Study design
This is a two months clinical trial following a protocol driven open labeled randomized controlled study that will be conducted at the National Ayurveda teaching hospital in Borella, Colombo, Sri Lanka. RDBD and Yogaraja Guggulu internally, KAP and SVL externally used in Sri Lankan traditional medicine as a regimen for knee OA will be the test products. The efficacy and safety of this regimen will be tested against the non-steroidal anti-inflammatory drugs (NSAIDS) Tab Paracetamol and Tablet Ibuprofen internally and external application of Diclofenac sodium gel and hot water fomentation. Patients with symptoms of Knee OA will be allocated randomly into two arms after a 1 week run – in period and the medications given orally for 60 days and externally for 30 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 the ethics Review Committee, Institute of Indigenous Medicine (ERCIIM), University of Colombo, Sri Lanka (ERC /20/105). The trial was registered in the ISRCTN registry (Trial number ISRCTN58050062) (Additional file 2)
Study Setting
The study will be conducted in the National Ayurveda Teaching Hospital, Borella, Colombo, Sri Lanka and Institute of Indigenous Medicine (IIM), University of Colombo, Rajagiriya, Sri Lanka. The study subjects will be recruited from the patients with symptoms of knee OA who visit to the Out Patient Department (OPD) of National Ayurveda Teaching Hospital and those who come responding to a newspaper advertisement on trial requirement.
Participants
Patients will be selected from those who seeking treatment for Knee OA. Participants in this research project is voluntary. Recruitment is done by screening for eligibility criteria (Inclusion and exclusion criteria). Eligible subjects will be randomly assigned to the Sri Lankan Traditional medicine regimen and the conventional treatment regimen group.
Inclusion Criteria and Exclusion Criteria
The inclusion criteria
Diagnosis of KOA will be based on history, clinical examination findings and classical radiological findings (ACR functional class I, II or III); and fulfilling the American College of Rheumatology (ACR) classification criteria except that the lower age limit was reduced to 40 years; and Radiographic evidence of OA will be based on the ranking score of the Kellgren-Lawrence radiographic system and pain severity will be based on VAS.
1. Three American College of Rheumatology (ACR) classification criteria for knee will be used. They are including:
1.1. The ACR Clinical classification criteria of knee OA
1.2. The ACR Clinical/Radiographic classification criteria of knee OA
1.3, The ACR Clinical/Laboratory classification criteria of knee OA
1.1. The ACR Clinical classification criteria for knee OA
In this criterion the presence of knee pain along with at least three of the following six items can classify the knee OA in the patients
- Age> 50 years old
- Morning stiffness < 30 minutes
- Crepitus on knee motion
- Bony tenderness
- Bony enlargement
- No palpable warmth
1.2. ACR Clinical/Radiographic classification criteria,
The presence of knee pain with at least one of the following three items along with osteophyte in knee X-Ray can classify the knee OA in the patients:
- Age> 50 years old
- Morning stiffness < 30 minutes
- Crepitus on knee motion
1.3. ACR Clinical/Laboratory classification criteria
The presence of knee pain along with at least 5 of the following 9 items can classify the knee OA in the patients:
- Age> 50 years old
- Morning stiffness < 30 minutes
- Crepitus on knee motion
- Bony tenderness
- Bony enlargement
- No palpable warmth
- RF < 1 40
- Synovial fluid compatible with OA
- Pain Visual Analogue Score
- A five-point Liker it scale version with five response levels for each item, representing different degrees of intensity: None (0), mild (1), moderate (2), severe (3), and extreme (4). The maximum score is 10 points for pain, Higher scores indicate more or worse symptoms, maximal limitations, and poor health. The patients will have reported a mean pain intensity in one or both knees while performing a weight bearing activity (e.g. walking, standing, climbing staircase) of ≥40 mm on a 100 mm Visual Analog Scale over the 7 days before baseline assessment, and provide written informed consent.
- Radiographic evidence of OA
This will be assessed on the ranking score of the Kellgren-Lawrence radiographic system (0-4) and 1- 3 grades will be considered.
Exclusion Criteria
- Subjects who have non-degenerative joint diseases or other joint diseases such as rheumatoid arthritis, psoriatic arthritis, gonococcal arthritis and haemoarthritis;
- Subjects with severe disabling arthritis and / or the patient are bedridden;
- Those that had history of intra-articular knee injection within the month preceding the study;
- Those with evidence of severe unstable renal, hepatic, diabetic, haemopoietic, cancer, hypertensive, cardiac disorder and mentally affected as revealed by history and / or investigation.
- concurrent anti-coagulant/antiplatelet drugs, corticosteroids or narcotic pain killers use; history of epilepsy or bleeding disorders; gastric ulcers; renal or hepatic disease; uncontrolled hypertension, or body mass index (BMI) >45 kg/m2.
