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

Nausea and Vomiting of Pregnancy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04401384
• Other study ID #: NVPAct
• Status: Completed
• Phase: Phase 3
• Start date: June 21, 2020
• Est. completion date: January 31, 2022

Study information

• Verified date: March 2022
• Source: Heilongjiang University of Chinese Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 352
• Est. completion date: January 31, 2022
• Est. primary completion date: June 23, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Women with 20-45 years of age;

2. PUQE score =6;

3. 7-14 weeks of gestation with viable fetus inside the uterine cavity confirmed by ultrasound dating;

4. Less than 20% weight loss.

Exclusion Criteria:

1. 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

2. Having chronic medical conditions such as poorly controlled diabetes, coronary heart disease, uncontrolled hypertension, etc

3. Coexistence of other diseases that cause vomiting such as infectious disease, gestational trophoblastic disease, etc

4. Having asthma, increased intraocular pressure, narrow-angle glaucoma, narrow peptic ulcer, pyloric obstruction, bladder neck obstruction, etc

5. Taking antiemetics such as vitamin B6, ondansetron, metoclopramide, prednisone, anti-vomiting Chinese medicine, etc., within the past week

6. Receiving conservative treatment such as dietary and lifestyle modification

7. 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)

8. Having mental handicaps or psychological disorders

9. Allergic to doxylamine, other ethanolamine-derived antihistamines, pyridoxine hydrochloride, or any inactive ingredient in diclectin

10. Using monoamine oxidase inhibitors

11. Driving or operating heavy machinery

12. Using alcohol or other central nervous system inhibitors

Related Conditions & MeSH terms

• Nausea
• Nausea and Vomiting of Pregnancy
• Vomiting

Intervention

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.
• 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).
• 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).

Locations

Country	Name	City	State
China	First Affiliated Hospital of Heilongjiang Chinese Medicine University	Harbin	Heilongjiang
China	Heilongjiang provincial hospital	Harbin	Heilongjiang
China	Hegang Maternal and Child Health Hospital	Hegang	Heilongjiang
China	Affiliated Hospital of Jiamusi Medical University	Jiamusi	Heilongjiang
China	Jiamusi Maternal and Child Health Hospital	Jiamusi	Heilongjiang
China	Jixi Maternal and Child Health Hospital	Jixi	Heilongjiang
China	Luoyang Hospital of TCM	Luoyang	Henan
China	Mudanjaing Maternal and Child Health Hospital	Mudanjiang	Heilongjiang
China	Jiangxi Maternal and Child Health Hospital	Nanchang	Jiangxi
China	Shuangyashan Maternal and Child Health Hospital	Shuangyashan	Heilongjiang
China	Suihua Maternal and Child Health Hospital	Suihua	Heilongjing
China	Xuzhou Central Hospital	Xuzhou	Jiangsu
China	Ningxia Hui Autonomous Region Hospital of TCM	Yinchuan	Ningxia Hui Autonomous Region

Sponsors (14)

Lead Sponsor

Collaborator

Xiaoke Wu

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

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Change of electrolyte index (sodium)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (potassium)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (calcium)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (chlorine)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (phosphorus)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (magnesium)	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of electrolyte index (iron)	Value changes from baseline to last Visit. Unit: µmol/L	Baseline to day 15
Secondary	Change of electrolyte index (zinc)	Value changes from baseline to last Visit. Unit: µmol/L	Baseline to day 15
Secondary	Change of AST	Value changes from baseline to last Visit. Unit: U/L	Baseline to day 15
Secondary	Change of ALT	Value changes from baseline to last Visit. Unit: U/L	Baseline to day 15
Secondary	Change of ALP	Value changes from baseline to last Visit. Unit: U/L	Baseline to day 15
Secondary	Change of creatinine	Value changes from baseline to last Visit. Unit: µmol/L	Baseline to day 15
Secondary	Change of urea	Value changes from baseline to last Visit. Unit: mmol/L	Baseline to day 15
Secondary	Change of TSH	Value changes from baseline to last Visit. Unit: mIU/L	Baseline to day 15
Secondary	Change of free triiodothyronine	Value changes from baseline to last Visit. Unit: pmol/L	Baseline to day 15
Secondary	Change of free thyroxine	Value changes from baseline to last Visit. Unit: pmol/L	Baseline to day 15
Secondary	Change of vitamin b1	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of vitamin b6	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of vitamin b12	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of cortisol	Value changes from baseline to last Visit. Unit: ug/dL	Baseline to day 15
Secondary	Change of ghrelin	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of leptin	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of 5-hydroxytryptamine	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Change of substance P	Value changes from baseline to last Visit. Unit: pg/ml	Baseline to day 15
Secondary	Change of arginine vasopressin plasma	Value changes from baseline to last Visit. Unit: pg/ml	Baseline to day 15
Secondary	Change of GDF 15	Value changes from baseline to last Visit. Unit: pg/ml	Baseline to day 15
Secondary	Change of IGFBP 7	Value changes from baseline to last Visit. Unit: ng/ml	Baseline to day 15
Secondary	Intravenous fluid treatment during treatment	Intravenous fluid treatment during treatment	Baseline to day 15
Secondary	Concomitant treatment	Concomitant treatment	Baseline to day 15
Secondary	Hospital admission during treatment	Hospital admission during treatment	Baseline to day 15
Secondary	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).
Secondary	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.
Secondary	Patient satisfaction with treatment	Such as loss of confidence or intolerance to daily acupuncture and so on	Baseline to day 15
Secondary	Treatment compliance	Such as the percentage of drug or needle used; or drug tablets or acupuncture sessions.	Baseline to day 15
Secondary	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.
Secondary	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
Secondary	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
Secondary	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)
Secondary	Quality of life: NVPQoL	Range 30-210, high being poor QoL	Baseline to day 15
Secondary	Quality of life: VAS	Ranged 0-10, high being more severe symptoms	Baseline to day 15
Secondary	Quality of life: SDS	Range 25-10, high being more severe	Baseline to day 15
Secondary	Quality of life: SAS	Range 25-100, high being more severe	Baseline to day 15
Secondary	Quality of life: global assessment of well-being	Range 0-10, low being more severe	Baseline to day 15
Secondary	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