This study aims to determine the effect of acupuncture treatments on homeostasis model assessment-insulin resistance (HOMA-IR), adiposity and health-related quality of life (HRQoL) in patients with type 2 DM.
This is a randomized, double-blinded (patients and practitioners), placebo and two-arm parallel controlled clinical trial. This study will be conducted at three public university teaching hospitals in Malaysia. The reporting of the trial will adhere to the CONSORT  and STRICRTA  guidelines.
The trial protocol has been approved by the Universiti Putra Malaysia Ethics Committee for Research Involving Human Subjects (JKEUPM-2018-294) and registered in ClinicalTrial.gov (NCT04829045). The study is performed according to Declaration of Helsinki and the guidelines for Good Clinical Practice. Permission to carry out the study will be obtained from the respective hospitals before conducting the research.
A total of 30 patients are required in each group to detect a significant mean difference of 1.23 % HOMA-IR, 1.25% standard deviation , 95% confidence level and 80% power, with an additional dropout rate of 30%.
Methods of recruitment
Subject recruitment is conducted at public university teaching hospitals in Malaysia by an endocrinologist and a TCM practitioner through patients’ routine medical check-up schedules. Patients will be provided study brochure and information sheet if they express interest to participate in the study. Upon agreement to participate in the study, patients will be requested to fill up a screening form to assess their study eligibility. For screening purpose, type 2 DM is defined as one abnormal fasting plasma glucose (FPG) ≥ 7.0 mmol/L (126 mg/dL), random venous plasma glucose ≥ 11.0 mmol/L (200 mg/dL), two hour plasma glucose measurement ≥ 11.0 mmol/L (200 mg/dL) or glycated hemoglobin (HbA1c) ≥ 6.5% based on subjects’ self-reported or through their DM book, medications packages, and clinic follows up cards. Those who are eligible will be invited to attend a blood collection session. Type 2 DM is confirmed with subject’s HbA1c ≥ 6.5% or morning FPG ≥ 7.0 mmol/L (126 mg/dL)(fasting at least 10 hours) based on American Diabetes Association recommendation . Patients are required to sign a written informed consent form once they fulfill all the study criteria and agree to further participate in the study.
The subject eligibility criteria for the study include Malaysian, age between 30–69 years old, have had type 2 DM (FPG ≥ 7.0 mmol/L [126 mg/dL] or HbA1c ≥ 6.5%.) for more than one year and with BMI ≤ 40.0 kg/m²; receive oral anti-diabetic agents on a stable dose over the previous 3 months. Patients with any of the following criteria will be excluded: 1) under insulin therapy; 2) with other acute or chronic health problems; 3) needle phobia or allergy to adhesive plaster; 4) planning to move out from Malaysia within 4 months’ and 5) being pregnant, planning for pregnancy or lactating women.
Randomization and allocation strategy
Blocked randomisation with block size of 2 will be performed in a 1:1 allocation ratio to minimise between-group differences on HOMA-IR level and body mass index (BMI). The press needles and placebos are identical in appearance. They are repacked in identical plastic containers and consecutively numbered for each subject according to the randomization schedule. Each subject is assigned an order number. The containers will be distributed to the principle investigator at the sites and practitioner(s) will receive the corresponding containers which contain either press needles or placebos. Randomization sequence and allocation will be concealed to all subjects, acupuncturists, laboratory personnel and partial researchers. Sequentially numbered, sealed opaque envelopes will be used to conceal treatment procedures. The randomization sequence will remain concealed until the end of the study.
Adherence to the protocol is assessed at every follow-up session and evaluation of intervention adherence will be assessed at post intervention.
Subjects will receive 10 sessions of real or placebo acupuncture treatment using Pyonex Press Needles or Pyonex Placebos. During the treatments, all subjects are required to take supine position. New, disposable, sterilized, stainless-steel press needles are utilized. The acupuncture points will be disinfected with a disposable 70% isopropyl alcohol cotton. After all the press needles are fixed, acupoints are pressed for at least three times (at 0, 15 and after 30 minutes) for about 30 seconds, with the degree that can be tolerated by the subject. The press needles and placebos are inserted according to the acupoints selection sequence, the product directions and following same procedures . The validity and credibility of the device have been well demonstrated in other studies [46, 47].
In this study, an irradiating needling sensation (de qi) does not have to be achieved. “De qi” is a tingling, numbness, and heaviness feelings that occur after an acupuncture needle had been inserted in the body . During the 45 minutes needle retention period, subject’s abdomen will be covered to prevent exposure. If the subjects are sick or not felling well on that day, they will not be given any treatment and are requested to come on other day. Similarly, if subject reports discomfort or encounter any adverse effect during intervention, acupuncture therapy is discontinued and the treatment for that particular session will not be included.
The study period is seven weeks with intervention period for 6 weeks and follow-up for any adverse event for 1 week. Treatments are performed twice per week. However, in certain circumstances, once-a-week treatment to a three-time per week treatment is permitted, but ten treatments must be completed within six weeks. For those who are under drug(s) or other treatments during intervention, they are required to continue with their existing treatment regimens. All medication and doses received by the subjects are recorded and monitored during the course of the study to ensure the medications are maintained throughout the study. Medications that are allowed in this study are oral anti-diabetic drugs, including hypertensive and hyperlipidemia medications. Nevertheless, medications that are not allowed in this study are all types of insulin; Glucagon-like peptide-1 receptor agonists such as Liraglutide, Exenatide, Dulaglutide, Semaglutide and thiazolidinediones (TZDs) such as Pioglitazone and Rosiglitazone. There will be no change in other treatment as long as patients are clinically stable. Subjects are also advised to notify the practitioners immediately if there are any changes in their current treatments/circumstances such as personal details, medication or pregnancy (for woman) during the study. Any changes in the treatment regimen will be documented. Subject’s is considered drop-outs if they have missed their appointments for more than three times, they do not attend the baseline or assessment session (cause missing data), they become pregnant (for women), inability to comply with protocol requirements, withdrawal of his/her own decision or advised by the researcher (for example participant increase 20% doses of DM medication or using acupuncture at other clinic during intervention). Safety or adverse event in each session will also be recorded in a case record form. Data will be collected and evaluated at the time of recruitment (baseline), after completion of 5 sessions (week 3/4) and 10 sessions (week 7) of the treatment.
