Study design
This is a three arm open label non-inferiority randomized controlled clinical trial that will be conducted at the National Ayurveda Teaching Hospital in Colombo, Sri Lanka. TMD12, used in traditional Ayurveda and its freeze-dried formulation will be the test products. The efficacy and safety of the two Ayurvedic dosage forms will be tested against the antihistamine loratidine. Patients with symptoms of AR will be allocated randomly into the 3 arms after a 1 week run-in period and the medications given orally for 28 days. 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) and the Ethics Committee of the Faculty of Medicine, University of Colombo, Sri Lanka (EC–18–090). The trial was registered in ISRCTN registry (Trial number ISRCTN18149439) (Additional file 2).
Study setting
The study will be conducted in the Ayurveda Teaching Hospital, Borella and the institute of Indigenous Medicine (IIM) University of Colombo, Sri Lanka. The study subjects will be recruited from the patients with symptoms of allergic rhinitis who visit to the Outpatient Department (OPD) of Ayurveda Teaching Hospital and those who come, responding to a newspaper advertisement on trial recruitment.
Participants
Patients will be selected from those seeking treatment for allergic rhinitis. Participation in this research project is voluntary. Patients’ recruitment is done by screening for eligibility criteria (inclusion and exclusion criteria). Eligible subjects will be randomly assigned to the TMD12 decoction group, TMD12 freeze dried group (TMD12-FD) or the antihistamine, loratidine 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 and as 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 Hampelet al[11]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 [11]. Therefore, a standardized effect size of 0.5 was considered as the non-inferiority margin using the effect reported by Hampel and team.
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 Leaflet (PIL) supplemented by verbal explanation of the study procedures. If the participants agree with the Information given in PIL the screening questionnaire will be completed. Informed written consent will be obtained from each participant by the investigators prior to initial interview. The activities in the initial interview will include complete history taking, physical examination and haematological and biochemical investigations (IgE level, FBS, FBC, ESR, ALT/AST, serum creatinine, UFR). Diagnosis of allergic rhinitis will be made according to the Allergic Rhinitis and its Impact of Asthma (ARIA) criteria. Among them the participants meeting the inclusion and exclusion criteria will be recruited 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 investigators. Patients will not be allowed to take any other medicine during the trial period. If they have to take any other medicine they should informed to the investigators and discontinues the trial.
Baseline assessment
Nasal symptoms (watery rhinorrhea, nasal obstruction, sneezing, nasal itching), Non-Nasal symptoms, HRQOL, hematological and biochemical investigations (IgE level, FBS, FBC, ESR, ALT/AST, serum creatinine, UFR) will be assessed at baseline.
Randomization
Randomization sequence will be generated using an online randomization website (www.randomisation.com). Block randomization will be done using blocks of 12 to generate the randomization schedule for 240 patients. The patients will be allocated to treatments based on the randomization sequence generated. One week’s supply of the assigned investigational products will be handed over to the patients according to the randomized allocation. Each group will be enrolled with an allocation ratio 1:1:1.The allocation for each randomization number will be put in to individually seal opaque envelops. The envelopes and allocation sequence will be kept under lock and key by one investigator not involved in recruiting patients. The patients meeting inclusion exclusion criteria and recruited into the study will be assigned a randomization number sequentially, according to the date and time of recruitment. The allocated treatments indicated in the sealed envelope for each randomization number will be supplied to each patient. The study design flow chart is shown in figure 1.
Figure1: Flow chart of study design
Intervention
Investigational products
Product I - Tamalakyadi decoction (TMD12)
Traditional TMD12 is a brown coloured liquid,prepared using 5 g of 12 plant ingredients: 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.The dried plant materials of the 12 ingredients will be ground separately to pre-preparea coarse powder pack weighing 60 g containing all 12 ingredients. One 60 g pack of this TMD12 dried powder pack will be used to prepare the decoction needed for one day. One week supply (7 packs) of this pre-prepared dried herbs pack will be supplied to the patient. They will be informed to put the supplied herbal pack into a 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 will be demonstrated to patients who are selected into the TMD12 arm at the Department of Dravyaguna Vignana of IIM using a video. They will be requested to take a daily dose 120 ml twice a day before meals.
