A Study Protocol for a Multicenter, Pragmatic, Randomized Controlled, Parallel-Grouped Pilot Clinical Trial: Effectiveness of Non-Pharmacological Versus Pharmacological Treatments for Non-Acute Lumbar Disc Herniation

Article information

Perspect Integr Med. 2023;2(1):59-64

Publication date (electronic) : 2023 February 21

doi : https://doi.org/10.56986/pim.2023.02.009

Hui Yan Zhao ¹^,²

, Purumea Jun ²

, Chaewon Lee ³

, In-Hyuk Ha ⁴

, Chang-Hyun Han ¹^,²^,

¹Korean Convergence Medical Science, University of Science and Technology (UST), School of Korea Institute of Oriental Medicine, Daejeon, Republic of Korea

²Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea

³St. Johnsbury Academy Jeju, Jeju Special Self-Governing Province, Republic of Korea

⁴Jaseng Spine and Joint Research Institute, Jaseng Medical Foundation, Seoul, Republic of Korea

^*Corresponding author: Chang-Hyun Han, Korean Medicine Science Research Division, Korea Institute of Oriental Medicine, 1672, Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea, E-mail: chhan@kiom.re.kr

Received 2022 October 24; Revised 2022 November 21; Accepted 2022 December 7.

Abstract

Background

This study was the development of a protocol for the comparison between the efficacy of non-pharmacological and pharmacological treatment approaches for lumbar disc herniation in a pragmatic environment to obtain real-world based study data.

Methods

The protocol sets out a two-armed, parallel, multicenter pragmatic, randomized-controlled trial (RCT) which will be conducted in four spine specialist hospitals in Korea to determine cost-efficiency.

Results

The study will enroll 36 participants and allocate patients into either the non-pharmacological treatment group or the pharmacological treatment group in a 1:2 ratio. Patients must have evidence of disc-related disease diagnosed using MRI, as well as having lower back pain or radiating leg pain (numeric rating scale score ≥ 5). The treatment will last for 8 weeks with a 26-week follow-up. The primary outcome will be measured using the Oswestry Disability Index score from Week 9. Secondary outcomes related to lower back pain and radiating leg pain will be measured using the scores from the numeric rating scale, the visual analogue scale, the European Quality of Life 5 Dimensions 5 Level Version), the 12-item Short Form Survey, and the patient global impression of change.

Conclusion

This is the first protocol for a pragmatic RCT evaluating the efficacy, safety, and cost-efficiency of non-pharmacological and pharmacological treatment strategies in a clinical setting. Following the basis of this protocol, RCTs may play an important role in establishing guidelines for treating radiating leg pain and lower back pain and provide effective information to clinicians in practical settings.

Keywords: disc back pain; herniation; leg; radiating pain; treatment

Visual abstract

Introduction

Lifetime prevalence of spinal pain and radiating leg pain has been reported as 84% worldwide [1], and the annual prevalence has been reported as approximately 60% [2]. The prevalence of sciatica is estimated to be from 1.2% to 43% [3]. The total costs attributable to lower back pain in the United States exceeded USD 100 billion [4]. Lumbar disc herniation (LDH) is the most common cause of lower back pain and radiating leg pain [5]. Most patients with radiating pain due to acute LDH improve over the course of 2 weeks to 3 months [6], while some patients suffer from repeated lower back pain due to chronic LDH [7].

Lumbar spine surgery [8,9], drug therapy, heat therapy, exercise therapy, or acupuncture treatment can be used to treat LDH [10]. The American College of Physicians (ACP) recommends that clinicians should preferentially use non-pharmacological interventions to treat patients with acute or chronic lower back pain with or without radiating leg pain [11]. In the ACP guidelines, non-pharmacological interventions include the application of superficial heat, massage, acupuncture, and spinal manipulation [11].

Medical practices performed in Korea differ from the ACP guidelines. A study using Korean Health Insurance data indicated that 78.5% of patients with LDH received nonopioid analgesics and approximately 14% of patients underwent a nerve block [12]. This means that in Korea, unlike ACP guidelines, active pharmacological treatments including nerve block is mainly used.

The reasons for the discrepancy between national recommendations and options chosen in the real world have not been reported. Therefore, this study aimed to set out a protocol to compare non-pharmacological and pharmacological treatment approaches for LDH in a pragmatic environment to obtain real-world study data.

Materials and Methods

1. Study design and setting

This will be a multicenter, pragmatic randomized controlled, parallel-grouped pilot study to compare the efficacy of Korean medicine non-pharmacological interventions and pharmacological interventions in patients with non-acute lumbar disc herniation. A total of 36 patients will be enrolled at four branches of Jaseng Hospitals of Korean Medicine (nine patients each from Jaseng Hospitals in Gangnam, Daejeon, Bucheon, and Haeundae). Patients will be enrolled and assigned to either the non-pharmacological intervention group (12 patients) or pharmacological intervention group (24 patients) in a ratio of 1:2 to compare therapeutic effects in the pragmatic clinical environment. Interventions will be conducted twice a week for a total of 8 weeks. Follow ups will be performed 9, 13, and 26 weeks after the randomization of participants (Fig. 1).

