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

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: June 23, 2021

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.

Interventions

  • 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.
  • 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).
  • 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).

Arms, Groups and Cohorts

  • 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).
  • 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).
  • Other: Placebo plus active acupuncture
    • Diclectin placebo (2-4 tablets/day) + active acupuncture (30 min / every day)
  • Other: Placebo plus sham acupuncture
    • Diclectin placebo (2-4 tablets/day) + sham acupuncture (30 min /every day)

Clinical Trial Outcome Measures

Primary Measures

  • Score change of pregnancy unique quantification of emesis (PUQE) scale from baseline to day 15
    • Time Frame: 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 Measures

  • Score change of maternal weight from baseline to the last visit
    • Time Frame: Baseline to day 15; no range of variation
    • Score change of maternal weight from baseline to the last visit
  • Change of electrolyte index (sodium)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (potassium)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (calcium)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (chlorine)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (phosphorus)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (magnesium)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of electrolyte index (iron)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: μmol/L
  • Change of electrolyte index (zinc)
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: μmol/L
  • Change of AST
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: U/L
  • Change of ALT
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: U/L
  • Change of ALP
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: U/L
  • Change of creatinine
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: μmol/L
  • Change of urea
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mmol/L
  • Change of TSH
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: mIU/L
  • Change of free triiodothyronine
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: pmol/L
  • Change of free thyroxine
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: pmol/L
  • Change of vitamin b1
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of vitamin b6
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of vitamin b12
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of cortisol
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ug/dL
  • Change of ghrelin
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of leptin
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of 5-hydroxytryptamine
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Change of substance P
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: pg/ml
  • Change of arginine vasopressin plasma
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: pg/ml
  • Change of GDF 15
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: pg/ml
  • Change of IGFBP 7
    • Time Frame: Baseline to day 15
    • Value changes from baseline to last Visit. Unit: ng/ml
  • Intravenous fluid treatment during treatment
    • Time Frame: Baseline to day 15
    • Intravenous fluid treatment during treatment
  • Concomitant treatment
    • Time Frame: Baseline to day 15
    • Concomitant treatment
  • Hospital admission during treatment
    • Time Frame: Baseline to day 15
    • Hospital admission during treatment
  • Termination of pregnancy
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: Baseline to day 15
    • Such as loss of confidence or intolerance to daily acupuncture and so on
  • Treatment compliance
    • Time Frame: Baseline to day 15
    • Such as the percentage of drug or needle used; or drug tablets or acupuncture sessions.
  • Offspring outcomes
    • Time Frame: 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
    • Time Frame: Baseline to day 15
    • Scores ranged 3 to 15, with higher scores indicating more severe NVP
  • PUQE score reduction based on different TCM patterns
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: Baseline to day 15
    • Range 30-210, high being poor QoL
  • Quality of life: VAS
    • Time Frame: Baseline to day 15
    • Ranged 0-10, high being more severe symptoms
  • Quality of life: SDS
    • Time Frame: Baseline to day 15
    • Range 25-10, high being more severe
  • Quality of life: SAS
    • Time Frame: Baseline to day 15
    • Range 25-100, high being more severe
  • Quality of life: global assessment of well-being
    • Time Frame: Baseline to day 15
    • Range 0-10, low being more severe
  • PUQE score reduction at different levels of NVP
    • Time Frame: Scores ranged 3 to 15, with higher reduction indicating the better
    • PUQE score reduction at different levels of NVP

Participating in This Clinical Trial

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

Gender Eligibility: Female

Minimum Age: 20 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Xiaoke Wu
  • Collaborator
    • Ningxia Hui Autonomous Region Hospital of TCM
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Xiaoke Wu, Director of obstetrics and Gynecology Department – Heilongjiang University of Chinese Medicine
  • Overall Official(s)
    • Xiaoke Wu, Ph.D, Study Chair, First Affiliated Hospital of Heilongjiang University of Chinese Medicine

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