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

Sponsor

Xiaoke Wu (Other)

Overall Status

Completed

CT.gov ID

NCT04401384

Collaborator

Ningxia Hui Autonomous Region Hospital of TCM (Other), Jiangxi Maternal and Child Health Hospital (Other), Jixi Maternal and Child Health Hospital (Other), Luoyang Hospital of TCM (Other), Xuzhou Central Hospital (Other), First Affiliated Hospital of Heilongjiang Chinese Medicine University (Other), Shuangyashan Maternal and Child Health Hospital (Other), Heilongjiang provincial hospital (Other), Jiamusi Maternal and Child Health Hospital (Other), Hegang Maternal and Child Health Hospital (Other), Suihua Maternal and Child Health Hospital (Other), Mudanjaing Maternal and Child Health Hospital (Other), Affiliated Hospital of Jiamusi Medical University (Other)

352

Enrollment

Locations

Arms

19.4

Actual Duration (Months)

27.1

Patients Per Site

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Nausea and Vomiting of Pregnancy	Drug: Diclectin Drug: Diclectin placebo Device: Active acupuncture Device: Sham acupuncture	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

352 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

Two by two factorial designTwo by two factorial design

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 21, 2020

Actual Primary Completion Date :

Jun 23, 2021

Actual Study Completion Date :

Jan 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Diclectin plus active acupuncture Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg) , 2-4 tablets/day) + active acupuncture (30 min /every day).	Drug: Diclectin 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. Device: Active acupuncture 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).
Other: Diclectin plus sham acupuncture Diclectin (combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg), 2-4 tablets/day) + sham acupuncture (30 min /every day).	Drug: Diclectin 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. Device: Sham acupuncture 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).
Other: Placebo plus active acupuncture Diclectin placebo (2-4 tablets/day) + active acupuncture (30 min / every day)	Drug: Diclectin placebo 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. Device: Active acupuncture 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).
Other: Placebo plus sham acupuncture Diclectin placebo (2-4 tablets/day) + sham acupuncture (30 min /every day)	Drug: Diclectin placebo 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. Device: Sham acupuncture 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).

Outcome Measures

Primary Outcome Measures

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]
Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15

Secondary Outcome Measures

Score change of maternal weight from baseline to the last visit [Baseline to day 15; no range of variation]
Score change of maternal weight from baseline to the last visit
Change of electrolyte index (sodium) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (potassium) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (calcium) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (chlorine) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (phosphorus) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (magnesium) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of electrolyte index (iron) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: μmol/L
Change of electrolyte index (zinc) [Baseline to day 15]
Value changes from baseline to last Visit. Unit: μmol/L
Change of AST [Baseline to day 15]
Value changes from baseline to last Visit. Unit: U/L
Change of ALT [Baseline to day 15]
Value changes from baseline to last Visit. Unit: U/L
Change of ALP [Baseline to day 15]
Value changes from baseline to last Visit. Unit: U/L
Change of creatinine [Baseline to day 15]
Value changes from baseline to last Visit. Unit: μmol/L
Change of urea [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mmol/L
Change of TSH [Baseline to day 15]
Value changes from baseline to last Visit. Unit: mIU/L
Change of free triiodothyronine [Baseline to day 15]
Value changes from baseline to last Visit. Unit: pmol/L
Change of free thyroxine [Baseline to day 15]
Value changes from baseline to last Visit. Unit: pmol/L
Change of vitamin b1 [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of vitamin b6 [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of vitamin b12 [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of cortisol [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ug/dL
Change of ghrelin [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of leptin [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of 5-hydroxytryptamine [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Change of substance P [Baseline to day 15]
Value changes from baseline to last Visit. Unit: pg/ml
Change of arginine vasopressin plasma [Baseline to day 15]
Value changes from baseline to last Visit. Unit: pg/ml
Change of GDF 15 [Baseline to day 15]
Value changes from baseline to last Visit. Unit: pg/ml
Change of IGFBP 7 [Baseline to day 15]
Value changes from baseline to last Visit. Unit: ng/ml
Intravenous fluid treatment during treatment [Baseline to day 15]
Intravenous fluid treatment during treatment
Concomitant treatment [Baseline to day 15]
Concomitant treatment
Hospital admission during treatment [Baseline to day 15]
Hospital admission during treatment
Termination of pregnancy [Data collected from baseline to the end of follow-up period (four weeks after the end of treatment).]
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.
Maternal outcomes [Data collected from baseline to 42 days after postpartum.]
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.
Patient satisfaction with treatment [Baseline to day 15]
Such as loss of confidence or intolerance to daily acupuncture and so on
Treatment compliance [Baseline to day 15]
Such as the percentage of drug or needle used; or drug tablets or acupuncture sessions.
Offspring outcomes [Data collected from baseline to to 42 days after postpartum.]
Including fetal and neonatal congenital anomalies, fetal and neonatal mortality, neonatal hypoglycemia and NICU admission.
Area under the curve (AUC) of PUQE score over treatment [Baseline to day 15]
Scores ranged 3 to 15, with higher scores indicating more severe NVP
PUQE score reduction based on different TCM patterns [Scores ranged 3 to 15, with higher reduction indicating the better]
PUQE score reduction based on different TCM patterns
Adverse events and serious adverse events [Baseline to the end of follow-up (four weeks after the end of treatment)]
The percentage of adverse events and serious adverse events
Quality of life: NVPQoL [Baseline to day 15]
Range 30-210, high being poor QoL
Quality of life: VAS [Baseline to day 15]
Ranged 0-10, high being more severe symptoms
Quality of life: SDS [Baseline to day 15]
Range 25-10, high being more severe
Quality of life: SAS [Baseline to day 15]
Range 25-100, high being more severe
Quality of life: global assessment of well-being [Baseline to day 15]
Range 0-10, low being more severe
PUQE score reduction at different levels of NVP [Scores ranged 3 to 15, with higher reduction indicating the better]
PUQE score reduction at different levels of NVP

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	First Affiliated Hospital of Heilongjiang Chinese Medicine University	Harbin	Heilongjiang	China
2	Heilongjiang provincial hospital	Harbin	Heilongjiang	China
3	Hegang Maternal and Child Health Hospital	Hegang	Heilongjiang	China
4	Affiliated Hospital of Jiamusi Medical University	Jiamusi	Heilongjiang	China
5	Jiamusi Maternal and Child Health Hospital	Jiamusi	Heilongjiang	China
6	Jixi Maternal and Child Health Hospital	Jixi	Heilongjiang	China
7	Mudanjaing Maternal and Child Health Hospital	Mudanjiang	Heilongjiang	China
8	Shuangyashan Maternal and Child Health Hospital	Shuangyashan	Heilongjiang	China
9	Suihua Maternal and Child Health Hospital	Suihua	Heilongjing	China
10	Luoyang Hospital of TCM	Luoyang	Henan	China
11	Xuzhou Central Hospital	Xuzhou	Jiangsu	China
12	Jiangxi Maternal and Child Health Hospital	Nanchang	Jiangxi	China
13	Ningxia Hui Autonomous Region Hospital of TCM	Yinchuan	Ningxia Hui Autonomous Region	China