Study design

This double-blind, randomised, placebo-controlled, parallel-group, five-centre trial will be conducted at the Department of Otorhinolaryngology of TKM in Kyung Hee University Hospital at Gangdong (Seoul, Korea), Kyung Hee University Medical Centre (Seoul, Korea), Pusan National University Hospital (Pusan, Korea), Dongguk University Medical Centre (Ilsan, Korea) and Semyung University hospital (Jecheon, Korea).

The trial will consist of a 4-week oral administration of SCRT with two visits at 2-week intervals and an 8 week follow-up period with two visits at 4-week intervals. Before enrolment, all subjects will undergo a 7-day run-in period. The enrolled subjects will be randomly allocated to two parallel groups: the SCRT group and the placebo group. The study design flow chart is shown in figure 1.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Study design flowchart. SCRT, So-Cheong-Ryong-Tang.

Sample size

Sample size calculations were performed to determine the number of subjects to be enrolled. The study aims to detect a difference between the two study groups in total nasal symptom score (TNSS) change prior to (visit 1) and following (visit 3) medication. To our knowledge, there exists one randomised clinical trial for SCRT use in patients with AR.10 However, primary outcome measurement conducted in that study was not suitable to estimate sample size. We applied effect size and SD values obtained from other trials that used herbal medicines in patients with AR.14–16 We thereby assumed that SCRT administration would improve TNSS score by 2.68 points, while placebo will improve it by 1.25 points and that the SD will be 2.809. The following formula was used to estimate the sample size:

In the present study, the ratio (r) of number of subjects in the SCRT group to the number in the placebo group will be 1:1. With a power of 80% (1−β) and a significance level of 5% (α), the required sample size is approximately 61 for each group. Considering an assumed dropout rate of 20%, 154 subjects will be required.

Recruitment

Subjects will be recruited using two strategies. One is to display recruitment posters outside the clinics of each centre. The posters will contain brief descriptions of inclusion and exclusion criteria, purpose of the study and intervention. The other is to place advertisements on the homepage of the hospitals and online communities of groups with geographical proximity to the hospital area.

Inclusion and exclusion criteria

The inclusion criteria are as follows: (1) age 18–60 years; (2) presence of two or more nasal symptoms (rhinorrhoea, nasal congestion, nasal itching and sneezing) with severity score ≥2 (0=no symptoms, 1=mild symptoms, 2=moderate symptoms, and 3=severe symptoms); (3) presence of nasal symptoms for over two consecutive years; and (4) positive reaction to one or more perennial allergens as evaluated in the skin prick test.

The exclusion criteria are as follows: (1) treatment with nasal/oral corticosteroids within the past month; nasal cromolyn or tricyclic antidepressants within the past 2 weeks or with nasal/oral decongestants, nasal/oral antihistamines or antileukotrienes within the past week; (2) presence of rhinosinusitis (paranasal sinus X-ray demonstrating mucosal thickening or partial or complete opacification of the paranasal sinuses); (3) presence of hypertension (systolic ≥180 mm Hg or diastolic ≥100 mm Hg); (4) presence of abnormal liver function (aspartate transaminase (AST) or alanine transaminase (ALT) ≥100 IU/L) or abnormal renal function (blood urea nitrogen (BUN) ≥30 mg/dL or creatinine ≥1.8 mg/dL (male), 1.5 mg/dL (female)); (5) presence of neoplasm, severe systemic inflammation or any other systemic disease that affects AR; (6) history of drug allergy; (7) history of anaphylaxis in response to allergic tests; (8) pregnancy or lactation or (9) participation in another clinical study within the past 3 months.

Subject withdrawal criteria

The subject withdrawal criteria are as follows: (1) use of medication that can affect nasal symptoms (nasal/oral corticosteroids, nasal cromolyn, tricyclic antidepressants, nasal/oral decongestants, nasal/oral antihistamines, antileukotriens and herbal medicines); (2) onset of rhinosinusitis (diagnosis with paranasal sinus X-ray); (3) onset or diagnosis of neoplasm, severe systemic inflammation or any other systemic disease that affects AR; (4) pregnancy; (5) medication compliance <80% at visits 2 and 3; (6) occurrence of a serious adverse event; (7) subjects’s withdrawal of consent and (8) detection of eligibility violations, occurrence of other significant protocol violations during the study.

Skin prick test

The skin prick test will be performed to screen patients with AR, in accordance with routine procedures. For this test, seven common aeroallergens (Dermatophagoides farinae, Dermatophagoides pteronyssinus, dog fur, cat fur, Alternaria tenuis, Aspergillus fumigatus and cockroach),17 negative controls (50% glycerine saline) and positive controls (0.1% histamine phosphate) will be used (Allergopharma GmbH & Co KG, Reinbek, Germany). The subjects who show a positive reaction to the skin prick test will be judged to have passed the screening phase.

