Study design
This is a three arm open label non-inferiority randomized controlled clinical trial that is conducting at the National Ayurveda Teaching Hospital in Colombo, Sri Lanka. The study duration is 28 days oral administration of the two Ayurvedic dosage forms and the antihistamine loratidine into the 3 arms allocated randomly. The study consists of two week run-in period, four visits at weekly intervals and two months follow up period. This study protocol was developed as required by the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 1).
Ethics approval has been obtained from Ethics Review Committee, Institute of Indigenous Medicine (ERCIIM), University of Colombo, Sri Lanka (ERC 18/76). The trial was registered in ISRCTN registry (Trial number ISRCTN18149439) (Additional file 2)
Participants
Patients will be selected from those seeking treatment for allergic rhinitis at Ayurveda teaching hospital, Borella, Sri Lanka. Participation in this research project is voluntary. Patients’ recruitment is done by screening for eligibility criteria (inclusion and exclusion criteria). After a 2 week run-in period, eligible subjects are randomly assign to the TMD12 decoction group, TMD12 freeze dried group (TMD12-FD) and the antihistamine group.
Inclusion and exclusion criteria
The inclusion criteria include (1) age group of 18–65 years at the time of enrollment, of either sex; (2) presence of two or more nasal symptoms (watery rhinorrhea, nasal obstruction, sneezing and nasal itching); (3) Total Nasal Symptom Score (TNSS) > 6 (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, 3 = severe symptoms); (4) have given written, informed consent to participate in this study.
The exclusion criteria include: (1) Patients with deviated nasal septum/ nasal polyps/ nasal growth/ adenoids/ asthma; (2) Patients with impaired liver and kidney functions, anaemia, and unstable cardiovascular conditions or cerebrovascular conditions; (3) currently or previously treated for any malignancy; (4) patients on steroid therapy; (5) Already on treatment with TMD12 decoction or antihistamines; (6) Pregnant or lactating mothers; (3) those who have known systemic disorders; (4) those who have any history of drug allergy to any of the investigational products; (7) Illiterate patients without a literate relative/guardian who can explain the procedures and maintain the patient diary (8) any other patients who are considered unsuitable for recruitment by the investigators.
Sample size
Sample size was calculated based on the primary outcome measurement of TNSS (Total Nasal Symptom Score) and for a non-inferiority clinical trial. This study is designed to evaluate the comparative clinical efficacy and safety of two Ayurvedic dosage forms with the antihistamine loratidine, assuming non-inferiority-between the 3 interventions. Sample size was calculated as specified by Hampel and team [8]
According to a previous study done among patients with allergic rhinitis using loratidine, clinically significant standardized effect sizes of TNSS are reported in the range of 0.57 to 0.67. Therefore, a standardized effect size of 0.5 was considered as the non-inferiority margin using the effect reported by Hampel and team [8].
Sample size was calculated for a significance level (α) of 5 % and power of 80 %. The sample size calculated using these values is 64 per group. With an expected dropout rate of 10 %, minimum sample size was calculated as 70 for one arm.
Recruitment
People who are interested in participating in this clinical study will be provided with a detailed Patient Information Sheet supplemented by verbal explanation of the study procedures. If the participants agree with the Information Sheet, asked to complete the screening questionnaire. Informed written consent will be obtained from each participant by the investigators prior to initial interview. The activities in the initial interview will include haematological and biochemical investigations (IgE level, FBS, FBC, ESR, ALT/AST, serum creatinine, UFR), complete history taking and physical examination. Diagnosis will be done according to the Allergic Rhinitis and its Impact of Asthma criteria (ARIA). The participants meeting the inclusion criteria will recruit for the study. All baseline assessment forms (Total Nasal Symptom Score, Quality of life questionnaire and Allergic rhinitis symptom score) will be completed by the investigator. The study design flow chart is shown in figure 1.
Randomization
Randomization sequence was generated using an online randomization website (www.randomisation.com). Block randomization was done using blocks of 12 to generate the randomization schedule for 240 patients. The patients are allocating to treatments based on the randomization sequence generated. One week’s supplies of the assigned investigational products are hand over to the patients according to the randomization number.
Intervention
Investigational products
Product I - Tamalakyadi decoction (TMD12)
This is a brown colour liquid prepared using 12 plant materials: Phyllanthus niruri L., Terminalia chebula Retz., Premna herbacea Roxb., Piper retrofractumVahl, Piper longum L., Solanum trilobatum L., Tinospora cordifolia (Thunb.) Miers, Zingiber officinale Roscoe, Piper nigrum L., Solanum indicum L., Solanum xanthocarpum L., Adhatoda vasica L. (5 g from each ingredient). Five grams of each ingredient of the TMD 12 decoction is ground separately to make a coarse powder and to prepare a packet weighing 60 g containing all 12 ingredients. This packet of ingredients is use to prepare decoction need for one day. This pre-prepared dried herbs pack is supply to the patient. They are informed to put the supplied herbal pack into pot, add 1920 ml of water and simmer under low flame until the volume is reduced to 240 ml. The process of preparation under standard conditions is demonstrate to the group of patients who are randomly selected for TMD12 group at the Department of Dravyaguna Vignana of Institute of Indigenous Medicine using a video. Daily dose is 120 ml twice a day after meals.
Product II - Freeze dried Tamalakyadi decoction (TMD12-FD)
This is a freeze-dried powder of 240 ml of TMD12 decoction (TMD 12- FD) which contains 6 g of TMD12-FD packed in triple laminated bags under room temperature 190 C to minimize the moisture absorbance. Preparation was done at the Research and Development Complex, Herbal Technology Section, Institute of Industrial Technology, Malabe, Sri Lanka under standard laboratory conditions.