A washout period of 7 days was required for NSAIDs users. Discontinuing the use of common CAM therapies for arthritis (e.g., glucosamine, chondroitin sulfate, bromelain, DMSO (DiMethyl SulfOxide), acupuncture and Ayurveda medicine) was required for 7 days prior to enrollment.
Sample Size
Sample size was calculated based on the primary outcome measurement of in WOMAC Index 10- point improvement of score from baseline after 12 weeks between both parallel groups of the clinical trial. This study is designed to evaluate the comparative clinical efficacy and safety of the Sri Lankan Traditional Medicine regimen with the conventional treatment regimen, assuming a parallel-group design between the two interventions. The sample size was calculated as specified by Kessler et al (22). According to a previous study done among patients with knee OA using Ayurveda treatment Regimen, clinically significant 12 weeks conventional
treatment response in about 30%, therefore the clinically important difference of 0.3 compared to the active drug is considered to be acceptable. The sample size was calculated for a significance level (α) of 5% and power of 80%. The sample size calculated using these values is 39 per group. With an expected dropout rate of 10%, the minimum sample size was calculated as 43 for one arm.
Recruitment of Patients
People who are interested in participating in this clinical study will be provided with a detailed Information sheet supplemented by verbal explanation of the study procedures. If the participants agree with the information given, 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 hematological and biochemical investigations (FBS, FBC, ESR, ALT/AST, serum creatinine, UFR). Diagnosis of Knee Osteoarthritis will be made according to history, clinical examination findings and classical radiological findings (ACR functional class I, II or III); and fulfilling the American College of Rheumatology (ACR) classification criteria and Radiographic evidence of OA will be based on the ranking score of the Kellgren-Lawrence radiographic system and pain severity will be based on VAS. Among them, the participants meeting the inclusion and exclusion criteria will be recruited for the study. All baseline assessment forms (WOMAC, KOOS and VAS) will be completed by the investigators. Patients will not be allowed to take any other medicines during the trial period. If they have to take any other medicine, they should inform the investigators and discontinue the trial.
Baseline Assessment
WOMAC, KOOS and VAS and heamatological and biochemical investigations (FBS, FBC, ESR, CRP, ALT/AST, serum creatinine, EGFR, UFR, Lipid Profile) 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 10 to generate the randomization schedule for 86 patients. The patients will be allocated to treatments based on the randomization sequence generated. Two week’s supplies 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. 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.
To monitor compliance and adverse events, two weekly follow up will be done at the Borella Ayurveda Teaching Hospital. The trial will be registered at clinical trial registry and approval will be taken by the University ethics committee. It will be followed the Declaration of Helsinki and Good Clinical Practice guidelines for trial conduct.
Participants will be assigned in the open labeled study and provided written informed consent before taking part for 8 weeks of regimen 1 (Arm I) or regimen 2 (Arm II). Outcomes will be assessed by weekly follow up at the Borella National Ayurveda Teaching Hospital and each assessment detail of the outcome study will be informed to the participant. The study design flow chart is shown in Fig.1.
Intervention
Investigational products
Sri Lankan Traditional Medicine Regimen
Product I - Rasnadvigunabhagasya Decoction (RDBD) and Yogaraja Guggulu
Traditional RDBD is a brown – colored liquid, prepared using 80g Alpinia calcarata and 1.6g other 24 plant ingredients: Tragia involucrate, Sida cordifolia, Ricinus Cummunis, Cedrus deodara, Curcuma zedoaria, Crocosmia aurea, Justicia adhatoda, Zingiber officinale, Terminalia chebula, Piper chavya, Cyperus rotundus, Boerhavia diffusa, Tinospora cordifolia, Argyreia populifolia, Anethum sowa, Tribulus terrestri, Withania somnifera, Aconitum heterophyllum, Cassia fistula, Asparagus racemosus, Piper longum, Nilgirianthus ciliates, Coriandrum sativum, Solanum indicum. The dried plant materials of the 25 ingredients will be ground separately to pre-prepare a coarse powered pack welighing 120g containing 25 ingredients. 120-g of dried powder pack of decoction will be used to prepare the decoction needed for 2 days. A two-week supply (Seven packs) of these pre- prepared dried herbs pack will be supplied to the patient. They will be informed to put the supplied herbal pack into an earthen pot or stainless-steel pot, add 3840 ml of water and simmer under low flame until the volume is reduced to 480 ml. The process of preparation under standard conditions will be demonstrated to the patients who are selected into the RDBD arm at the Department Dravyaguna Vignana or Department of Kayachikithsa of IIM using video. They will be requested to take a daily dose 120 ml of decoction before breakfast (6am) and before dinner (6pm) daily rest for the next day before breakfast (6am) and before dinner.
