Effectiveness and Safety of an Herbal Medicine Strategy for Chronic Low Back Pain: Protocol for a Prospective, Multicenter, Pragmatic, Randomized, Non-Inferiority Trial

Introduction

Background and Rationale

In 2020, the global number of cases of low back pain (LBP) was estimated to be 619 million, representing a substantial increase since 1990. There were 69.0 million years lived with a disability attributable to LBP, making it a major contributor to the global disability burden.¹ Chronic LBP (CLBP) is closely associated with a reduced quality of life and an increased risk of comorbid physical and psychological conditions, including musculoskeletal or neuropathic pain conditions, depression, anxiety, and sleep disorders.^2–4

Pharmacological treatments such as oral nonsteroidal anti-inflammatory drugs (NSAIDS), along with physical exercise, physiotherapy, cognitive behavioral therapy, and patient education, are generally recommended for CLBP in multiple international guidelines.⁵ In Korea, combinations of various Korean medicine (KM) treatment modalities, including acupuncture, moxibustion, cupping, and physiotherapy, are widely used in the management of CLBP.[Cheon, 2020 #15] Given that CLBP exhibits a high recurrence rate of 22.1%–77.1%,⁶ continuous management is necessary to mitigate long-term impacts on both physical and mental well-being. However, current non-pharmacological approaches require sustained strategies to maintain patient compliance,^7–10 and pharmacological treatments are temporary, offering benefits primarily in pain relief rather than long-term functional improvement.

Herbal medicines (HMs) effectively improve pain intensity and function in patients with LBP.¹¹

International guidelines also indicate that evidence for herbal medicine remains limited and inconsistent.[Krenn, 2020 #51] A Chinese clinical practice guideline for lumbar disc herniation recommends several specific herbal formulae, but such recommendations do not address the effectiveness of a real-world herbal medicine strategy, including healthcare utilization and economic outcomes.[Qin, 2024 #52].

Therefore, we designed a randomized controlled trial (RCT) to examine the effectiveness and safety of an herbal medicine strategy (HMS) compared with those of non-pharmacological Korean medicine treatment (NPKM). Because herbs are combined according to each patient’s pattern identification and associated symptoms in the HMS,¹² the combinations are individualized and expected to improve overall health in addition to alleviating LBP.

Previous studies have evaluated individual herbal substances for low back pain. A systematic review of 14 randomized controlled trials involving 2050 participants reported that some single herbal substances showed potential benefit over placebo, although the certainty of evidence was no better than moderate.[Gagnier, 2016 #50] However, such studies differ from the present trial, which evaluates an individualized herbal medicine strategy using combinations of multiple herbal components tailored to each patient’s condition.

Several observational studies in Korea have reported the use of diverse HMs for the treatment of LBP.^13,14 For example, in a prospective registry conducted across seven Korean medicine KM hospitals,¹⁴ a total of 16 different herbal decoctions were prescribed to 38 patients who were hospitalized, showing high clinical diversity in real-world settings. To address this variability and provide practical evidence, we designed a protocol for a pragmatic clinical trial (PCT) to investigate the effectiveness and safety of HMS in patients with CLBP.

Choice of Comparators

According to a 2017 survey on KM utilization and HM consumption, NPKM is commonly used for LBP in KM clinical practice. For example, 25.0% of patients with LBP who utilized KM services received integrative treatments composed of acupuncture, moxibustion, cupping, and physiotherapy (13.0%) or acupuncture combined with physiotherapy (12.0%).¹⁵ In this pragmatic trial, NPKM was selected as the comparator not merely because it represents a clinically relevant usual-care strategy routinely provided to patients with LBP in Korean medicine settings. This makes it an appropriate benchmark for evaluating HMS in real-world clinical practice, particularly because the two strategies differ in treatment delivery and healthcare utilization. For example, while NPKM requires frequent clinic visits, HMS does not necessitate regular in-person treatments and is expected to improve both the primary symptoms and comorbidities of CLBP.

Objectives

This pragmatic RCT aims to evaluate the effectiveness of HMS compared with that of NPKM in patients with CLBP, with a focus on improvements in pain intensity and functional disability.

