2.1. Sample size calculation and study design
This is a randomized, single-blind, sham-controlled, parallel-group clinical trial. This clinical trial explores the practical effects of pharmacotherapy using the minimum sample size. Ver 1.1 of the protocol was approved by the relevant institutional review board on May 15, 2023. This study protocol is prepared according to the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT). A total of 44 participants with LBP will be recruited from DUCKMH through Banner promotion; recruitment commenced in June 2023. The effect size of pharmacopuncture was based on the suggestions of Park et al. [11]. The effect size on the evaluation variables (VAS, NRS for back pain) for chronic LBP in this study shows a distribution between 0.16 and 0.51. The power was set to 80% and the effect size of the clinical trial was conservatively considered as 0.1 to 0.3. According to Whitehead et al., we plan to recruit 40 participants, 20 people per group [12]. The dropout rate reported by Park et al. was 3%; considering the dropout rate of this clinical trial to be 5%, the final sample size to be recruited has been set to 44.
All subjects will receive a written explanation of the study protocol and an informed consent form by investigator. Clinical laboratory tests including whole-cell tests, liver function tests, and inflammation levels, including complete blood cell count (CBC), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), Total Bilirubin, erythrocyte sedimentation rate (ESR), Blood Urea Nitrogen (BUN), creatinine, total protein, albumin, and albumin/globulin (A/G) will be conducted. Clinical laboratory tests for women of childbearing age will include an additional urine hCG test to confirm negative results. If another medical institution or hospital has diagnosed a participant with lumbar intervertebral disc herniation through lumbar MRI or CT examination within the past six months, MRI or CT will be performed again for this study. If there is no lumbar MRI or CT examination within the last six months, lumbar CT will be performed in the hospital to check for intervertebral disc herniation. Participants should visit V1-16 within 8 weeks ± 5 days and V17 within 9 weeks ± 5 days. Visit 1 is considered to be within 1 week of screening. The study flow chart is presented in Table 1, Fig. 1.
Table 1
Schedule for the enrollment, intervention, and assessments
| | Study period |
| Recruitment | Enrollment, Allocation | Intervention period | Observation period |
| Enrollment |
| Visit | Screening | Week 0 (Baseline) | V1 | V2 | V3 | V4 | V5 | V6 | V7 | V8 | V9 | V10 | V11 | V12 | V13 | V14 | V15 | V16 | V17 |
| Checking the selection/exclusion criteria | ● | ● | | | | | | | | | | | | | | | | | |
| Vital signs | ● | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
| Demographic surveys and body measurements | ● | | | | | | | | | | | | | | | | | | |
| Medical history of lumbar and other body organs | ● | | | | | | | | | | | | | | | | | | |
| Physical examination | ● | | | | | | | | | | | | | | | | | | |
| Clinical laboratory test | | | ● | | | | | | | | | | | | | | | | |
| Lumbar spine X-ray and computed tomography (CT) | ● | | | | | | | | | | | | | | | | | | |
| Random allocation | | ● | | | | | | | | | | | | | | | | | |
| Interventions |
| pharmacopuncture with KMT | | | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | ◉ | |
| General KMT | | | | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
| Assessments |
| Visual Analog Scale | ● | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
| Patient Global Impression of Change | | | | | | | ● | | | | ● | | | | ● | | | | ● |
| no worse than mild pain | | | | | ● | | ● | | ● | | ● | | ● | | ● | | ● | | |
| ROM | | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
| Oswestry Disability Index | | | ● | | | | ● | | | | ● | | | | ● | | | | ● |
| Safety assessment | | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
| Suspending the test and checking the criteria for elimination | | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● |
| Visit schedule training | | | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | ● | | |
| KMT = Korean medicine treatment, ROM = Range of motion |
2.2. Inclusion and exclusion criteria
The inclusion criteria are:19–64 years of age; VAS ≥ 50 mm; and HIVD diagnosed through lumbar MRI or CT imaging within the last 6 months. The exclusion criteria are: history of spinal metastasis, acute fracture, and spinal dislocation of the tumor; spinal surgery; neurological symptoms of sensory and motor paralysis; abnormalities detected on L-spine radiography and CT examination; other chronic diseases; stroke and myocardial infarction; kidney disease; diabetic neuropathy; dementia; other medications (current steroids, immunosuppressants, and mental illness medications); cardiovascular disease; tumors; alcoholism; drug abuse; and participation in other clinical trials within 30 days.