Product II - Freeze dried Tamalakyadi decoction (TMD12-FD)
This is a freeze-dried powder prepared from 240 ml of TMD12 decoction (TMD 12- FD), which contains 6 g of TMD12-FD packed in triple laminated sachets under a temperature of 19o C to minimize the moisture absorbance. Preparation will be 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 120 ml taken 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 [12]. These included freeze dried formulation, spray dried formulation and Ganasara formulation and detailed physicochemical and phytochemical analysis were performed. The results are now published and showed that the freeze dried formulation is quantitatively and qualitatively closest to TMD 12 [12]. 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 will be purchased from one single batch, directly from the importer for the purpose of the trial. The certificate of analysis of the batch will be obtained to check and ensure the quality of the product used. The purchased products will be 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.
To minimize the compliance, patients are advised to submit the patient diary and empty containers of the drugs during weekly visits.
Table 1: Investigational products
|
Drug
|
Dose
|
Mode of administration
|
Route
|
Method of preparation
|
1
|
Tamalakyadi decoction (TMD12)
|
120 ml
|
Morning and evening before meals
|
Oral
|
60 g (1 packet) of dried powder of plant materials boiled with 1920 ml of water and reduced to 240ml
|
2
|
Freeze dried Tamalakyadi decoction
|
120 ml
|
Morning and evening before meals
|
Oral
|
6 g (1 sachet) of freeze dried powder dissolve in 240 ml of warm water.
|
3
|
Loratidine
|
10 mg
|
Evening before meals
|
Oral
|
Ingested with 240 ml of water
|
Storage, Packaging and dispensing of investigational drugs
All three investigational products (herbal materials of decoction, freeze dried powder and loratidine) will be packed for 7 days and labeled which would indicate the batch number, dose, time of administration, mode of administration. These will be stored in the clinic of the Ayurveda Teaching Hospital, Sri Lanka to be provided to randomized patients according to the predetermined allocation sequence. Supply of drugs for seven days will be dispensed to the study participants at weekly visits with instructions.
Outcome measurements
Primary outcome
TNSS of the patients will be used as the primary efficacy endpoint, which has been previously used in allergic rhinitis clinical trials. The mean difference in TNSS will be compared between the 3 arms at baseline and 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 (signs/symptoms clearly present, but minimal awareness; easily tolerated), 2 = moderate symptoms (definite awareness of signs/symptoms that are bothersome but tolerable), 3 = severe symptoms (signs/symptoms that are hard to tolerate; causes interference with activities of daily living and/or sleep).
Secondary outcomes
The following four symptom scores will be used as secondary end points.
- Mean score of daytime nasal symptoms
- Mean score of night time nasal symptoms
- Mean score of non-nasal symptoms
Patient’s self-rated symptom scores (daily rhinitis diary card) and allergic rhinitis grading symptoms will be used as secondary measures of the efficacy in the clinical trial. Such symptom scores will be collected on a weekly basis during the assessment period. The measurement of symptoms on a 4-point rating scale with the following definitions will be used.
- 0 = absent symptoms (no signs/symptoms evident)
- 1 = mild symptoms (signs/symptoms clearly present, but minimal awareness; easily tolerated)
- 2 = moderate symptoms (definite awareness of signs/symptoms that are bothersome but tolerable)
- 3 = severe symptoms (signs/symptoms that are hard to tolerate; causes interference with activities of daily living and/or sleep).
- 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.