Trial Design

This study is a multicenter, pragmatic, parallel-group, assessor-blinded RCT with a 1:1 allocation ratio, designed as a non-inferiority trial.

Methods and Analysis

Study Setting

The study will be conducted at seven KM hospitals in South Korea: Jaseng Korean Medicine Hospital (n = 24), Daejeon Jaseng Korean Medicine Hospital (n = 22), Bucheon Jaseng Korean Medicine Hospital (n = 22), Haeundae Jaseng Korean Medicine Hospital (n = 22), Kyung Hee University Korean Medicine Hospital (n = 20), Kyung Hee University Korean Medicine Hospital at Gangdong (n = 20), and Pusan National University Korean Medicine Hospital (n = 20). A total of 150 participants will be competitively recruited across the sites. (Figure 1)

Figure 1 CONSORT flow diagram of the study protocol.

Eligibility Criteria

Inclusion Criteria

1. LBP persisting for at least 3 months.
2. Numeric rating scale (NRS) score of LBP ≥ 5.
3. Age between 19 and 70 years.
4. Provision of written informed consent for study participation.

Exclusion Criteria

1. Diagnosis of a serious condition that can cause LBP or radicular pain (eg, spinal metastasis, acute fracture, or dislocation).
2. Presence of progressive neurological deficits or severe neurological symptoms.
3. LBP attributable to non-spinal soft tissue disorders (eg, tumors, fibromyalgia, rheumatoid arthritis, or gout).
4. Comorbid chronic diseases that may interfere with treatment effects or data interpretation (eg, stroke, myocardial infarction, renal disease, diabetic neuropathy, dementia, or epilepsy).
5. Current use of steroids, immunosuppressants, psychiatric medications, or other drugs that may affect trial outcomes.
6. Contraindications to acupuncture (eg, bleeding disorders, anticoagulant therapy, uncontrolled diabetes with increased infection risk).
7. Contraindications to HM (eg, history of conditions affecting drug administration or absorption, post-surgical digestive dysfunction, severe hepatic or renal dysfunction defined as aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, or serum creatinine ≥ 2 times the normal upper limit).
8. Recent treatment (within 1 week) with medications (eg, NSAIDS) or acupuncture that may influence pain.
9. Pregnancy, planning pregnancy, or breastfeeding.
10. Lumbar surgery within the previous 3 months.
11. Participation in another clinical trial within the previous month, or planned participation during the study period or within 6 months after enrollment.
12. Inability to provide informed consent.
13. Any other condition deemed inappropriate for study participation by the investigator.

Intervention

Description

Herbal Medicine Strategy

Participants allocated to the HMS group will visit the hospital every 10 days for prescription refills and follow-up. HM will be prescribed orally for 10 days at each treatment visit, over a total treatment period of 30 days. Considering feasibility in real-world clinical practice, the 30-day course will be completed within a 5-week treatment period. A doctor of Korean medicine (KMD) will determine the type of HM, dosing interval, and dosage based on clinical judgment, considering symptoms, imaging findings, and treatment response. For each prescription, the following details will be documented: HM type, herbal composition per package (g of each ingredient), total quantity (number of packages and treatment days), dosage per package (fixed per prescription), and daily frequency of administration.

Non-Pharmacological Korean Medicine Treatment

Treatment Methods

Participants in the NPKM group will receive a combination of NPKM treatments for CLBP. Specific treatment details may vary according to the clinical judgment of the KMD, and all treatment modalities will be recorded, including acupoints used for acupuncture and electroacupuncture.

