Effect of Electroacupuncture on Opioid-induced Constipati... | NCT03797586

NCT03797586

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Description Module

Brief Summary

Approximately 70-80% of patients with advanced disease will be affected by moderate to severe pain. Opioid analgesics represented by morphine and oxycodone are the cornerstone of cancer-pain management, and recommended for use in the management of moderate to severe cancer pain according to WHO Cancer Pain Relief Guidelines. One view is that a trial of systemic opioid therapy should be administered to all cancer patients with pain of moderate or greater severity regardless of the pain mechanism. Although opioids analgesics do work well as relieving pain and improving quality of life via their action at opioid receptors in the central nervous system (CNS) and the peripheral nervous system, they also have powerful adverse effects. The overall occurrence of opioid-related adverse drug events has ranged from1.8% to 13.6%. Opioid-induced constipation (OIC), one of the most prevalent adverse events (AEs) in patients receiving opioid analgesics, defined as a change in baseline bowel habits or defecatory patterns following initiation, alteration, or increase in opioid therapy. The prevalence of OIC has been estimated to affect 41% of patients with chronic noncancer pain taking opioids and 94% of cancer patients taking opioids for pain. Unlike many other opioid-related AEs, OIC is persistent and rarely tolerated. OIC impacts pain control, patients' quality of life and may cause patients to reduce the dose or discontinue opioid use.

Acupuncture, a traditional Chinese medicine, has been used to treat gastrointestinal disease including constipation for thousands of years. Two systematic reviews concluded that acupuncture can improve spontaneous bowel movements for functional constipation, and our recent study indicated that electroacupuncture(EA) could increase complete spontaneous bowel movements and is safe for chronic severe functional constipation. Acupuncture could improve gastrointestinal function via facilitating gastrointestinal motility. Currently, there is little detailed information available regarding the acupuncture use for OIC. The objective of this study is to assess the efficacy and safety of EA for OIC in patients with cancer.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Electroacupuncture group	Experimental	Bilateral ST25,SP14, ST37 will be used in the EA group. For ST25 and SP14, 0.30×50mm or 0.30×75mm needles will be vertically inserted to the muscle layer of the abdominal , where patients will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Then paired alligator clips of the EA apparatus will be attached to the needle holders of the bilateral ST25, SP14, and ST37. EA stimulation will be retained for 30 minutes with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA.	Other: Electroacupuncture group
Sham electroacupuncture group	Sham Comparator	Bilateral sham ST25, SP14, and ST37 will be used in the SA group. After sterilizing the skin, 0.30×40mm needles will be straightly inserted at the sham points about 2-3mm until they can be fixed on the skin when attached by the alligator clips. No manipulation will be used, and no deqi sensation are elicited for all sham points. The bilateral sham ST25, SP14, and ST37 points will be attached by the same EA apparatus with a continuous wave of 10 Hz and current intensity of 0.1 to 0.2 mA for 30 minutes with only the initial 30 seconds on.	Other: Sham electroacupuncture group

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Electroacupuncture group	Other	Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. With the local skin of the patients was routinely sterilized in a prone position in relaxation, acupuncturists will insert needles into the acupuncture points. For ST25 and SP14, 0.30×50mm or 0.30×75mm needles will be vertically inserted to the muscle layer of the abdominal wall, where participants will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Then paired alligator clips of the EA apparatus will be attached to the needle holders of the bilateral ST25, SP14, and ST37. EA stimulation will be retained for 30 minutes with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Response	A responder（Participant With Response） is defined as a patient that has at least three spontaneous bowel movements (SBMs) per week and an increase of at least one SBM a week from the baseline for at least 6 of the 8 weeks of the treatment period.	weeks 1-8

Secondary Outcomes

Measure	Description	Time Frame
A Change in the Mean Weekly Spontaneous Bowel Movements (SBMs) From the Baseline During Weeks 1-8 and Weeks 13-16.	An SBM was defined as a bowel movement that occurred without any medication or intervention to assist defection within the previous 24 hours. A bowel movement occurring within 24 hours of an optional assisted method for defecation was not considered to be an SBM. The mean weekly spontaneous bowel movements (SBMs) during weeks 1-8 and weeks 13-16 is calculated by dividing the total frequency of SBMs by the number of weeks recorded.

