Study design
An open-label, non-inferiority, randomized controlled trial was carried out to investigate the efficacy of BMD on symptoms, life quality and nasal resistance (NR) in PAR patients. All participants were recruited from the Otorhinolaryngology Department of Beijing Hospital of Traditional Chinese Medicine (BJHTCM). The study design and protocol were approved by the Ethics Committee of Beijing Hospital of Traditional Chinese Medicine affiliated to Capital medical University (code 2016BL-047). The study was conducted in accordance with the principles of the Declaration of Helsinki (2004) and the Medical Research Involving Human Subjects Act (WMO). Registration in China Clinical Trial Registry Center (ChiCTR-INR-16010063) was completed on 2 December 2016. This article will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines [10].
Participants
Recruitment information was posted in Beijing Hospital of Traditional Chinese Medicine and publicized through the Internet. Participants with PAR volunteered for the study were selected from January 2017 to April 2018 by physicians of otorhinolaryngology clinics. All the participants should meet the Western medicine diagnostic criteria for AR and the TCM syndrome diagnostic criteria for LQDCS. Syndrome differentiation was determined by two independent qualified TCM otolaryngologists independently.
Inclusion criteria:
(1) patients aged 18 to 65 years, no sex limitation (2) symptoms including sneezing, rhinorrhea, nasal obstruction and itching, occurred at least 4 days per week and lasted more than 4 weeks [11], with positive skin prick test to house dust mites (+++ or more, ALK reagent) according to the Allergic Rhinitis and its Impact on Asthma criteria (ARIA, 2008); (3)the syndrome differentiation corresponded with LQDCS which contains a light pink tongue with thin white coating and weak pulse [12]; (4) patients who signed the informed consent form volunteered to participate in the study; (5) patients without allergy to Chinese herbal medicine.
Exclusion criteria:
(1) women who were pregnant or ready to conceive in past 6 months, or during lactation; (2) patients with nasal polyps, rhinosinusitis, obvious deviated nasal septum, or upper respiratory tract infection; (2) patients who were undergoing treatment for AR; (3) those who have serious disorders such as vascular malformation, hypertension, hematologic diseases, diabetes mellitus, malignant tumor, or mental disorders.
Randomization and blinding
The physicians were responsible for recruitment and therapeutic assessment of the patients. Participants recruited were randomly allocated into either the BMD group (n = 54) or the control group (n = 54) in a 1:1 ratio by a computer-generated random sequence in Good Clinical Practice Office of BJHTCM after a 7-day washout period, and the sequence could not be viewed by the physicians. The investigators were responsible for the distribution of drugs. All research team members were required not to communicate with the participants regarding their allocation. The flow chart and the study period are listed below (Fig.1 and table 1).
Fig 1 (additional file 1)
Table 1 Study design schedule
Week
|
-1
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0
|
1
|
2
|
3
|
4
|
|
Baseline
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Treatment and follow-up phase
|
Patient enrollment
|
√
|
|
|
|
|
|
Medical history
|
√
|
|
|
|
|
|
Skin prick tests
|
|
√
|
|
|
|
|
Informed consent
|
|
√
|
|
|
|
|
Randomization
|
|
√
|
|
|
|
|
TNSS
|
|
√
|
√
|
|
|
√
|
RQLQ
|
|
√
|
√
|
|
|
√
|
Adverse event
|
|
√
|
√
|
√
|
√
|
√
|
TNSS, Total Nasal Symptoms Score;
RQLQ, Rhinoconjunctivitis Quality of Life Questionnaires.
Intervention
All the patients completed the Total Nasal Symptom Score (TNSS), the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), nasal resistance and acoustic rhinometry under instruction. The participants in BMD group received BMD while the control group received fluticasone furoate spray (Flixonase, 50μg*120press, Glaxo Wellcome, S.A) and loratadine tablets (Clarityne, Shanghai Schering plough Pharmaceutical Co. Ltd.). Ingredients and dosage of BMD are presented below in table 2. Herbal medicines involved in the study were all produced by Beijing Institute of Traditional Chinese Medicine in the same batch. Every dose was decocted twice. All the herbals should be socked in cold water for 1 hour before decoction. The first decoction was boiled over high heat and remained boiling with low heat for 30 minutes, then filtered and reserved the liquid. The second decoction was boiled over high heat with cold water and then remained boiling with low heat for 15 minutes. Liquid was filtered and combined with that of the first decoction and the total volume added up to 400ml approximately. Patients took 200ml orally at 30 minutes after breakfast and dinner respectively for 4 weeks. According to the step-up therapy recommended by ARIA [13], the participants in control group were given fluticasone furoate spray 2 press per nostril and loratadine tablets 10mg per night. No other medicine or spicy, fishy, cold food was allowed during treatment for all participants.