Table 2: Study procedures
|
Study period
|
|
Screening
(run-in period)
|
Recruitment
|
Treatment
|
Follow up
|
Time point (weeks)
|
-1
|
0
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
8
|
9
|
10
|
11
|
12
|
Eligibility screening
|
♦
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Informed consent
|
♦
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Recruitment
|
|
♦
|
|
|
|
|
|
|
|
|
|
|
|
|
Randomization
|
|
|
♦
|
|
|
|
|
|
|
|
|
|
|
|
ARMS
|
Arm – 1(TMD12 decoction)
|
|
|
♦
|
|
|
♦
|
♦
|
|
|
|
|
|
|
♦
|
Arm – 2
Freeze dried preparation
|
|
|
♦
|
|
|
♦
|
♦
|
|
|
|
|
|
|
♦
|
Arm – 3
Loratidine
|
|
|
♦
|
|
|
♦
|
♦
|
|
|
|
|
|
|
♦
|
Investigations*
|
♦
|
|
|
|
|
|
♦
|
|
|
|
|
|
|
|
Assessment
|
TNSS
|
♦
|
|
|
|
|
♦
|
|
|
|
♦
|
|
|
|
♦
|
HRQoL
|
|
|
♦
|
|
|
♦
|
|
|
|
♦
|
|
|
|
♦
|
Adverse events
|
|
|
♦
|
♦
|
♦
|
♦
|
|
|
|
|
|
|
|
|
Safety assessment
Each patient will undergo hematological and biochemical investigations (FBS, FBC, ESR, AST/ALT, and Serum Creatinine/GFR), Urine full report before and after the interventions, which are done primary for safety assessment.
All adverse events experienced by patients will be recorded weekly by the investigators at every visit to the clinic. Further patients will be advised to record any adverse reactions in their patient diaries and will be advised to inform the investigators using the given contact numbers. They will also be advised to come to the clinic for assessment when they have any unexpected symptoms or complaints. If any serious adverse events occur they will be carefully assessed and reported to the ERC of IIM and Medical Faculty within 5 working days. No serious adverse reactions are expected with all 3 study medications. However if any serious adverse drug reactions suspected related any study medication, the patient will be given the opportunity to leave the trial according to his or her wishes respecting patients’ autonomy.
Data handling, record keeping and dissemination
An individual file for each participant will be used to archive a hard copy of the case record forms including informed consent, results of the haematological and biochemical investigations, results of the physical examinations and completed questionnaires. These data will be retained with the researchers and will not be handed over to any other party under any circumstance. The study participant’s information will be securely stored at each clinic visit during the study. At the end of the study, all records will continue to be kept in a secure location for a 2-year period.
Study participant’s data will be stored at the department of Dravyaguna Vignana, IIM, which will be used for statistical analysis and scientific reporting. Participant’s contact or identifying information will be separately stored. Individual participants and their research data will be identified by a unique study identification number. At the end of the study, all study databases will be de-identified and archived. Data Safety Monitoring Board has been appointed according to the guidelines of Ethics Review Committee of Faculty of Medicine for safety monitoring. Data safety monitoring board consists of three independent expert members. Further we have not planned the auditing of this clinical trial, because it is a single center trial which involving only 210 patients. The results of the study will be used for scientific reporting in the conferences and will be published in peer reviewed journals. Further results of the study and the grouping information of the participants will be provided to the individual after completion of the trial.”
Ethical considerations
The approval of the research protocol has been 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 (IIM) and Faculty of Medicine, University of Colombo. The trial was registered in ISRCTN registry (Trial number ISRCTN18149439 https://doi.org/10.1186/ISRCTN18149439). The study will be conducted adhering to Good Clinical Practice (GCP) guidelines. Protocol modifications will be informed to Ethics Review Committees and the trial registry for their approval.
Patients will be provided with an information sheet with the details of the research given in all three languages (Sinhala/Tamil/English) and written consent will be obtained before participation. The information provided 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 will be interviewer based administrated and anonymous. Minimal amount of data needed to assess the socio demographic data will be gathered. This will include occupation and nature of health condition. Researchers will 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, difference in primary and secondary outcome measures before and after the intervention period will be compared using paired sample T test or non-parametric Wilcoxan Signed rank test, depending on the normality of the data. 95 % Confidence intervals will be calculated for all outcome measures that are normally distributed. Categorical variables will be compared between groups using chi square test. Possible confounders will be adjusted using ANCOVA. Following adjustment for confounding using ANCOVA, adjusted mean values with confidence intervals will be calculated and reported. 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.Missing data at outcome assessment will be replaced with the available latest values of the outcome measure. Intention to treat analysis will be performed for all efficacy outcomes and safety outcomes. In addition, per protocol analysis will be performed for the efficacy outcomes, by including only the patients completing the follow up.