Fig. 1

Flow chart.

2. Participants

This study will be conducted on patients aged 19–69 years who have had radiating leg pain for more than 3 months and a NRS score of 5 or higher for leg pain or back pain. Detailed inclusion criteria and exclusion criteria are shown in Supplementary 1.

3. Intervention

Patients enrolled in each group will be informed about Korean medicine non-pharmacological intervention and pharmacological intervention, and they will be asked to receive applicable intervention. Each intervention will be conducted in real clinical settings. It is not necessary to confine real clinical settings to the inside of the clinical study institutions. Interventions will be determined by the clinician’s medical decision based on each therapeutic strategy.

3.1. Non-pharmacological treatment group

Korean medicine non-pharmacological interventions will be performed twice a week for 8 weeks (a total of 16 times). However, the frequency of treatment can be adjusted according to the patient’s condition and clinician’s judgment. The typical Korean medicine non-pharmacological therapies will include acupuncture, electro-acupuncture, and spinal manipulation. The type of interventions used will be recorded in the case report form.

3.2. Pharmacological treatment group

Pharmacological interventions include the use of medication and a nerve block. Patients will be advised that they will receive a nerve block three times during the 8 weeks of treatment, and visit a medical center twice a week for their drug prescription. However, actual number of nerve blocks, visits, prescriptions, and the number of days for which a prescription is intended will be based on the clinician’s judgment. Based on the patients’ conditions, physical therapy such as transcutaneous electrical nerve stimulation and interferential current therapy may also be used. Detailed treatment will be recorded in the case report form.

4. Outcome

The primary outcome of the study will be measured using the Oswestry Disability Index (ODI) [13]. The secondary outcomes will be measured using scores from the NRS [14–16] and the VAS [15,17] to determine lower back pain and radiating leg pain, and the patient global impression of change (PGIC) [18], Short Form-12 Health Survey, version 2 (SF-12 v2) [19], together with 5-level European Quality of Life-5 dimensions (EQ-5D-5L) [20], and credibility, expectancy, costs (medical/non-medical costs, time costs), productivity loss [21], and drug consumption will be recorded. Detailed potential outcomes are shown in Supplementary 2.

5. Timeline of participants

The protocol for the timeline is shown in Table 1.

Table 1

The Timeline for the RCT.

6. Sample size estimation

There is no previous study that could be used as the basis for calculating the sample size. This study allocated participants in a 1:2 ratio. The larger number of patients for pharmacological intervention is to confirm the feasibility of pharmacological group. The minimum sample size considered necessary for the pilot study is 12 participants per group. Accordingly, the study is designed to enroll a total of 36 participants: 12 in the Korean medicine non-pharmacological intervention group and 24 in the pharmacological intervention group.

7. Recruitment

This study will recruit participants by issuing a press release, posting recruitment advertisement in or outside the study institutions, and using the recruitment announcement website on the Internet.

8. Randomization and allocation concealment

Study participants who fulfill the inclusion and exclusion criteria and voluntarily sign the informed consent form will be allocated into one of the two groups in a 1:2 ratio (12 vs. 24) using a randomization list. The randomization list will be created by a statistician using R studio 1.1.463 (2009–2018 RStudio, Inc.). To generate the random sequence, permuted block randomization will be performed. The size of one block is set to 3, and patients are allocated into either the study or control group in a 1:2 ratio. Nine study participants will be stratified and allocated into one study site. The generated randomization result will be sealed in an opaque envelope and stored in a cabinet with double locks. The investigator of each study site will open a randomization envelope and allocate the participants into a group. The randomization number given to each participant should be recorded in the electronic chart.

9. Blinding

Since this study design cannot be blinded, it will be conducted as an open-label design, but the assessors will be blinded. The assessors will not participate in the interventions, and the evaluations will be conducted in a separate space before the interventions, while they are blinded to the group allocation.

10. Data management

This study will use an electronic Case Report Form (e-CRF) based on the internet-based clinical research management systems operated by the Korea Centers for Disease Control and Prevention. Before initiating the study, investigators of each study site will be educated about the standard operating procedures and the guidelines on how to complete the e-CRF. The accuracy and reliability of the data entered into the e-CRF will be guaranteed through double data entry verification. The data entered into the e-CRF will be locked and concealed from all study staff, except for the person responsible for data management.