The treatment group will receive real acupuncture treatments using Pyonex Press Needles (Pyonex ø0.20×1.5mm made by Seirin Corporation). A standardized treatment with 6-10 needles on abdomen area such as Zhongwan (Ren-12), Xiawan (Ren-10), Qihai (Ren-6), Guanyuan (Ren-4), Tian Shu (St-25), Daheng (Sp-15), Shangqu, Jinhe (M-HN)/Qixue (Kd-13), Shuidao (St-28) and Liang Men (St-21) are selected based on literature reviews [18,22,49,50] and recommendation by international experts. The number and name of acupuncture points used in each session will be documented.
The same procedure and acupuncture points are used for the control group. Subject are given placebo which is identical to the press needle except the needle element has been removed and replaced with a blunt knob in all aspects are indistinguishable to the press needles .
Practitioners’ background and training
Interventions are administered by 3 qualified TCM practitioners or acupuncturists with at least five years of clinical experience and have had degree academic qualification in relevant field. They are required to undergo an intensive training to ensure consistency of the intervention. A standard operation procedure will be provided during the training such as identification of the acupoint location, compulsory acupoints to be used in each session, technique in performing the study treatment and the time to press needles after insertion of the needles. They will also be briefed about risk management of the trial during the training. To ensure the practitioners are masked to the group allocation, practitioners are requested not to check for the presence of a sharp tip below the plaster during the intervention.
Socio-demographic backgrounds of patients which include patients’ age, gender, ethnicity, marital status, educational level, personal monthly income, duration of DM, and family history of DM will be obtained through a questionnaire at recruitment. The primary and secondary outcomes will be measured at baseline, during and after the treatment is completed. Table 1 shows the schedule for data collection during the 7 weeks of study period. Data will be collected at the time of recruitment (baseline), after completion of 5 sessions (week 3/4) and 10 sessions (week 7) of the treatment.
The primary outcome of this trial is the change in HOMA-IR after treatment. Fasting insulin and glucose concentrations will be used to derive the HOMA-IR [fasting serum insulin (μU/ml)×fasting plasma glucose (mmol l-1)/22.5]. Fasting insulin levels and fasting glucose will be analyzed using heparin tubes and sodium fluoride tubes respectively by an enzyme-linked immunosorbent assay, also called ELISA or EIA. Peripheral blood will be drawn from the antecubital veins of the subjects at baseline and at week 7 after a 10 hour overnight fasting. A total of 10 ml/L of venous blood will be obtained using venipuncture method. These blood samples are then centrifuged for 10 minutes at the speed of 35000rpm to separate the blood serum. Subsequently, serum will be put in an Eppendorf tubes for preservation. The serum is preserved in a low temperature freezer which shall maintain at a temperature of -70 Celsius.
The secondary outcomes are changes in health-related quality of life (HRQoL) and anthropometry parameters such as weight, body mass index (BMI) and waist circumference (WC). Subject’s HRQoL will be assessed using a validated World Health Organization Quality of Life Assessment: Brief Version (WHOQoL-BREF [English/Malay]) questionnaire [53,54]. Anthropometry measurements will be measured according to the standard procedure. Subjects will be measured for weight in kilogram to the nearest 0.1 kilogram, using a digital scale TANITA model HD-382 weighing machine in a standing position. Height will be measured using SECA body meter model 208 to the nearest 0.05 centimetre. BMI is calculated weight in kilogram divided by height in meters squared (BMI=Weight(kg)/Height2(m²). WC will be measured midway between the lowest rib and the iliac crest using SECA measuring tape to the nearest 0.05 centimetre. Central obesity for Asian population is defined as having WC ≥ 90cm for men and ≥ 80cm for women based on WHO/IASO/IOTF criteria .
Data will be analyzed using SPSS Statistics 26.0 (IBM Corp., New York, USA). Kolmogoro-Smirnov tests for normality will be performed on each variable prior to analysis. Comparisons of baseline continuous variables between intervention and control group will be examined using independent t test, while for categorical variables the chi-square test will be used. Paired t test will be used for within group differences. Intention-to-treat analysis (ITT) will be performed, and all patients enrolled will be included in the analysis, irrespective of compliance. Missing data is imputed using last observation carried forward method. The GLM procedure for repeated-measures ANCOVA will be performed to test the main effect of within-subject and between-subject factors as well as the interaction of these factors while controlling for possible baseline covariate. The significant level for all tests is set at p<0.05 (two-tailed).
Safety or adverse event suspected related to the treatment, through the symptoms reported by the patients, and observations by researcher at every visit are collected. Adverse event is defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure . Possible adverse events related to acupuncture are bruising, nausea, temporary pain, dizziness or faintness, or discomfort . Details about the event time, severity, and duration, causal relationship with the treatment, other treatments or medications that are suspected to cause the adverse event will be recorded.