Other Outcomes

Measure	Description	Time Frame
Patients'Expectation of the Acupuncture Efficacy	Participants will be asked to answer the following questions before the intervention: "Do you think acupuncture will be effective in treating the disease in general?" "Do you think acupuncture will be effective in improving the OIC?" and "which acupuncture modalities do you prefer, EA or SA?" For each question, patients will choose one of the following answers: "unclear/whatever", "EA", or "SA"

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Cancer patients who conformed to all the following conditions will be further screened for eligibility:

Cancer patients must meet the Rome IV[1] diagnostic criteria for OIC: New or worsening symptoms of constipation following initiation, alteration, or increase in opioid treatment. For patients with a history of chronic functional constipation, he/she must have worsening symptoms of constipation when the opioid therapy is initiated, changed, or the dose is increased;
Patients recruited in this trial must have a history of OIC symptoms for at least 1 week;
Patients must be ≥18 years of age and ≤85 years of age;
Patient's cancer condition must be stable with a life expectancy that is more than six months;
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3;
Patients must have been receiving a relatively stable maintained opioid regimen, consisting of a total daily dose of 30 mg to 1000 mg oral morphine equivalents for at least 2 weeks prior to screening for cancer pain. Furthermore, it must be anticipated that the opioid will be maintained for at least 10 weeks;
The SBM frequency of the patients must be ≤ 2 times a week when laxatives are not being taken;
Patients must be capable of oral intake of drugs, food and beverages;
Provision of written informed consent before participation.

Exclusion Criteria:

Participants who fulfill any of the following criteria will be excluded:

Patients diagnosed with clinically significant abnormal defecation due to structural abnormalities of the gastrointestinal tract and other tissues related to gastrointestinal tract (not including OIC): inflammatory bowel disease, rectal prolapse, gastrointestinal obstruction, peritoneal metastasis, or peritoneal tumor at the time of enrollment;
Patients with a history of gastrointestinal tract operation, abdominal operation, or abdominal adhesion within one month prior to screening; history of intestinal obstruction within three months prior to screening;
Diagnosis of active diverticular disease; or severe hemorrhoid; or anal fissure; or artificial rectum or anus;
Patients with an intraperitoneal catheter or a feeding tube;
Diagnosis of pelvic disorder which are considered to have obvious effects on the intestinal transport of feces (such as uterine prolapse ≥degree 2, uterine fibroids [located in the posterior of the uterus with a diameter ≥ 5 cm] affecting bowel movement);
Patients that are being treated with a new cancer chemotherapy, which had never been administered in the past, within 14 days of the screening or are scheduled to receive such therapy during the study;
Patients that received radiotherapy within 28 days of the screening or are scheduled to receive such therapy during the study;
Patients that underwent a surgery or intervention that is considered to have an obvious effect on the gastrointestinal functions within 28 days of the screening or are scheduled to receive surgery or intervention which is considered to have obvious effects on the gastrointestinal functions during the study, or scheduled to receive surgery or intervention which will be anticipated to prevent the patients from completing the trial;
Patients with uncontrolled hyperthyroidism, severe hypertension, heart disease, systematic infection or blood coagulation disorders (hypercoagulation status or hemorrhagic tendency) at the time of study inclusion;
Patients that consumed >4 additional opioid doses per day, for breakthrough pain, for more than 3 days during the baseline period, or if their maintenance opioid dosing regimen was modified during this period;
Patients with severe cancerous pain (e.g., typical average daily pain intensity rating of 7 to 10 on a numerical rating scales (NRS; 0 [no pain] to 10 [the worst pain possible]) after the use of routine dose and frequency of opioids) refractory to opioid therapy;
Patients with a history of opioid discontinuation due to severe adverse events or patients that are expected to discontinue opioid use due to the potential risk of adverse events;
Patients that received an opioid receptor antagonist within one month of the screening, or those who are scheduled to receive such therapy during the study;
Patients with a history of nerve neurolysis;
Patients with severe cognitive impairment, aphasia, or psychiatric disorders; abdominal aortic aneurysm; hepatomegaly(liver span > 14cm at the mid-clavicular line by ultrasound examination); or splenomegaly (spleen length [cranial to caudal] > 13cm by ultrasound examination);
Patients that have received acupuncture within three months of the screening;
Other patients who are considered ineligible for the study by the investigator on the basis of concomitant therapy and medical findings.