2 pills of Yogaraja Guggulu will be purchased from Sri Lanka Drug cooperation and Ayurveda Drug cooperation and will 56 pills will be packed in light and waterproof polythene provided which be requested to take along the decoction for rescue pain.
Product II - Sandhi Vadam Lepaya (SVL)
Pastes or Lepa or Paththu will be prepared according to the standardized and quality-controlled methods described in Sri Lankan Traditional Medicine. Paththu will be given for the external application on Knee prepared by 15 ingredients: Asparagus racemosus (Both tube and leaves) 50g, Crataeva nurvala (Leaves and Bark) 50g, Moringa oleifera (Bark) 50g, Vitex negundo (Leaves and Bark) 50g, Caesalpinia bonduc (Leaves and Bark) 50g, Alstonia scholaris(Bark) 50g pounded well and take 1920ml juice after squeezing and heated upto 480ml. Piper nigrum (Fruit) 10g, Allium sativum (Bulb) 5g, Zingiber officinale (Rhizome) 5g, Pipper longum(Fruit) 5g, Ferula asafoetida (Resin) 5g, Trachyspermum ammi(Seeds) 5g, Cuminum cyminum (Seeds) 5g, Caesalpinia bonduc (Seeds) 5g grounded separately and grinded with lime juice and add it to 240ml of lime juice and mixed well. Add this mixture to the previously prepared juice and keep it in flame until turn thick by evaporating its water content. One packet of 50g in light and waterproof packed will be provided to use for one day. 14 packets will be provided for evenly applied over the knee it should be covered with a cotton wool and properly bandaged with a gauze bandage. Keep it for 8hrs and removed and ask to cleanse the knee area properly.
Product III – Kumburuatadi Pottaniya (KAP)
Herbal fomentation bollus (Pottaniya) prepared with 10 ingredients: Caesalpinia bonduc(Seed Pulp) 7.5g, Ferula asafoetida(Resin) 7.5g, Zingiber officinale (Rizome) 7.5g, Pipper longum (Fruit) 7.5g, Allium sativum (Bulb) 7.5g, Terminalia chebula (Fruit) 7.5g, Maduka Indica (Seed) 7.5g, Ricinus communis (Seed) 7.5g, Sesamum indicum (Seed) 7.5g, Cococus nucifera (Seed pulp) 7.5g Taken and pounded well and make a pollute and steam it. Dip in a heated mixture of oils of Mee thel (Oil extracted from seeds of Maduka Indica), Erdu thel (Oil extracted from seeds of Ricinus communis), Thala thel (Oil extracted from seeds of Sesamum indicum), Elagithel (Ghee) and Polthel (Oil extracted from seed pulp of Cococus nucifera) collectively known as Pasthel (Five types of Oils) used commonly in Sri Lankan Traditional Medicine. Two pottani will be given to the patient and they will be informed to steamed properly and dip in lightly heated mixture of 5ml oil from each above mentioned five oils (Mee, Eradu, Thala, Ethagithel and Pol thel) and fomentation done for 30 min after removing the paste.
Product IV - Tablet Paracetamol and Tablet Ibuprofen
Individualized conventional care for knee OA according to current practices, Non-Steroid Anti-Inflammatory Drugs (NSAIDs) - Paracetamol (500mg) and Ibuprofen (200mg) as rescue medication were selected as the comparator for this clinical trial. Total quantity of Paracetamol and Ibuprofen required for clinical trial, from one of the leading brands of paracetamol and Ibuprofen will be purchase from one single batch, directly from the State Pharmaceutical Company (SPC) for the purpose of the trial. The purchased products will be stored under the 250 C in an air- conditioned environment at the IIM. Patients allocated to conventional arm are requested to take a daily dose of two tablets of Paracetamol (500mg) and two tablets of Ibuprofen (200mg) twice a day after breakfast and after dinner
Product V - Diclofenac Sodium gel and fomentation with warm water
Topically applied NSAIDs reduce systemic exposure compared with oral NSAIDS, and European guidelines recommend their use. The NSAID is available in a range of topical formulations. Topical formulation of 2% Diclofenac Sodium gel aims to reduce adverse systemic problem and fomentation with warm water recommended before applying it. Total quantity of 2% Diclofenac Sodium gel required for clinical trial, from one of the leading brands of 2% Diclofenac Sodium gel will be purchase from one single batch, directly from the State Pharmaceutical Company (SPC) for the purpose of the trial. The purchased products will be stored under the 250 C in an air- conditioned environment at the IIM. Patients allocated to conventional arm are requested to applied 2% Diclofenac Sodium gel over knee and carried fomentation with warm water once a day.
Details of the investigational drugs are shown in Table 1. To minimize the compliance, patients are advised to submit the patient’s diary and empty containers of the drugs during weekly visits. Also, the day before the clinic date of every week, the chief investigator will be telephoned and send a text message to a mobile phone to be reminded of the clinic date.