2.3. Randomization and blinding procedures
Random allocation should will be performed so that treatment allocation is not biased and is not exposed to the subjectsparticipants and researchers. An independent statistician (IS) will randomly assign 22 individuals toper each group using the statistical program SAS® Version 9.4 (SAS installation. Inc., Cary, NC, USA). The generated random assignment tables will remain with are held by the ISIS of this test. TheAn IS will protects the file from public disclosure. SubjectsParticipants will be assigned using balanced block randomization, without stratification. The clinical trial manager will assign screening numbers to the subjectsparticipants in the order in which they have provided informed consent. The Subjects will be assigned to the treatment group or control group according to their randomization identification codes. After confirming the inclusion/exclusion criteria and screening process, the final eligible subjectparticipants will beis evaluated before treatment within Visit 1. Random assignment will be is performed andused to assign participants assigned toas a the treatment group or control groups. Target random numbers will be are assigned as HIVD2023-R001. The random assignment codes will beis placed in an envelope and stored in a locked cabinet with a lock. The researcher will opens a randomized envelope to assign for each subjectsparticipant. The opened envelope shall contains the date of opening and the researcher's signature and keep itis kept separately.
2.4. Pharmacopuncture
According to the authoritative interpretation proposed by the Ministry of Health and Welfare, pharmacopuncture is a Korean medical practice. Pharmacopuncture fluids are equivalent to herbal medicines. According to Article 8 of the Addenda of the Pharmaceutical Affairs Act, Korean medical doctors determine that it is possible to prepare and use medicinal acupuncture directly for patient treatment. Among the list of non-benefits of health insurance activities, herbal procedures, and prescription treatments, include pharmacopuncture. This can provide an institutional basis for conducting a practical comparative clinical study of pharmacopuncture for lumbar intervertebral disc herniation. The pharmacopuncture to be used in this study is manufactured by the Korea Medicine Industrial Institute (KIRIN) UNIMED (Gangwon-do, Republic of Korea).
2.5. Intervention
All operators must have at least two years of clinical experience in acupuncture and pharmacological acupuncture after obtaining a single qualified Korean medical doctor (KMD) license. The operator will disinfect the treatment area with alcohol and perform acupuncture on the affected side. The procedure will be performed twice a week for 8 weeks total. Depending on the patient's condition, sessions can be added or deferred once a week, and treatment is possible up to three times a week,but at least once a week. A total of 16 procedures will be performed. The frequency of the procedure will be based on the clinical judgment of the procedure by an oriental medical doctor. For accurate evaluation, all treatment areas will be recorded. The frequency of the procedure will be determined based on clinical judgment of the KMD. On the day of the procedure, participants will be instructed to refrain from excessive movement or extreme exercise and avoid bathing in addition to a simple shower after the session. This is to prevent infection of the treatment area after the procedure. The KMD guides the subject to allow tenderness or foreign body sensation to naturally disappear for approximately two days after the procedure. Visit 1–16: Record the p treated for each patient, type of medication used, and total dose (ml) in a separate sheet for each procedure. According to the clinical judgment of the KMD, cupping may also be performed at the lumbar region (L2-S1) for 5 min before and after acupuncture treatment. Additionally, infrared rays will be performed on the patient's magnetic needle for 15 min simultaneously with the acupuncture.
2.6. Outcome measures
The primary outcome is the VAS score, which will be used to assess LBP at each visit. The primary outcome is the average change in the VAS score for back pain and lower extremity radiation pain after treatment (V17) compared to baseline (V1). The secondary outcomes are the average change in the Oswestry Disability Index (ODI) score after treatment (V7) compared with baseline (V1), Patient Global Impression of Change (PGIC) and ROM ch visit.
2.6.1. VAS (Visual Analogue Scale, 0 ~ 100)
The VAS is used to evaluate the intensity and frequency of pain. The visual reflection scale is used by the patient himself, indicating the degree of pain on a 10-cm horizontal straight. It uses "no pain" at the left end and "maximum pain imaginable" at the right end. In addition to linguistic explanations, numbers '0' and '100' are sometimes added at both ends. Scores are mainly calculated as 1 point per 1 mm, and it is common to use scores between 0 and 100 [13].
2.6.2. ODI (Oswestry Disability Index)
The ODI indicates dysfunction due to pain. It consists of 6 questions for 10 items, total of 60 question. For each question, subjects use a score from 0 to 5 points, with higher scores indicating greater disability [14].
2.6.3. PGIC (Patient Global Impression of change)
The PGIC evaluates the improvement perceived by the subject after treatment versus baseline using the following answers: “Substantially better”, “A lot better”, “A little better”, “No change”, “A little worse”, “A lot worse”, and “Very much worse” [15].
2.6.4. No worse than mild pain
It is a form in which the subject responds subjectively to the response to treatment. It is an indicator that expresses that there is a minimal clinically significant effect. The intensity of pain is compared with before treatment to reflect improvement and satisfaction with treatment [16].
2.6.5. ROM (Range of motion)
The operator measures the maximum ROM angle (active joint range) at which the patient can move without pain.