Randomisation and blinding

Institute of Safety, Efficacy and Effectiveness Evaluation for Korean Medicine (ISEE), the contract research organisation (CRO) of this trial will enforce randomisation using an ISEE-developed web-based central randomisation programme. The randomised allocation sequence will be generated by researchers from ISEE using Microsoft Excel with block sizes of 2 and 4, and an allocation ratio of 1:1. Institution and age group stratifications are also performed. Following study drug manufacture by the pharmaceutical company (Hanpoong Pharm & Foods Co), drugs sealed in an opaque aluminium package will be labelled by number together alongside placebo drugs and allocated based on the randomisation number. Accordingly, SCRT and placebo packages will be provided to each centre. Following the screening phase, the screening number of each subject and the centre code are entered in the randomisation website. The subjects will be assigned a randomisation number and will receive the corresponding package, containing either SCRT or the placebo drug. All researchers and all subjects, excluding the statistician of ISEE, will be blinded for the assignments process until the trial is completed.

Intervention

Hanpoong Pharm & Foods Co manufactures the SCRT and placebo in compliance with Korea Good Manufacturing Practice standards. SCRT used in this study (Socheongryongtang extract granule Hangpoong) is comprised of dried, bitter, brown granules extracted with water. The extract is permitted and regulated by the Korean Food & Drug Administration and is composed of eight herbs: Glycyrrhiza uralensis Fischer 1 g Zingiber officinale Roscoe 0.5 g Cinnamomum cassia Blume 0.2 g, Ephedra sinica Stapf 0.5 g, Pinellia ternata Breitenbach 2.67 g, Paeonia lactiflora PALL 1 g, Asiasarum sieboldi F. Maekawa 0.5 g, Schisandra chinensis 2.67 g (per 9 g of granules). The placebo is made of lactose, corn starch and caramel colouring and has the appearance, shape, weight, taste and colour of the SCRT being administered. SCRT and placebo granules are sealed in opaque aluminium bags and administered to subjects in doses of 3 g. The pharmacists will instruct the subjects to dissolve SCRT or placebo from each package in water and take the solutions 30 min after each meal three times per day for 4 weeks. All subjects will be required to return remains of drugs for calculating compliance.

Outcome measurement

Secondary outcomes

Rhinoconjunctivitis Quality of Life Questionnaire score

Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) is self-report questionnaire used to assess the quality of life in patients with AR. The questionnaire has seven domains: activity limitations, sleep disturbances, non-hay fever symptoms, practical problems, nasal symptoms, ocular symptoms and emotional problems. Subjects will be asked to recall their experiences during the previous week and to rate each question on a ranging from 0 (no impairment) to 6 (severe impairment).18 19 RQLQ baseline value will be measured just prior to the start of the experiment and then again during visits 1, 2, 3, 4 and 5.

Total serum IgE, eosinophil count and cytokines levels

Cytokines will not be measured for all participants and cytokines level will be measured only in one centre (32 subjects), Kyung Hee University Hospital at Gangdong, as a pilot study. Total serum IgE, eosinophil count and cytokine levels (interferon gamma, interleukin (IL)-4, IL-5, IL-8, IL-10, IL-13 and tumour necrosis factor alpha) will be measured during visits 1 and 3. SCRT has been observed to regulate cytokines in animal studies.10–12 However, no clinical study has observed the effect of SCRT on cytokine regulation.

Nasal endoscopy index for pattern identification

For PI of AR, nasal endoscopy index was developed in 2013 (figure 2) and inter-rater and intrarater reliability study was conducted.7 8 In this study, one specialist in the department of Otolaryngology of Korean Medicine at each centre will evaluate the nasal endoscopy index during visits 1 and 3.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Nasal endoscopy index for pattern identification.

Scoring method is as follows: the doctor checks the score following observation of the nasal membrane and inferior turbinate of the patient via nasal endoscopy. In evaluating the nasal membrane colour, either the pale score or hyperaemia score must be 0 (for example, when pale score is 2, hyperaemia score should be 0; if the nasal membrane colour is normal, both pale and hyperaemia scores are 0). The same rule is applied in case of the rhinorrhoea score. If there is no rhinorrhoea, both the watery score and the yellow score are 0. Cold score is the sum of the pale score as measured while evaluating the nasal membrane parameter and the watery score as measured while evaluating the rhinorrhoea parameter. Heat score is the sum of the hyperaemia score as measured while evaluating the nasal membrane parameter, and the yellow score as measured while evaluating the rhinorrhoea parameter. Inferior turbinate swelling score is not used to evaluate cold or heat patterns but used to evaluate nasal obstruction.