Table 1 Investigational Products
|
Treatment Regimen
|
Treatment Duration
|
Interventional Group – Arm I
|
Conventional Group Arm II
|
|
External Thermotherapy
|
30 days
|
Fomentation (pottani) – KAP
100gms daily
|
Hot water
Sufficient amount daily
|
|
Topical Application
|
30 days
|
Paste – SVL
Necessary Amount daily
|
2% Diclofenac sodium gel
Sufficient amount daily
|
|
Internal
|
60 days oral
|
Rasnadvigunabhagasya Decoction – RDBD
120ml x bd before meals
|
Tab Paracetamol
(500mg x2) xbd
After meals
|
|
Rescue Medication
|
60 days
oral
|
Yogaraja Guggulu Pill
(500gms x2) xbd before meals
|
Tablet Ibuprofen
(200mg x2) xbd
After meals
|
|
Follow up after very two week for three months (no intervention)
|
Storage, packaging, and dispensing of investigational drugs
Decoction, paste and pottani will be manufactured and other drugs will be purchase from Sri Lanka Drug cooperation and Ayurveda Drug cooperation. Decoction, paste and pottani drugs used for study will be prepared at the Pharmacology department of IIM under GMP conditions. Decoction drugs, pottani, pills, tablets will be packed in light and waterproof polythene and pottani will be packed in light and waterproof sealed plastic container. Each drug will be packed for 14 days and labeled which indicate the cord number, arm, dose, time of administration, mode of administration (oral or external use etc.). 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. A supply of drugs for 14 days will be dispensed to the study participants at two weekly visits with instructions and patient diary will be provided for all.
Outcome Measurements
Primary Outcome
The primary endpoint is a change in the score on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) measured at the baseline and the end of the intervention (after 8 weeks and 1 month of follow-up).
Secondary Outcome
Secondary outcome measurements will use WOMAC subscales, a pain disability index, a visual analog scale for pain and sleep quality, a quality-of-life index measured at the baseline and the end of the intervention (after 8 weeks and 1 month, 2month and 3 month of follow-up).
Changes in ESR and CRP 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
|
12
|
16
|
20
|
|
Eligibility
Screening
|
+
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Informed Consent
|
+
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Recruitment
|
|
+
|
|
|
|
|
|
|
|
|
|
|
|
|
Randomization
|
|
|
+
|
|
|
|
|
|
|
|
|
|
|
|
Arms
|
|
Arm I -STM
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Arm II
Conventional
|
|
|
|
|
Safety Assessment
Each patient will undergo hematological and biochemical investigations (FBS, FBC, Lipid Profile, ESR, CRP, AST/ALT, and serum creatinine and 5ml blood will be drawn), urine full report before and after the interventions which are done primary for safety assessment.
All adverse events experienced by patients will be recorded regularly after two weeks 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 within 5 working days. No serious adverse reactions are expected with any of the two study medications. However, in the events of an adverse reaction requiring in-hospital management, the facilities and expert management would be provided and the complete clinical trial will be terminated prematurely if there is evidence that the safety of the trial participants can no longer be assured or new scientific information arises during the course of the clinical trial regarding patient safety.
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 heamatological and biochemical investigations, results of the physical examinations, and completed questionnaires.
The data will be retained with the researchers alone and will not be handed over to any other party under any circumstance. The data sheets will be kept under lock and key until the database is created. As soon as the database is created, burning will destroy the datasheets. This will approximately take 6 months from the onset of data collection.
Data will be entered by a minimum number of dedicated staff and saved in a dedicated computer with password protection. 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 participants’ data will be stored at the Institute of Indigenous Medicine, which will be used for statistical analysis and scientific reporting. Each 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. A data safety monitoring board has been appointed according to the guidelines of Ethics Review Committee of IIM for safety monitoring. The board consists of three independent expert members. Further, we have no planned the auditing of this clinical trial, because it is a single – center trial involving 86 patients. The results of the study will be used for scientific reporting in 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 Committee od the Institute of Indigenous Medicine, University of Colombo. The trial was registered in ISRCTN registry (Trial Number ISRCTN58050062 https://doi.org/10.1186/ISRCTN58050062). The study will be conducted adhering Good Clinical Practice (GCP) guidelines. Protocol modifications will be informed to Ethics Review Committee and the trial registry 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 the nature, duration, and possible consequences of the trial. A 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 – administrated and anonymous. A 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 mean differences will be compared between the two arms using depending on the normality of the data. Within each treatment arm, the difference in the primary and secondary outcome measures before and after the intervention period will be compared. 95% confidence intervals will be calculated for all outcome measures that are normally distributed. Categorical variables will be compared between groups using the chi -square test.
Statistical analysis will be performed using the SPSS statistical Package program (Version 18), and the level of significance will be established at a =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.