2.7. Data collection and monitoring
During screening, the participants will complete a questionnaire regarding their sociodemographic characteristics and provide their medical history. The history of drug administration (product name, purpose, dosage and duration of administration, etc.) will be recorded in the Case Report Form (CRF). If there is a change in the drugs taken at any visit, it will be recorded. Participants will be confirmed to have undergone L-spine MRI or CT scans within the last six months. If there is no test history, lumbar spine CT will be performed at the hospital and to diagnose lumbar intervertebral disc escape. When a dropout occurs, as many outcomes as possible will be obtained from the records. The investigators will manage personal information and data. The final trial dataset will be accessible to statisticians and the principal investigator (PI),and can be accessible to other individuals with permission from the PI. All information regarding the participants and interventions will be kept confidential. All documents related to the clinical trial will be recorded and classified using identification codes. An independent contract research organization (CRO), MEDI CRO Co., Ltd. (Seoul, Republic of Korea), will monitor the research plans, case records, and annexed documents according to the schedule included in the clinical trial protocol. The CRO has no competing interests to declare. The CRO will review all evidence related to clinical trials and perform data quality control. At the end of the trial, the case report forms will be stored in a locked cabinet in accordance with IRB regulations.
2.8. Statistical analysis
AThe analysis offor the primary and secondary outcomes will be performed on both the intention-to-treat (ITT) and per-protocol (PP) sets, with ITT being the primary analysis. The PP set will consist of participants who have completed at least 16 sessions over a 9-week period.
Missing data will be imputed using the last observation carried forward (LOCF). Although LOCF is known to generate bias in the statistical analysis[17], we considered it applicable becauseis applicable since the imputation of the same values from the previous session does not lead to an overestimation of the effect in either treatment groups. For the sensitivity analysis, missing values will also beare also imputed using the multiple imputation (MI) algorithm [18] when performing the analysis of covariance (ANCOVA) for continuous outcomes.
DThe demographic characteristics will be assessed inaccording to both treatment groups. CThe continuous variables will be summarized using means and standard deviations (SDs) or medians, ranges, and inter-quartile ranges, and the categorical variables will beare summarized asin the frequenciesy and percentages (%). The differences in the baseline characteristics will be analyzed by using an independent two- sample t-test or Wilcoxon’s rank sum test for the continuous variables after checking forthe normality using the Shapiro- Wilk’s test. For the categorical variables, χ^2 tests or Fisher’s exact tests will be applied.
The endpoints of continuous variables, including both primary and secondary outcomes, wil beare differences in changes at each time point from the baseline between the two treatment groups. For the primary analysis, an ANCOVA will be conducted to test the group difference in the change from the baseline to the primary endpoint (visit 17). In addition to the primary analysis, we will ustilize linear mixed-effects models for repeated measures (MMRMs) to examine changes over time within and between treatment groups. This analysis will include baseline values, group, time, group-by-time interaction, and baseline-by-time interaction terms as fixed effects. In aAdditionally, random intercepts for each participant's group will be included as a random effects. For both the ANCOVA and MMRM analyses, the significantly different demographic characteristics will beare included as covariates. The level of statistical significance is set to a two-tailed α = 0.05 and all statistical analyses described in this paper will be conducted using R statistical software (version 4.3.0, released on 2023-04-21).
2.9. Safety
Adverse events (AEs) refer to undesirable and unintended symptoms (such as abnormalities in laboratory test values), symptoms, or diseases that appear during clinical research. AEs do not necessarily have a causal relationship with treatment. Diseases that existed before the study are considered as AEs only when they worsen after the study period. The AEs symptoms, start date, duration, and so on) should be recorded in the CRF, and those that are not recorded classified as subjective symptoms. In principle, the PI evaluates the degree of AEs according to symptom severity by referring to the evaluation criteria. The doctor in charge evaluates the causal relationship between the AEs and this test in six stages, according to the evaluation criteria. The PI evaluates the degree of self-perceptive symptoms of AEs using the Spilker classification method.
2.10. Ethics
The PI will conduct the clinical research in accordance with the Declaration of Helsinki. This study was approved by the IRB of DUCKMH ( DJUMC-2023-BM-03). The study protocol was registered in the Korean National CRIS (CRIS-KCT0008542 ). When reporting clinical research results, the PI will describe and evaluate all symptoms that occur during the clinical research period. Any case of serious adverse event (SAEs) during the study period will bereported to the IRB to determine whether to continue or stop the study. Only PI has access to destaset. Additional safety information should be periodically reported until the AE is terminated (such as loss of adverse reactions, inability to follow-up investigation,). Harmful and unintended reactions during clinical trials of medical devices are compensated for in accordance with the Victim Compensation Protocol.