11. Statistical analysis

In this study, intention-to-treat analysis will be the primary analysis. Participants’ socio-demographic characteristics and treatment expectancy will be evaluated for each group. Efficacy endpoint of this study is change from baseline in continuous outcomes (NRS, VAS, ODI, EQ-5D-5L, and SF-12) between two groups at a specific timepoint. The time when the ODI reduces to ≤ 70% from the baseline will be judged as the time at which efficacy is obtained. The survival analysis between two groups will be performed.

If a superiority test fails, a non-inferiority test can be performed. Significant level of all analyses will be set to 0.05, and all data will be analyzed using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA) or R studio 1.1.463 (2009–2018 RStudio, Inc.). Detailed statistical analysis is shown in Supplementary 3.

12. Economic evaluation

This study protocol includes a comparison of the cost-effectiveness between Korean medicine non-pharmacological interventions and pharmacological interventions. The primary economic evaluation index is an Incremental Cost-Effectiveness Ratio of the Korean medicine non-pharmacological intervention group against the pharmacological intervention group. Economic evaluation will be analyzed during the intervention and entire follow-up period. Detailed is shown in Supplementary 4.

13. Adverse events

All adverse events (AEs) that occur during the study will be checked and recorded. AEs are any undesirable and unintentional signs (e.g., abnormal laboratory findings), symptoms, or illnesses that occur after the procedures in the course of the study, which do not necessarily have a causal relationship with the treatment. AEs will be collected through participants’ complaints or by monitoring the participants. AEs between groups will be reported by frequency.

The investigator will assess the causal relationship between each intervention and AE using a 6-point scale. The severity of AEs will be classified into three levels according to the Spilker classification [22]. Study staff should explain to the study participants or caregivers all the AEs which may result from the intervention and emphasis the importance of reporting all AEs that occur after the intervention. All AEs should be recorded in the case report form.

14. Data monitoring

Monitoring should be conducted to review the safety of participants, and the case report form and source document should be compared to assure participant safety and study data integrity. Monitoring is planned for a minimum of 2 time points including baseline and endpoint measurements.

15. Ethical consideration and dissemination

15.1. Ethical approval

All study-related documents such as the protocol, CRF, and ICF are required to be approved by the Institution review board of Jaseng Hospital of Korean Medicine before initiating patient enrollment (Aprooval no.: JASENG 2021-05-016, JASENG 2021-05-017, JASENG 2021-05-018, and JASENG 2021-05-019). Revision to documents will be subject to the IRB’s approval. The protocol was registered on Clinicaltrials.gov (NCT05003726), and any revision will be updated to the mentioned website.

To protect the patients enrolled in this study, all clinical investigators will be educated on the Helsinki Declaration, the Korean Good Clinical Practice Guidelines, and the study protocol.

15.2. Patient consent

Before initiating the study, the investigator will meet each participant face-to-face to fully inform the patients about the clinical trial (effects, AEs, and safety issues). Then, the signed ICF will be obtained. A copy of the ICF will be provided to the participants.

16. Confidentiality

Any personal information about participants will be controlled under the strict supervision of the IRB. The Principal Investigator will encode the participant information by assigning them a unique identification number. Any personal information and medical information about the participants which will be recorded are confidential and can be released to third parties according to the ICF signed by the participants (or a separate written authorization form for the use and release of personal information). Only when appropriate, data from this study should be provided to monitors, affiliates, and IRBs of the study sites for investigation, on request.

Discussion

There are various guidelines for lower back pain with or without radiating leg pain. The ACP preferentially recommends non-pharmacological treatments for patients with acute, subacute, and chronic lower back pain because of drug side effects [11]. On the other hand, the UK National Institute for Health and Care Excellence primarily recommends pharmacological treatments for acute lower back pain [23]. In general, guidelines are designed based on key clinical questions, collecting evidence to critically appraise (including systemic review including RCTs conducted in well-controlled settings) and a review of the evidence. Meanwhile, clinicians may not always comply with guidelines. In Korea, 78.5% of patients with lumbar disc herniation received nonopioid analgesics, 4% of patients received opioid analgesics, and ≥ 14% of patients had undergone nerve blocks in 2016 [12].

Accordingly, this study protocol was designed for the comparison of the efficacy and safety of non-pharmacological and pharmacological treatment strategies in the real world. Although the participants will be randomly allocated to either the non-pharmacological or pharmacological intervention group, they will receive treatment with the corresponding intervention in the real world. There will be no predetermined study sites. Each patient can choose a medical center and a physician, and the physician will determine the treatment to be conducted. Participants will provide the details and outcome of the treatment received in real world to the study staff. In general, pharmacological interventions are referred to as an intervention using drug/medication. However, this study has included nerve blocks (which are commonly used in clinical settings as a pharmacological intervention) to determine the effects of non-pharmacological treatment to compare with the efficacy of pharmacological treatment.