• Acupuncture: Disposable, sterilized stainless-steel acupuncture needle (0.25 mm × 30 mm) will be inserted into 10–20 points selected from bilateral BL23, BL25, GV3, GV4, BL32, BL40, BL60, GB30, GB34, and SP6, and retained for 10–20 minutes.
• Electroacupuncture: Electrical stimulation (3 Hz) will be applied for 10–15 minutes at four points bilaterally: BL23, BL25, GV3, GV4, and BL32. The stimulation intensity will be adjusted to induce mild muscle contractions without causing pain.
• Infrared therapy: Infrared irradiation will be applied to the treatment area at approximately 30 cm distance for 10–15 minutes.
• Cupping: The KMD will select blood-letting or dry cupping depending on the patient’s condition. Blood-letting cupping will be applied at 2–4 tender points along the BL meridian in the lumbar area. After pricking the target points with a sterile lancet (10 pricks per site), negative pressure will be applied with disposable cups for approximately 5 minutes. For dry cupping, disposable cups will be applied to the same points as blood-letting cupping and operated up to three times to create a negative pressure, which will be maintained for approximately 5 minutes.
• Moxibustion: Moxibustion will be applied to two sites around the painful lumbar area at 43 ± 1°C for 10–15 minutes.
• Physiotherapy (Interferential Current Therapy or Transcutaneous Electrical Nerve Stimulation): In the prone position, physiotherapy will be applied to the quadratus lumborum region for 10–15 minutes.

Treatment Frequency

Treatment will be administered twice per week for 5 weeks. Depending on clinical judgment, frequency may be adjusted to once per week or up to three times per week. The total number of sessions will not exceed 10, and the actual number of sessions will be documented.

Modification

Treatment may be discontinued or modified in the following cases:

1. Discovery of eligibility violations after enrollment.
2. Identification of conditions that may affect outcomes during the study.
3. Participant or legal representative requests for discontinuation or withdrawal of consent.
4. Pregnancy confirmed during the study period.
5. Situations in which KM interventions for CLBP are deemed inappropriate.
6. Any other circumstances judged by the investigator to render participation inappropriate.

Adherence

Herbal Medicine Strategy

From Week 1 to Week 5, participants will be asked weekly to report the number of days they did not take the prescribed HM after receiving it. At Week 7, the number of prescribed HM packages and remaining packages will be checked and recorded in the case report form (CRF).

Non-Pharmacological Korean Medicine Treatment

The total number of NPKM sessions will be assessed at Week 7 and recorded in the CRF.

Concomitant Care

Participants will not be restricted from receiving concomitant treatments during the trial, reflecting real-world clinical practice. Investigators will record all concomitant treatments in the CRF, including the type, frequency, and purpose.

Outcomes

Primary Outcomes

Numeric Rating Scale of Low Back Pain

The first primary outcome will be the change in NRS score for LBP from baseline to Week 7. The participants will rate their lumbar pain over the previous week on a scale from 0 (no pain) to 10 (worst imaginable pain).

Oswestry Disability Index (ODI)

The second primary outcome will be the change in the ODI from baseline to Week 7. Functional status will be assessed using the validated Korean version of the ODI questionnaire, consisting of 10 items scored from 0 to 5. The total score will be divided by the maximum possible score (50) and expressed as a percentage, with higher scores indicating greater disability.

Secondary Outcomes

Numeric Rating Scale of Radiating Leg Pain

The intensity of radiating leg pain over the previous week will be assessed using the NRS.

Visual Analogue Scale (VAS) of Low Back Pain and Radiating Leg Pain

The intensity of LBP and radiating leg pain will be measured with a 100 mm horizontal line, anchored by “no pain” at one end, and “worst imaginable pain” at the other. Participants will report their pain intensity over the previous week.

Roland-Morris Disability Questionnaire-6 (RMDQ-6)

The RMDQ-6 is a validated short form of the RMDQ-24 that assesses disability related to LBP and allows the rapid evaluation of treatment effects. Participants will respond to six items concerning their back condition, with higher scores indicating greater disability.¹⁶

Patient Global Impression of Change (PGIC)

Participants will subjectively rate their improvement on a 7-point scale: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.

5-Level EuroQol-5 Dimension (EQ-5D-5L)

Health status will be evaluated using the EQ-5D-5L across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each item has five levels, and responses will be converted into preference-based scores using established weights and formulas.

Health-Related Quality of Life Instrument with 8 Items (HINT-8)

The HINT-8, developed for the Korean population, measures health-related quality of life using eight items: climbing stairs, pain, vitality, working, depression, memory, sleep, and happiness. The participants will rate their health status over the previous week using a 4-level response scale.