The powder should be dissolved in 240 ml of hot water and should take 120 ml twice a day after meals. This reconstituted powder also contains the above mentioned 12 ingredients in almost the same quantities. In order to develop a ready to use formulation of the TMD 12, with composition similar to the TMD12 after preparation, three different formulations were developed and analyzed [9]. These included freeze dried formulation, spray dried formulation and Gnanasara formulation and detailed physicochemical and phytochemical analysis were performed. The results are now published and showed the freeze dried formulation to be quantitatively and qualitatively closest to TMD 12 [9]. Therefore the freeze-dried formulation was selected for evaluation of clinical efficacy and safety in this clinical trial.
Product III - Loratidine 10 mg
Non-sedating antihistamine-loratidine 10 mg was selected as the comparator for this clinical trial. Total quantity of loratidine required for the clinical trial, from one of the leading brands of Loratidine was purchased from one single batch, directly from the State Pharmaceuticals Corporation, Sri Lanka for the purpose of the trial. The certificate of analysis of the batch was obtained to check and ensure the quality of the product used. The purchased products were stored under 25oC in an air-conditioned environment at the IIM. Patients allocated loratidine arm are requested to take one tablet daily at night with 240 ml of water. Details of the investigational drugs are shown in Table 1.
Storage, Packaging and dispensing of investigational drugs
All three investigational products (herbal materials of decoction, freeze dried powder and loratidine) are packed for 7 days and labeled which would indicate the batch number, dose, time of administration, mode of administration. These are stored in the clinic/Ayurveda Teaching Hospital, Sri Lanka. Drugs are dispensing to the study participants at each visit with instructions.
Outcome measurements
Primary outcome
Total Nasal symptom Score (TNSS) of the patients are used as the primary efficacy outcome which has been previously used in allergic rhinitis clinical trials. The mean difference in TNSS is compared between the 3 arms as the primary end point. TNSS is recorded and compared in all 3 arms prior to visit 1, at the end of 28 days, end of the first month of follow up and second month of follow up. The TNSS assesses the symptoms of watery rhinorrhea, nasal obstruction, sneezing and nasal itching on a four point scale. The total score range from 0 to 12 where 0 = absent symptoms (no sign/symptom evident), 1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily tolerated), 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but tolerable), 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping).
Secondary outcomes
The following four symptom scores are using as secondary end points.
- Mean score of daytime nasal symptom score
- Mean score of night time nasal symptom score
- Mean score of non-nasal symptoms
Patient’s self-rated symptom scores (daily rhinitis diary card) and allergic rhinitis grading symptoms are using as secondary measures of the efficacy in the clinical trial. Such symptom scores are collected on a weekly basis during the assessment period. The measurement of symptoms on a 4-point rating scale with the following definitions is used.
- 0 = absent symptoms (no sign/symptom evident)
- 1 = mild symptoms (sign/symptom clearly present, but minimal awareness; easily tolerated)
- 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but tolerable)
- 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with activities of daily living and/or sleeping).
- Mean score of Health Related Quality of Life score—Health related quality of life is measured using allergic rhinitis symptoms at the baseline and end of the intervention (after four weeks, one month of follow up and two months of follow up).
Changes in the serum IgE level and eosinophil count will be studied by comparing before and after treatment values. Procedures related to the study are shown in Table 2.
Safety assessment
Each patient is undergo hematological and biochemical investigations (FBS, FBC, ESR, AST/ALT, and Serum Creatinine/GFR), Urine full report before and after the treatment, which are done primary for safety assessment.
All adverse events experienced by patients are record weekly during treatment. Patients are advised to come for assessment if they have any unexpected symptoms complaints. If any serious adverse events occur they will be carefully assessed and reported to the ERCIIM and regulatory authority within 5 working days.
Data handling and recordkeeping
The data is retain with the researchers alone and will not be handed over to any other party under any circumstance. The study participant’s information are securely stored at each clinical visit for internal use during the study. At the end of the study, all records continue to be kept in a secure location for six months period.
Study participants research data, which is for purposes of statistical analysis and scientific reporting, is transmitted to and stored at the department of DravyagunaVignana, Institute of Indigenous Medicine. This will not include the participant’s contact or identifying information. Rather, individual participants and their research data is identified by a unique study identification number. At the end of the study, all study databases will be de-identified and archived.
Ethical consideration
The approval of the research protocol was obtained from the Research approval committee of the Faculty of Graduate Studies, University of Colombo and the Ethics Review Committees of Institute of Indigenous Medicine. The trial was registered in ISRCTN registry (Trial number ISRCTN18149439 https://doi.org/10.1186/ISRCTN18149439). The study will be conducted adhering to GCP guidelines.
Selected patients are provided with an information sheet with the details of the research given in all three languages (Sinhala/Tamil/English) and written consent are obtained before participation. The information will include about the nature, duration and possible consequences of the trial. Patient may withdraw his or her consent to participate in this study at any time, with no penalty or effect on medical care or loss of benefits. The questionnaire is interviewer administrated and anonymous. Minimal amount of data needed to assess the socio demographic data is gathered. This will include occupation and nature of health condition. Researchers do not collect any other personal data.
Method of data analysis
For primary and secondary outcome measures, the mean values at baseline and at the end of the study and the mean differences will be compared between the three arms using ANOVA (analysis of variance) or the non-parametric Kruskal-Wallis test, depending on the normality of the data. Within each treatment arm, the before and after difference in primary and secondary outcome measures will be compared using paired samples T test or non-parametric Wilcoxan Signed rank test, depending on the normality of the data. Categorical variables will be compared between groups using chi square test. Possible confounders will be adjusted using ANCOVA. Statistical analysis will be performed using the SPSS statistical package program (ver. 18.0), and the level of significance will be established at α = 0.05.