination of doxylamine succinate (10mg) and pyridoxine hydrochloride (10mg) are The American College of Obstetricians and Gynecologists recommends with Level A evidence the use of vitamin B6 in combination with doxylamine as first-line pharmacotherapy for treatment of NVP. The efficacy and safety of Diclectin has been confirmed in many years of research, but there is no evidence of high-level evidence-based medicine for the Chinese population. The purpose of this multicenter, randomized, double-blind, placebo-controlled trial was to investigate the efficacy and safety of acupuncture versus Diclectin in the treatment of NVP. We hypothesis that: (1)Sham acupuncture and Diclectin (Arm B) is more effective than sham acupuncture and placebo (Arm D); (2)Active acupuncture and placebo (Arm C) is more effective than sham acupuncture and placebo (Arm D); (3) There is no interaction (either synergistic or antagonistic effects) between the two interventions of active acupuncture and Diclectin in patients with NVP.

Detailed Description
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Subjects will be randomized into one of the four treatment arms: A) active acupuncture (30 min /every day) + Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg) , 2-4 tablets/day); B) sham acupuncture (30 min /every day) + Diclectin (2-4 tablets/day); C) active acupuncture (30 min / every day) + Diclectin placebo (2-4 tablets/day); D) sham acupuncture (30 min /every day) + Diclectin placebo (2-4 tablets/day). Participants will receive active acupuncture or sham acupuncture treatment daily, 14 times in total, and receive Diclectin or placebo treatment every day (2 tablets at bedtime for the first two days, if the symptoms are unrelieved, add one tablet in the morning, if the symptoms are still unrelieved, add another one tablet at three o 'clock in the afternoon) for 2 consecutive weeks, 28-56 tablets in total. Daily measurement PUQE score, Visual analog scale (VAS), Adverse events and concomitant medications. Weekly visits will include global assessment of well being, adverse events and concomitant medications. The visit after treatment will assess NVP quality of life (NVPQoL), SAS, SDS and so on. Participants will be followed up 30 days after treatment. Primary outcomes is difference of the mean change in PUQE score from baseline to the last visit. Secondary outcomes were some core outcome set for hyperemesis gravidarum, including weight difference, quality of life (change in Global assessment of well-being, NVPQOL, VAS, SDS and SAS), pregnancy complication, treatment compliance, neonatal outcomes; area under the curve of PUQE score, effect of intervention on PUQE score reduction over treatment period and adverse events.

Official Title
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Effectiveness of Acupuncture and Doxylamine/Pyridoxine for Moderate to Severe Nausea and Vomiting in Pregnancy: A Randomized Controlled Two-by-two Factorial Trial

Conditions
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Nausea and Vomiting of Pregnancy

Intervention / Treatment
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* Drug: Diclectin
* Drug: Diclectin placebo
* Device: Active acupuncture
* Device: Sham acupuncture


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with 20-45 years of age; PUQE score ≥6; 7-14 weeks of gestation with viable fetus inside the uterine cavity confirmed by ultrasound dating; Less than 20% weight loss. Exclusion Criteria: Having major medical problems such as malignant tumor, acute or subacute severe hepatitis, severe aplastic anemia, idiopathic thrombocytopenic purpura, acute appendicitis, acute pancreatitis, TORCH syndrome, etc Having chronic medical conditions such as poorly controlled diabetes, coronary heart disease, uncontrolled hypertension, etc Coexistence of other diseases that cause vomiting such as infectious disease, gestational trophoblastic disease, etc Having asthma, increased intraocular pressure, narrow-angle glaucoma, narrow peptic ulcer, pyloric obstruction, bladder neck obstruction, etc Taking antiemetics such as vitamin B6, ondansetron, metoclopramide, prednisone, anti-vomiting Chinese medicine, etc., within the past week Receiving conservative treatment such as dietary and lifestyle modification Abnormal physical examination and laboratory tests (minor abnormalities in laboratory tests due to pregnancy vomiting, such as liver function and ions, are acceptable for inclusion) Having mental handicaps or psychological disorders Allergic to doxylamine, other ethanolamine-derived antihistamines, pyridoxine hydrochloride, or any inactive ingredient in diclectin Using monoamine oxidase inhibitors Driving or operating heavy machinery Using alcohol or other central nervous system inhibitors