Patient Health Questionnaire-15 (PHQ-15)

The Korean version of the PHQ-15 will be used to assess overall health and subjective somatic symptoms. Participants will rate 15 symptoms over the previous 4 weeks on a 3-point scale (0 = not bothered at all, 1 = bothered a little, 2 = bothered a lot). The total scores range from 0 to 30, with severity classified as minimal (0–4), mild (5–9), moderate (10–14), and severe (15–30).

Credibility and Expectancy

Participants’ expectations of treatment effectiveness will be assessed using a 9-point Likert scale during the screening visit. They will respond to the question, “How much do you think HMS and NPKM will relieve your symptoms?” (1 = not at all, 5 = somewhat, and 9 = very much).

Cost Data

Cost data will be collected using a structured questionnaire covering direct medical costs (formal medical services), informal medical costs (eg, health supplements and medical devices), non-medical costs (eg, transportation, patient time, and caregiver costs), and productivity loss Productivity loss will be estimated using the Work Productivity and Activity Impairment Questionnaire, and the data will be converted into costs for cost-effectiveness analysis.

Drug Consumption

Concomitant medications will be recorded according to type and dose at each visit. Other treatments, such as physical therapy or injections, will be documented based on frequency.

Adverse Events (AEs)

Investigators will assess causality using the World Health Organization–Uppsala Monitoring Centre (WHO-UMC) system (1 = certain, 2 = probable/likely, 3 = possible, 4 = unlikely, 5 = conditional/unclassified, and 6 = unassessable/unclassifiable). All AEs will also be graded using Spilker’s classification: mild (1) = no treatment required, minimal impact on daily life; moderate (2) = significant interference with daily life, may require treatment but is recoverable; and severe (3) = serious AE requiring intensive treatment with potential sequelae. Serious AEs will be described in detail. AEs will be identified through participant reports and investigator observations, and their incidence will be compared between groups.

Participant Timeline

The participant timeline, including enrollment, interventions, assessments, and visits, is presented in Table 1.

Table 1 Participant Timeline

Sample Size

No previous RCT has directly compared the effectiveness of HMS with that of NPKM for CLBP. Therefore, the sample size was calculated based on the most comparable study design using HM. In a randomized controlled study¹⁷ comparing HM plus acupuncture to acupuncture alone, the mean change in VAS was 2.5 ± 0.6 in the intervention group and 3.0 ± 0.4 in the control group. For the non-inferiority margin, we referred to a previous study¹⁸ reporting a minimum clinically important difference (MCID) for physical therapy in CLBP ranging from 1.5 to 2.2. Half of the average MCID (0.83) was adopted as the non-inferiority margin. With a significance level of 0.025 and 90% power, and assuming a dropout rate of 30%, the required sample size was 72 participants per group. Accordingly, the total sample size was set at 150 participants.

Recruitment

Participants will be recruited through press releases, posters placed inside and outside research institutions, subway advertisements, announcements on websites, and posts on Internet recruitment platforms.

Assignment of Allocation

Sequence Generation

Randomization

The randomization sequence will be generated by a statistician using R version 4.1.1 (©; R Foundation for Statistical Computing, Vienna, Austria). Participants will be randomized in a 1:1 ratio to the HMS or NPKM group. Permuted block randomization will be applied with block sizes of 2, 4, or 6. According to the randomization table, participants will be assigned a randomization number and treatment arm in order of enrollment. Each participant’s randomization number will be recorded in their electronic medical records.

Concealment Mechanism

Central randomization will be implemented using the iClick web-based allocation system.

Blinding

Due to the nature of the interventions, the participants and physicians cannot be blinded. Instead, the outcome assessors will remain blinded. Assessments will be performed in separate spaces before treatment. However, outcome measures that could potentially unblind the assessor (Credibility and Expectancy, cost data, drug consumption, and AEs) will be excluded from the blinded assessment.

Data Collection Plan

All the data will be initially recorded on paper worksheets and entered into an electronic eCRF system (iClick). Patient-reported outcomes will be collected at each scheduled visit using validated questionnaires.