Name	Affiliation	Role
Zhishun Liu	China Academy of Chinese Medicine Sciences	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Guang An Men Hospital		Beijing		100053	China

PubMed Identifier	Type	Citation	Retractions
36811861	Derived	Wang W, Liu Y, Yang X, Sun J, Yue Z, Lu D, Zhou K, Sun Y, Hou A, Zang Z, Jin X, Liu C, Wang Y, Yu J, Zhu L, Liu Z. Effects of Electroacupuncture for Opioid-Induced Constipation in Patients With Cancer in China: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230310. doi: 10.1001/jamanetworkopen.2023.0310.
35492306

Arm/Group Information

ID	Title	Description
FG000	Electroacupuncture Group	Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. With the local skin of the patients was routinely sterilized in a prone position in relaxation, acupuncturists will insert needles into the acupuncture points. For ST25 and SP14, 0.30×50mm or 0.30×75mm needles will be vertically inserted to the muscle layer of the abdominal wall, where participants will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Then paired alligator clips of the EA apparatus will be attached to the needle holders of the bilateral ST25, SP14, and ST37. EA stimulation will be retained for 30 minutes with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA.
FG001	Sham Electroacupuncture Group	Bilateral sham ST25, SP14, and ST37 will be used in the SA group. After sterilizing the skin, 0.30×40mm needles will be straightly inserted at the sham points about 2-3mm until they can be fixed on the skin when attached by the alligator clips. No manipulation will be used, and no deqi sensation are elicited for all sham points. The bilateral sham ST25, SP14, and ST37 points will be attached by the same EA apparatus with a continuous wave of 10 Hz and current intensity of 0.1 to 0.2 mA for 30 minutes with only the initial 30 seconds on.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Electroacupuncture Group	Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. The location of the acupoints will be based on Nomenclature and location of acupuncture points34 drafted in 2006 by the National Standard of the People's Republic of China (GB/T 12346-2006). The local skin will be routinely sterilized while the patient is in a supine position. For ST25 and SP14, 0.30×50 mm or 0.30×75 mm needles will be gently vertically inserted to the muscle layer of the abdominal wall, where patients will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Paired alligator clips of the EA apparatus will then be attached to the needle holders of the bilateral ST25, SP14, and ST37. The stimulation will be retained for 30 minutes, with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA. All needles will be removed after 30 minutes and pressure will be applied using a dry sterilized cotton ball to avoid bleeding. Patients will receive 24 treatment sessions over an 8-week period (3 sessions each week, ideally every other day). Patients will be followed up for another 8 weeks after the treatment stopped.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Response

A responder（Participant With Response） is defined as a patient that has at least three spontaneous bowel movements (SBMs) per week and an increase of at least one SBM a week from the baseline for at least 6 of the 8 weeks of the treatment period.

Three participants in the electroacupuncture group and 5 participants in the sham electroacupuncture group did not complete 8-week treatment over weeks 1-8.

Posted

Number

participants

weeks 1-8

ID	Title	Description
OG000	Electroacupuncture Group	Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. With the local skin of the patients was routinely sterilized in a prone position in relaxation, acupuncturists will insert needles into the acupuncture points. For ST25 and SP14, 0.30×50mm or 0.30×75mm needles will be vertically inserted to the muscle layer of the abdominal wall, where participants will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Then paired alligator clips of the EA apparatus will be attached to the needle holders of the bilateral ST25, SP14, and ST37. EA stimulation will be retained for 30 minutes with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Electroacupuncture Group	Bilateral Tianshu (ST25), Fujie (SP14), Shangjuxu (ST37) will be used in the EA group. With the local skin of the patients was routinely sterilized in a prone position in relaxation, acupuncturists will insert needles into the acupuncture points. For ST25 and SP14, 0.30×50mm or 0.30×75mm needles will be vertically inserted to the muscle layer of the abdominal wall, where participants will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30×40 mm needles will be vertically inserted approximately 15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi. Then paired alligator clips of the EA apparatus will be attached to the needle holders of the bilateral ST25, SP14, and ST37. EA stimulation will be retained for 30 minutes with a continuous wave of 10 Hz and current intensity of 0.5 to 4 mA.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Death	Respiratory, thoracic and mediastinal disorders		Non-systematic Assessment	Death was due to lung cancer. It was considered not related to acupuncture treatment by the investigator.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_ICF	Yes	No	Yes	Study Protocol and Informed Consent Form	Nov 29, 2019	Aug 6, 2022	Prot_ICF_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Dec 10, 2021	Aug 6, 2022	SAP_001.pdf