Pattern identification by the clinician

Specialists in the department of Otolaryngology of TKM at each centre will select a pattern for each subject from among lung–heat, lung–cold and spleen qi deficiency through face-to-face diagnoses, based on body and nasal conditions. We will investigate the efficacy of SCRT based on PI.

Pattern identification questionnaire for allergic rhinitis

PI questionnaire for AR V.1.0 was developed in 2008 by specialists in the Department of Otolaryngology of TKM, based on systemic and nasal symptoms and signs.20 However, that questionnaire had many problems in application to clinical practice and has since been revised based on several studies and discussions.21–23 Consequently, the PI questionnaire for AR V.3.0 has been developed.24 This questionnaire classifies patients with AR as possessing lung-heat, lung-cold or spleen qi deficiency and can be applied for both SAR and PAR. We plan to conduct a validation and reliability study and revise the questionnaire based on the results of this study (table 2).

View this table:

• View inline
• View popup

Table 2

Pattern identification questionnaire for allergic rhinitis, V.3.0

Safety outcomes

The levels of AST/ALT, BUN/creatinine and complete blood counts including white blood cell, red blood cell, haemoglobin, haematocrit and platelet count will be measured at screening and during visit 3 and visit 5. The investigator will ask subjects questions regarding adverse events (AEs) during every visit and record details of AEs in case report forms. All AEs will be monitored by independent clinical research associate (CRA). When serious adverse events occur, the investigator will provide treatment immediately and report to the institutional review board (IRB) within 24 hours from the time of recognition.

Quality control

To protect the rights and welfare of the subjects and to maintain the quality of the study, monitoring will be performed. ISEE, the CRO of this study, will send a clinical research associate (CRA) to five centres at least four times (after the first subject is enrolled, after half of planned enrolment is complete, after planned enrolment is complete and after all visits of subjects have occurred) during the study and the CRA will visit each centre additionally on request. The CRA will check if the trials are proceeding according to the protocol by performing cross-checks of the informed consent form, CRF, original chart of subjects and drug management records.

Statistical analysis

A statistician independent from researchers will use SPSS V.21 (IBM) to manage and analyse the data. An intent-to-treat (ITT) analysis is an analysis method employed for evaluating data collected from a subject who takes the study drug at least once. In ITT analysis, missing data are replaced via the last observation carried forward method. A per-protocol (PP) analysis is used to evaluate data collected from a subject who completes all steps of the experimental protocol. Efficacy measurement analysis will mainly use ITT analysis while PP analysis will be additionally carried out if statistically significant. Further, the analyses will be fully described. Safety evaluation will be conducted by ITT analysis.

Data will be displayed as the mean and SD for continuous variables and n (%) for categorical data. The baseline characteristics will be compared by an independent t-test for continuous values and χ² test or Fisher’s exact test for categorical values. The differences of TNSS, RQLQ, IgE, eosinophil count and cytokines during visit 1 and visit 3 between the SCRT and placebo groups will be compared using an independent t-test. A repeated-measures analysis of variance (ANOVA) test with Bonferroni post hoc test will be used to evaluate the changes in TNSS, RQLQ, IgE, eosinophil count, cytokines and safety assessment measurements throughout the experiment. Pearson correlation test will be used to analyse the relationship between cold and heat scores of nasal endoscopy index and TNSS changes. ANOVA will be used to analyse correlation between PI pattern (PI of clinician and PI questionnaire for AR) and TNSS changes. In all tests, a value of p<0.05 will be considered statistically significant.

Ethics and dissemination

This study was approved by the IRB of Kyung Hee University Hospital at Gangdong (KHNMC-OH-IRB 2015-04-009), Kyung Hee University Medical Centre (KOMCIRB-160321-HRBR-011), Pusan National University Hospital (2016–004), Dongguk University Medical Centre (2016–03) and Semyung University hospital (2016–01). This trial has been registered with ClinicalTrials.gov (NCT03009136) on January 2017. The trial will be performed in compliance with the Declaration of Helsinki and according to Good Clinical Practices as described by the Korea Food and Drug Administration.

Written informed consent will be obtained by the investigator from all subjects prior to enrolment. The investigator will explain the study in non-scientific language. All subjects will be given enough time to decide whether they wish to participate in the trial. The confidentiality of their personal information will be protected. Each subject will be assigned a study identification number at enrolment and will be represented in the data by that number. Throughout and subsequent to the trial, all documents and data will remain secure in a locked cabinet or as password-protected computer files.