Retention

To minimize the loss to follow-up, the coordinator will contact participants before each scheduled visit. Visits at Weeks 12, 19, and 26 may be replaced by telephone interviews if in-person visits are not feasible. All efforts will be made to encourage participation throughout the study period.

Data Management

A Data Monitoring Committee (DMC) will be established to monitor participant safety and data integrity throughout the trial. The DMC will consist of a data management manager (serving as an independent clinician), a clinical data manager (serving as an independent biostatistician), a clinical research associate (CRA), and study coordinators. All members will be independent of the funder. The clinical data manager will communicate with the funder as needed. To ensure data quality, the assessors will receive standardized training before trial initiation. Access to the eCRF will be restricted to authorized personnel. Data quality will be regularly monitored by an independent CRA throughout the study period. Any discrepancies or missing values will be resolved using standard operating procedures. All data management procedures will comply with the Good Clinical Practice guidelines.

Statistics

Outcomes

Continuous variables will be summarized as mean ± standard deviation, and differences between groups will be tested using Student’s t-test. When data are not normally distributed, medians and interquartile ranges will be reported, and nonparametric tests will be performed.

Effectiveness will be evaluated by between-group differences in changes from baseline at each time point for continuous outcomes. The primary analysis will use a linear mixed model for repeated measures, with baseline values and clinically meaningful covariates showing baseline imbalance included as covariates and the group as a fixed factor. The primary analysis will be a non-inferiority test. The non-inferiority margin will be set at −0.83 for NRS and −4 for ODI. Non-inferiority will be concluded if the lower bound of the 95% confidence interval for the between-group difference does not exceed the margin. For the primary analysis, the significance level will be set at a one-sided α of 0.025, whereas for other analyses, two-sided p-values < 0.05 will be considered statistically significant. All statistical analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Additional Analyses

Superiority analyses will be conducted for outcomes where non-inferiority has been demonstrated.

Analysis of Population and Missing Data

Both intention-to-treat (ITT) and per-protocol (PP) analyses will be performed, with ITT serving as the primary analysis. Participants with ≥70% adherence to HM ( and those who received ≥7 NPKM sessions will be included in the PP set.

For sensitivity analyses, missing data will be handled using multiple imputations and the last observation carried forward, followed by an analysis of covariance.

Monitoring

Formal Committee

The principal investigator, co-investigators, and CRA will oversee the protocol adherence, trial process, and data quality.

Interim Analysis

Interim analyses will not be performed. All efficacy and safety data will be analyzed after completion of follow-up for the last participant.

Adverse Events

All AEs will be defined as any undesirable or unintended sign, symptom, or disease occurring after the intervention, regardless of causal relationship with the treatment. Serious adverse events (SAEs) will be defined as death, life-threatening events, hospitalization, disability, or other medically important conditions. In situations with a significant impact on participants’ health status, the KMD and relevant specialists will determine whether the event should be considered an SAE, and appropriate measures will be taken accordingly. Causality will be assessed using the WHO-UMC causality assessment system, and severity will be graded according to Spilker’s classification.

Auditing

Monitoring will include an initial visit at first enrollment, two monitoring visits during the trial, and a close-out visit after trial completion, totaling four planned visits. The number of monitoring visits may be adjusted following discussions with the investigators.

Ethics and Dissemination

Research Ethics Approval

This study will be conducted in accordance with the principles of the Declaration of Helsinki. This protocol, the informed consent form, all information provided to participants, and related documents have been approved by the institutional review boards (IRBs) of the seven participating sites (Jaseng Hospital of Korean Medicine, JASENG 2024–07-025-011; Daejeon Jaseng Hospital of Korean Medicine JASENG 2024–07-026; Bucheon Jaseng Hospital of Korean Medicine, JASENG 2024–07-024-006; Haewoondae Jaseng Hospital of Korean Medicine, JASENG 2024–07-022-006; Kyung Hee University Medical Center, KOMCIRB IRB 2024–11-010-010; Kyung Hee University Hospital at Gangdong, KHNMCOH IRB 2024–08-004-004; Pusan National University Korean Medicine Hospital,PNUKHIRB IRB 2024–08-004-007).