Another major objective of this pilot study protocol was to test the feasibility of a subsequent study. During the process of protocol development, discussions with the investigators in four study institutions were focused on understanding the study design, the study purpose, and treatment strategy for the patients. In addition, we intend to observe the actual degree of performance. From the patient’s point of view, we intend to observe if the patients receive treatment according to the assigned strategy from the external environment, and if they adequately convey the details and outcome of the treatment to the study staff. This study intends to test the possibility of recruiting patients. When this protocol study was first planned, the intention was to recruit patients who had radiating leg pain with a NRS score ≥ 5. However, recruiting these patients would be difficult. Accordingly, the inclusion criteria were changed to include those who had lower back pain and radiating leg pain with a NRS score ≥ 5.

This is a protocol for a pragmatic, pilot RCT that evaluates the efficacy, safety, and cost-effectiveness of non-pharmacological and pharmacological treatment strategies in real-world clinical settings and assesses whether such a pragmatic study can be performed. A subsequent study will be designed based on the progress and results of the resultant study based on use of the protocol described in this article. The results of such studies may play an important role in establishing guidelines for the treatment of radiating leg pain and lower back pain, and provide useful information to clinicians.

Supplementary Materials

Supplementary material is available at doi: https://doi.org/10.56986/pim.2023.02.009.

pim-2023-02-009-Supplementary-1.docx

pim-2023-02-009-Supplementary-3.docx

pim-2023-02-009-Supplementary-4.docx

Notes

Author Contributions

Conceptualization: IHH. Methodology: CL and IHH. Formal investigation: CHH. Writing original draft: HYZ and PJ. Writing - review and editing: CHH.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Ethical Statement

All study-related documents such as the protocol, CRF, and ICF were approved by the IRB of Jaseng Hospital of Korean Medicine before initiating patient enrollment (Approval no.: JASENG 2021-05-016, JASENG 2021-05-017, JASENG 2021-05-018, and JASENG 2021-05-019). Revision to the documents is subject to the IRB’s approval. The protocol was registered on Clinicaltrials.gov (NCT05003726), and any revision will be updated on the mentioned website.

Data Availability

Raw data cannot be disclosed, and all relevant analyzed data are included in the manuscript and supplementary files.

Funding

None.

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Article information Continued

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Table 1

The Timeline for the RCT.

Time point	Screening	Enrollment, allocation	Intervention				Follow-up			Unscheduled visit
	Screening	Enrollment, allocation
	Wk −1	Wk 0	Wk 1	Wk 2, 3, 4	Wk 5	Wk 6, 7, 8	Wk 9	Wk 14	Wk 27
Visit window	−10–0	Control point	± 3	± 3	± 3	± 3	± 7	± 14	± 14
Enrollment

Written informed consent	○
Eligibility screening	○
Vital signs	○	○	○	○	○	○	○	○	○	○
Sociodemographic characteristics	○
Medical history	○	○
Review of system	○
L-spine MRI	○								○
Blood analysis	○								○
Randomized allocation		○

Interventions (data collection only)

Treatment in non-pharmacological group (experimental group)			○	○	○	○	○
Treatment in pharmacological group (control group)			○	○	○	○	○

Assessments

Education for strategy		○
Drug consumption	○	○	○	○	○	○	○	○	○	○
Adverse events		○	○	○	○	○	○	○	○	○
NRS of LBP			○	○	○	○	○	○	○
NRS of leg pain	○		○	○	○	○	○	○	○
VAS of LBP			○	○	○	○	○	○	○
VAS score for leg pain			○	○	○	○	○	○	○
Oswestry Disability Index			○		○		○	○	○
PGIC							○	○	○
SF-12			○		○		○	○	○
EQ-5D-5L			○		○		○	○	○
Physical • sensorineural examination			○		○		○	○	○
Credibility and expectancy	○
Healthcare costs			○	○	○	○	○	○	○
Non-healthcare costs				○ (Wk 2)
Loss of productivity			○	○	○	○	○	○	○
Compliance evaluation							○

Week −1, Week 0, and Week 1 records can be completed on the same day. If a blood test has been conducted within the last 2 weeks and a lumbar spine MRI has been performed following the onset of symptoms, and within the last 3 months, the results can be used (including results from this as well as other hospitals). At the end of the study visit (Week 27), if the participants have undergone a blood test and lumbar spine MRI within the last 2 weeks from the visit date, the results can be used (including results from this hospital and other hospitals). If the participant is not be able to visit at Weeks 14 and 27, the questionnaires can be completed over the phone or via the website.

EQ-5D-5L, the European Quality of Life 5 Dimensions 5 Level Version; LBP, lower back pain; MRI, magnetic resonance imaging; PGIC, patient global impression of change; SF-12, the 12-item Short Form Survey; VAS, visual analogue scale.