For participants who withdrew or were excluded, information were recorded and the medicines were returned to investigators immediately. Patients who completed the study were followed up by the physicians and required to fulfill the TNSS score, RQLQ score, nasal resistance and acoustic rhinometry at the end of the treatment.
Table 2 The ingredients, dosage and actions of herbal medicines in Bimin Decoction (Every 7 dose)
Ingredients
|
Dosage(g)
|
Actions
|
Saposhnikovia divaricata root (fangfeng)
|
10
|
Dispelling wind-cold to prevent muscular interstices from invasion of exogenous pathogenic factors
|
Astragalus root (huangqi)
|
15
|
Strengthening the defense and removing edema
|
Atractylodes root (baizhu)
|
10
|
Consolidating the exterior and enhancing immunologic function
|
Cassia twig (guizhi)
|
6
|
Warming yang and dispelling cold
|
Radix paeoniae alba root (baishao)
|
10
|
Astringing the acid to nourishing yin of the body
|
Prunus mume fruit (wumei)
|
6
|
Astringing lung qi to consolidate the base of life
|
Fructus chebulae fruit (hezi)
|
6
|
Astringing lung qi to consolidate the base of life
|
Asarum heterotropoides root (xixin)
|
3
|
Eliminating wind to dispersing cold and removing edema
|
Schisandra chinensis fruit (wuweizi)
|
6
|
Astringing lung qi to consolidate the base of life
|
Herba ephedrae stem (mahuang)
|
3
|
Relieving exterior and eliminating wind to dispersing cold
|
Licorice root (gancao)
|
6
|
Reconciling all the other herbals
|
Main outcome
The main outcome of this study was the change of TNSS. The measurement was based on four nasal symptoms including sneeze, rhinorrhea, itchy nose and nasal obstruction, each was scored from 0 to 3 (0 = none, 1 = mild, 2 = moderate, and 3 = severe).
Secondary outcomes
The authorized and Sinicized RQLQ was applied. RQLQ consists of 28 questions on a 7-point scale (0 = not impaired at all, 6 = severely impaired) in 7 domains: activity limitations, sleep problems, nose and eye symptoms, non-nose/eye symptoms, practical problems, and emotional functions [14]. Total score and seven domain scores between groups were compared.
All participants rested for 20~30 minutes and required to clean up nasal secretions before nasal resistance (NR) and acoustic rhinometry measurements (model: NR-6, British GM). Bilateral exhalation and inhalation resistance, total nasal resistance and nasal minimum cross-sectional area (NMCA) were analyzed. The nasal volume (NV) was set between 0 and 7cm. Each patient underwent 4 times measurements on each side and the average was calculated for data analysis.
Sample size
The sample size was evaluated with SAS 9.3 software (SAS Institute Inc., Cary, NC, USA) in the Clinical Evaluation Center of Beijing Hospital of TCM. The mean change in TNSS pre-and post-treatment was set as the indicator in the calculation. Results from our previous studies showed that the mean TNSS change of the BMD group was 6.62 ± 2.84 and that of the control group was 5.79 ± 2.18 [15], considering a power of 80 %, alpha of 0.05, an acceptable delta of 0.2, a non-inferiority margin of 0.77 [15], a clinically important difference can be detected by a sample size of at least 49 in each group. This number was then increased to 59 each group (total of 108) to allow for a predicted 20% dropout rate.
Statistical analysis
All statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL, USA; version 22.0) by qualified statisticians according to the intention-to-treat principle. We evaluated the baseline value and the corresponding outcomes. Descriptive statistics were used to compare baseline measures and patients’ characteristics between groups. Least-squares mean changes from baseline were evaluated using analysis of covariance (ANCOVA) models for the primary outcome.. The two-sample independent t test was used to compare the differences of secondary outcomes. Numeration data were assessed using Fisher's exact test. Level of α = 0.05 was defined as statistically significant.