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Two by two factorial design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Diclectin plus active acupuncture<br>Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg) , 2-4 tablets/day) + active acupuncture (30 min /every day). | Drug: Diclectin<br>* Diclectin (combination of 10 mg doxylamine and 10 mg pyridoxine hydrochloride in a delayed release tablet) During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of Diclectin or placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.<br>Device: Active acupuncture<br>* Participants will receive active acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).<br>|
| Other: Diclectin plus sham acupuncture<br>Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg), 2-4 tablets/day) + sham acupuncture (30 min /every day). | Drug: Diclectin<br>* Diclectin (combination of 10 mg doxylamine and 10 mg pyridoxine hydrochloride in a delayed release tablet) During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of Diclectin or placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.<br>Device: Sham acupuncture<br>* Blunt-tipped placebo needles will be used. Participants will receive sham acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6). Then, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).<br>|
| Other: Placebo plus active acupuncture<br>Diclectin placebo (2-4 tablets/day) + active acupuncture (30 min / every day) | Drug: Diclectin placebo<br>* Diclectin placebo will be packed and tested by a commercial pharmacy supply company specifically for this study. It have the same appearance, size, batch, odor, and taste compared with Diclectin. During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.<br>Device: Active acupuncture<br>* Participants will receive active acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).<br>|
| Other: Placebo plus sham acupuncture<br>Diclectin placebo (2-4 tablets/day) + sham acupuncture (30 min /every day) | Drug: Diclectin placebo<br>* Diclectin placebo will be packed and tested by a commercial pharmacy supply company specifically for this study. It have the same appearance, size, batch, odor, and taste compared with Diclectin. During the first two days, patients will start with an initial oral dose of 2 tablets at bedtime. If the symptoms assessed on the second day are not relieved, 3 tablets will be administered on the third day (1 tablet in the morning and 2 tablets at bedtime). On the third day if the symptoms are still not relieved, another tablet will be added in the afternoon on the fourth day (1 tablet in the morning, 1 tablet in the afternoon and 2 tablets at bedtime). Therefore, the maximum assigned dosage of placebo tablets do not exceed 4 tablets per day. The treatment duration will lasts for 14 days.<br>Device: Sham acupuncture<br>* Blunt-tipped placebo needles will be used. Participants will receive sham acupuncture every day for 2 consecutive weeks, a total of 14 sessions. The needle will be left for 30 minutes. After de qi induced by acupuncture, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6). Then, the paired electrodes of the electroacupuncture device will be connected to the needle handle horizontally (except for PC6).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15 | Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15 | Baseline to day 15; Scores ranged 3 to 15, with higher scores indicating more | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score change of maternal weight from baseline to the last visit | Score change of maternal weight from baseline to the last visit | Baseline to day 15; no range of variation | 
| Change of electrolyte index (sodium) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (potassium) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (calcium) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (chlorine) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (phosphorus) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (magnesium) | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of electrolyte index (iron) | Value changes from baseline to last Visit. Unit: μmol/L | Baseline to day 15 | 
| Change of electrolyte index (zinc) | Value changes from baseline to last Visit. Unit: μmol/L | Baseline to day 15 | 
| Change of AST | Value changes from baseline to last Visit. Unit: U/L | Baseline to day 15 | 
| Change of ALT | Value changes from baseline to last Visit. Unit: U/L | Baseline to day 15 | 