Protocol Amendments

All amendments to the protocol will be submitted for IRB approval. Except for modifications intended to eliminate immediate hazards to participants or administrative changes, all amendments will receive approval from the IRB before implementation.

Consent

Before initiating the study, participants will be fully informed about its purpose, potential benefits, risks, and safety considerations. Written informed consent will be obtained from each participant by the investigators before enrollment, based on voluntary agreement.

Ancillary Studies

Separate consent for the provision of research information to third parties and secondary use will be obtained. Research data will be shared for secondary research purposes only from participants who provide additional consent. The research data will be anonymized before disclosure and used only after review and approval by the IRBs of the respective institutions.

Confidentiality

All personal and medical information of participants will be strictly managed under the supervision of the IRB. All data will be kept confidential and protected. The principal investigator will assign unique identification numbers to the enrolled participants, thereby coding their data to maintain confidentiality.

Data Access

Medical information will be available to physicians for treatment purposes. Where appropriate, data may be reviewed by the CRA, collaborating organizations, or the IRB upon request for inspection.

Data sharing is not applicable because this manuscript reports a study protocol and no datasets have yet been generated.

Ancillary and Post-Trial Care

Participants who feel that they have not fully recovered or who experience recurrence after treatment completion will be allowed to seek care of their choice. In such cases, treatment details will be recorded at follow-up visits. For any unexpected delayed AEs, participants will also be permitted to receive medical care according to the investigator’s instructions.

Dissemination Policy

The study results will be disseminated to medical specialists and the general public through publications and presentations at academic conferences. The results may not have been published or used without prior approval from the Jaseng Korean Medical Hospital.

Discussion

HM is a key component of KM practices. In the 2020 National HM Consumption Survey, 18.8% of outpatients and 43.0% of inpatients visiting KM institutions were administered HM.¹⁹ Moreover, a survey of KM practice patterns for lumbar intervertebral disc displacement found that over 95% of KMDs utilize HMS as one of their main treatment modalities.²⁰ Clinical guidelines also provide recommendations for the use of HM in LBP-related conditions, such as nonspecific CLBP (A/High),²¹ lumbar disc herniation (B/Moderate),²² and lumbar spinal stenosis (C/Very Low; for combined use with non-operative treatments).²³ A recent systematic review¹¹ revealed that HM is significantly more effective than usual care in improving pain and functional disability.

However, the current clinical evidence on HM has intrinsic limitations. Although approximately 90% of KMDs apply pattern identification in their clinical practice,²⁴ few clinical studies have incorporated this process into trial designs.²⁵ In addition, during long-term HM treatment, KMDs usually modify HM composition according to each patient’s changing symptoms and conditions as part of a personalized treatment strategy. However, most existing RCT protocols do not allow such modifications. Although such designs enable precise evaluation of the efficacy of individual HMs, they differ substantially from the individualized treatment approaches of KM, thereby limiting the demonstration of the true therapeutic effectiveness of HMS in real clinical settings.

In this regard, we planned a PCT to reflect real-world clinical practice and generate evidence that is more informative for clinicians and policymakers. PCTs aim to evaluate whether interventions work in everyday clinical settings, maximizing their applicability and generalizability. The comparison group was selected from treatments commonly used in routine practice. Outcome measures included a wide spectrum of patient-centered variables.²⁶

In this study, the prescription interval and duration of HMS will follow the reimbursement standards of the National Health Insurance for herbal decoctions in Korea. In the current pilot project for insurance reimbursement of herbal decoctions in Korea, health insurance benefits are provided for prescribing a 20-day supply of HM dispensed in two 10-day portions. Accordingly, in this study, the participants in the HMS group will visit the institution every 10 days during the treatment period to receive HM. To ensure an adequate treatment duration, the total dose is set for 30 days, which is 10 days longer than the health insurance coverage. Considering the time required for HM preparation and delivery across the seven institutions, the total treatment period is set at 5 weeks. In addition, the primary endpoint will be set at Week 7 to capture the period during which the effects of both interventions are expected to appear and be maintained. This design reflects the pragmatic nature of this study, based on the assumption that patients’ responses to HM would not only appear immediately after treatment but also be sustained for a certain period thereafter in real-world clinical settings. Participants will be encouraged to complete the full 30-day course of HM within this 5-week period. In the HMS group, KMDs will be allowed to modify or adjust prescriptions according to the patients’ clinical symptoms. In the comparison group, KMDs will be permitted to provide individualized NPKM treatments within the health insurance coverage, thereby reflecting routine KM practices.

