Participants will be asked to avoid consuming alcohol, caffeine, smoking, taking hot showers, and exercising hard for at least 2 hours before the measurement. After 10 minutes of sitting and resting with at least 10 cm of exposure above both elbows and the lower garment up to the knees in a room with 24℃±1℃ and 40–60% humidity, BT of both palms (PC8), the center of the anterior upper arms (LU4), the center of the front thighs (ST32), and frontal part of the dorsum of feet (LR3) will be measured within 10 minutes before and after treatment using a thermometer (Testo 835-T1, Lenzkirch, Germany) at visits 0, 1, 10, and 11 in the untreated control group. It will be measured at every visit in the acupuncture treatment and EA treatment groups.
WHOQOL-BREF
The WHOQOL-BREF, a questionnaire estimating quality of life, is composed of 26 items. It contains five domains: psychological health, physical health, environmental health, general quality of life, and social relationships. The Korean version of the WHOQOL-BREF by Min et al. [12] will be used for evaluating the quality of life of CHHF patients at visits 1, 10, and 11.
Questionnaire of health-related quality of life (EQ-5D)
It consists of five categories: capacity for locomotion, self-management, daily life, pain/discomfort, and anxiety/depression. It will be checked at visits 1, 10, and 11.
Questionnaire of pattern identification
Pattern identification will be checked at screening visit to correlate the symptoms and change of VAS score in patients with CHHF with pattern identification index.
Questionnaire of cold hypersensitivity
Cold hypersensitivity will be checked at visits 1, 10, and 11 for examining subjective or objective symptoms of the patient's coldness.
Safety assessment
To assess safety, vital sign and general physical state will be examined at every visit. Hematological examination (WBC, RBC, Hb, platelet), blood chemistry test (BUN, Cr, AST, ALT, r-GTP, glucose), thyroid function test (free T4, TSH), urine test, and pregnancy test (urine hCG) will be performed at screening visit in all three groups. Hematological examination (WBC, RBC, Hb, platelet) and blood chemistry test (BUN, Cr, AST, ALT, r-GTP) will be performed at visit 10 in two treatment groups. Adverse event (AE) monitoring will be conducted from visit 2 to visit 11.
Compliance calculation
Compliance will be calculated from visit 2 to visit 11. Acupuncture treatment compliance will be calculated as follows: Acupuncture treatment compliance (%) = (the number of acupuncture treatments that participants have received/10 times of acupuncture treatment) × 100.
AE reporting
AEs are instances of undesired or unintended symptoms or illness occurring during the clinical trial and do not necessarily have a causal relationship with intervention. The PI should educate participants and the co-investigator about any AEs that may occur after acupuncture or EA interventions and should educate them to report all symptoms occurring after the intervention.The investigator should check the occurrence of abnormal cases through clinical laboratory test results and questionnaires. All symptoms after intervention should be recorded on the CRF in detail with items such as type, time of occurrence, extent, treatment, medication, course, acausal relationship with intervention, etc. The PI should report immediately to the investigational review board (IRB) if SAEs occur during the trial to decide whether to continue or discontinue the study. Medical expenses for physical damage incurred in the study will be paied by the insurance company subscribed for this study unless it is a serious negligence due to the intention or carelessness of the subject.
Sample size calculation
This study was designed on the assumption that there would be a difference in results among the acupuncture treatment group, EA treatment group, and no treatment control group after interventions. The hypothesis based on the above assumptions is as follows:
H0: δ = Δ1 = Δ2 = Δ3
H1: δ = Δ1 ≠ Δ2 orΔ1 ≠ Δ3 or Δ2 ≠ Δ3
Δ1: Average change in CHHF VAS score ten weeks after randomization (within ± 3 days) in the acupuncture treatment group.
Δ2: Average change in CHHF VAS score ten weeks after randomization (within ± 3 days) in the EA treatment group.
Δ3: Average change in CHHF VAS score ten weeks after randomization (within ± 3 days) in no treatment control group.
Since there were no reference studies using acupuncture or EA for CHHF, we intended to calculate the number of participants based on the VAS score of the CHHF clinical trial using the oxygen chamber [13]. Therefore, this study was designed to enroll 72 patients, 24 patients in each group, considering the dropout rate of 25%.
Statistical analyses
The basic analysis method will be the degree of change between the results of the basic test performed before and after the clinical trial. For the evaluation of the efficacy of this study, both ITT, a method of including all randomized participants in the analysis, regardless of dropout or protocol violation, and per-protocol analysis (PP), a method of excluding participants with missing data or non-compliance from the analysis, will be performed. Missing data of the efficacy evaluation variables will be adjusted using the last-observation-carried-forward (LOCF) method. For safety evaluation variables, missing values will be considered as missing. The statistical significance level will be set at P < 0.05 using a two-sided test. For conducting statistical analyses, SPSS for windows version 25.0 (IBM Inc., Chicago, IL, USA) will be used.