| Change of ALP | Value changes from baseline to last Visit. Unit: U/L | Baseline to day 15 | 
| Change of creatinine | Value changes from baseline to last Visit. Unit: μmol/L | Baseline to day 15 | 
| Change of urea | Value changes from baseline to last Visit. Unit: mmol/L | Baseline to day 15 | 
| Change of TSH | Value changes from baseline to last Visit. Unit: mIU/L | Baseline to day 15 | 
| Change of free triiodothyronine | Value changes from baseline to last Visit. Unit: pmol/L | Baseline to day 15 | 
| Change of free thyroxine | Value changes from baseline to last Visit. Unit: pmol/L | Baseline to day 15 | 
| Change of vitamin b1 | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of vitamin b6 | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of vitamin b12 | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of cortisol | Value changes from baseline to last Visit. Unit: ug/dL | Baseline to day 15 | 
| Change of ghrelin | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of leptin | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of 5-hydroxytryptamine | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Change of substance P | Value changes from baseline to last Visit. Unit: pg/ml | Baseline to day 15 | 
| Change of arginine vasopressin plasma | Value changes from baseline to last Visit. Unit: pg/ml | Baseline to day 15 | 
| Change of GDF 15 | Value changes from baseline to last Visit. Unit: pg/ml | Baseline to day 15 | 
| Change of IGFBP 7 | Value changes from baseline to last Visit. Unit: ng/ml | Baseline to day 15 | 
| Intravenous fluid treatment during treatment | Intravenous fluid treatment during treatment | Baseline to day 15 | 
| Concomitant treatment | Concomitant treatment | Baseline to day 15 | 
| Hospital admission during treatment | Hospital admission during treatment | Baseline to day 15 | 
| Termination of pregnancy | Termination of pregnancy. If the patient is suffering further aggravation of hyperemesis gravidarum, the termination of a wanted pregnancy will be done due to life in danger. Or congenital anomalies are found by ultrasound, the termination of a wanted pregnancy will be done. | Data collected from baseline to the end of follow-up period (four weeks after the end of treatment). | 
| Maternal outcomes | Including pregnancy complications, termination of pregnancy and birth outcomes. Pregnancy complications including miscarriage (in the first trimester and in the second trimester), hypertensive disorders, and gestational diabetes; birth outcomes including live birth, vaginal delivery, cesarean section, gestational age, preterm, birth weight and small for gestational age. | Data collected from baseline to 42 days after postpartum. | 
| Patient satisfaction with treatment | Such as loss of confidence or intolerance to daily acupuncture and so on | Baseline to day 15 | 
| Treatment compliance | Such as the percentage of drug or needle used; or drug tablets or acupuncture sessions. | Baseline to day 15 | 
| Offspring outcomes | Including fetal and neonatal congenital anomalies, fetal and neonatal mortality, neonatal hypoglycemia and NICU admission. | Data collected from baseline to to 42 days after postpartum. | 
| Area under the curve (AUC) of PUQE score over treatment | Scores ranged 3 to 15, with higher scores indicating more severe NVP | Baseline to day 15 | 
| PUQE score reduction based on different TCM patterns | PUQE score reduction based on different TCM patterns | Scores ranged 3 to 15, with higher reduction indicating the better | 
| Adverse events and serious adverse events | The percentage of adverse events and serious adverse events | Baseline to the end of follow-up (four weeks after the end of treatment) | 
| Quality of life: NVPQoL | Range 30-210, high being poor QoL | Baseline to day 15 | 
| Quality of life: VAS | Ranged 0-10, high being more severe symptoms | Baseline to day 15 | 
| Quality of life: SDS | Range 25-10, high being more severe | Baseline to day 15 | 
| Quality of life: SAS | Range 25-100, high being more severe | Baseline to day 15 | 
| Quality of life: global assessment of well-being | Range 0-10, low being more severe | Baseline to day 15 | 
| PUQE score reduction at different levels of NVP | PUQE score reduction at different levels of NVP | Scores ranged 3 to 15, with higher reduction indicating the better | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nausea and Vomiting of Pregnancy, PUQE, Acupuncture, Diclectin