NPKM is a routine intervention widely used for CLBP in Korean medical settings,¹⁵ and its effectiveness has been well established. For instance, in an RCT of lumbar disc herniation (a common cause of LBP), compared with usual conservative care (patient education, rest, analgesics, or physical therapy), combined NPKM treatments (electroacupuncture, pharmacopuncture, topical applications, Chuna therapy, and exercise) resulted in greater improvements at 1 month, with mean differences of 6.37 (95% CI: 2.54–10.20) in VAS and 15.55 (95% CI: 12.18–18.92) in ODI.²⁷

Accordingly, this study will test the primary outcome using a non-inferiority design; if non-inferiority is confirmed, a superiority analysis will subsequently be conducted. The non-inferiority design is particularly meaningful in the context of a PCT. If HMS demonstrates a similar level of effectiveness to NPKM under real-world clinical conditions, it would provide supportive evidence for its practical applicability and for future health insurance coverage and clinical guideline development. To enable a multidimensional assessment, data on pain, function, quality of life, physical health, and healthcare costs will be collected through multiple outcome measures.

A related published protocol is registered under a different CRIS number (KCT0010035). While two protocols share some elements, our study was independently developed for CLBP, to enhance feasibility in the KM primary care setting. For example, the target population differs: KCT0010035 focuses on patients with radiating symptoms and requires imaging-confirmed disc pathology, whereas our study enrolls adults with chronic low back pain without requiring imaging confirmation for eligibility. These design choices were made to improve external validity in the intended primary care setting.

This protocol is the first prospective pragmatic RCT to evaluate the effectiveness of HMS for CLBP. However, this study has some limitations. First, because HMS is prescribed in an individualized manner, heterogeneity in herbal prescriptions may reduce internal validity and limit the ability to attribute outcomes to any specific HM formulation; however, the types and compositions of HMs used in the study will be thoroughly summarized and presented to assist clinicians in understanding real-world prescription patterns and developing treatment strategies. Second, although the NPKM interventions were implemented within a predefined treatment framework, some degree of treatment heterogeneity is unavoidable because limited individualization was allowed to reflect real-world clinical practice. Site will be considered as a clinically meaningful covariate in the analysis to partially account for between-site differences, although residual heterogeneity may remain.

Third, the treatment patterns observed in this study may not be representative of all KM clinical settings. To address this limitation, seven research institutions will be included to ensure clinical diversity, and certain restrictions will be applied to NPKM so that they remain within the clinical considerations outlined in the clinical practice guideline for nonspecific CLBP.²¹

Fourth, concomitant treatments, including analgesic or anti-inflammatory medications, were not fully restricted. These treatments will be documented throughout the study and taken into account in interpreting the results, including analyses related to healthcare utilization.

Fifth, because the treatment characteristics differed substantially between the two groups, blinding of participants and treating clinicians was not feasible. In this context, blinding of outcome assessors was considered the most feasible method to reduce bias. To partially account for this issue, treatment credibility and expectancy will be assessed and included as a clinically meaningful covariate in the analysis.

Despite these limitations, this pragmatic design is expected to generate comprehensive data on the overall effectiveness and safety of HMS. The results of this study will contribute to the practical evidence base for CLBP management and healthcare policies in KM.

Conclusion

This protocol was designed to investigate the effectiveness and safety of the HMS in improving pain intensity, functional status, and quality of life in patients with CLBP. By allowing clinical diversity in the HMS group and comprehensively analyzing the treatment and prescription details, along with participants’ healthcare utilization, this study may provide practical evidence relevant to real-world clinical practice and future healthcare decision-making. This study may help build the evidence base to support HMS as an additional treatment option for CLBP management and may also serve as a basis for future guideline development.