EFFICACY OF TWO AYURVEDA DRUG REGIMENS FOR UTERINE FIBROIDS, A RANDOMIZED, SINGLE BLIND, THREE-ARM, CLINICAL TRIAL- STUDY PROTOCOL

EFFICACY OF TWO AYURVEDA DRUG REGIMENS FOR UTERINE FIBROIDS, A RANDOMIZED, SINGLE BLIND, THREE-ARM, CLINICAL TRIAL- STUDY PROTOCOL

Kaumadi Karunagoda ¹, Pathirage Kamal Perera ^{* 2} and Hemantha Senanayake ³

Department of Ayurveda Obstetrics, Gynecology and Pediatrics ¹, Department of Ayurveda Pharmacology and Pharmaceutics ², Institute of Indigenous Medicine, Department of Obstetrics and Gynecology ³, Faculty of Medicine, University of Colombo, Rajagiriya, Sri Lanka.

ABSTRACT: Uterine fibroids are the most common genital tract tumor in reproductive age women. The main treatment option for fibroid is surgical intervention. Options for medical therapy are currently limited to preoperative reduction of symptoms related to uterine bleeding and fibroid size. Ayurveda treatment for this condition is widely practiced in Sri Lanka. We aimed to evaluate the efficacy of two Ayurveda treatment regimes in patients with uterine fibroids. The study is designed as a randomized, single blind, three arm clinical study with 30 participants in each arm. Participants diagnosed with uterine fibroids size 2 cm or more and meet the inclusion criteria are enrolled to this study. Arm I and Arm II undergo two Ayurveda treatment regimens and Arm III is the control group. Endpoint will be calculated from baseline in volume of the largest fibroid by two dimension ultrasound scan after 12 weeks of treatment intervention and repeat in four weeks follow up. Clinical improvements and quality of life is assessed by Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL). Effect of therapy on each arm is assessed based on the Ayurveda body constitution (Prakriti). Haematological investigations are conducted before and after the treatment as safety parameters. Statistical analysis will be done using SPSS version 16. All statistical tests will be performed, two-tailed with significance determined by reference to the 5% level. Outcome of this study will be to developed evidence-based effective alternative to standard methods of treating uterine fibroids.

Uterine fibroids, Treatment regimen, Ayurveda, UFS-QOL, Prakriti

INTRODUCTION: Uterine fibroids (leiomyomas or myomas) are the most common benign neoplasm of the uterus ¹, is known to occur in 20%-40% of reproductive age females ². Abnormal uterine bleeding, pain and complaints related to pelvic pressure are common symptoms associated with this condition ³. These can have a remarkable impact on women’s health.

To date, most therapy for fibroids has been surgical, either myomectomy or hysterectomy. Surgical interventions require general anesthesia, lengthy hospital stays, and long recovery periods. Therefore, it would be highly desirable for the condition to be treated as conservatively as possible.

In this context, various complementary and alternative medicine treatments have been administered for uterine fibroid, including Sri Lankan Ayurveda, the most popular complementary medicine in Sri Lanka. From the few trials that are available, it is difficult to reach firm conclusions due to the quality and the small sample sizes.

The purpose of this study is to establish basic clinical efficacy and safety data for two Ayurveda drug regimens. All the drugs selected for the study are documented in texts ^{4, 5, 6}. According to an observational study did kaumadik et al., 2016 ⁷ found that selected drug regimen has been widely used in the treatment of uterine fibroids in the system of Sri Lankan Ayurveda. But these regimes have not been clinically tested for efficacy and safety on uterine fibroids. Therefore we have designed a Randomized Clinical Trials to detect the efficacy and safety of these drug regimens.

METHODOLOGY:

Design of the Study: This study is designed as a randomized, single-blind, three-arm clinical study with 30 participants in each arm.

Recruitment of Cases: Women seeking treatment for uterine fibroids will be screened for inclusion and exclusion criteria for participation in the study. Women with uterine fibroids confirmed by ultrasound scanning, CT, MRI, or a combination of these modalities will be eligible to be included.

The participants will be provided with a detailed information sheet supplemented by a verbal explanation. They will be reviewed at a later date to obtain informed written consent to give them an opportunity to discuss their participation with family and other relevant persons. Consented participants will be recruited to the three arms Fig. 1. Demographic data and other basic information will be collected at the same time.

FIG. 1: STUDY FLOW CHART

Participant Inclusion Criteria: Women aged between 18 to 50 years ⁸ will be included. They need to have the ability to take medication, be willing to adhere to the medication regimen, willing and able to give informed consent to be included in the study. At least one fibroid of diameter ≥2 cm confirmed by pelvic ultrasound must be present ⁹.

Participant Exclusion Criteria: Women with a history of having had hormonal steroid therapy for a minimum of 03 months prior, pregnancy or desire to become pregnant within the study period, lactating mothers, menopausal women and those who are not within the inclusion age limits will be excluded. Fibroid cases who have heavy menstrual bleeding will also be to prevent interruption of the treatment protocol. To ensure correct clinical assessment, conditions other than fibroids contributing to dysmenorrhoea or pressure symptoms will be excluded. Presence of any severe medical or psychological condition that, in the opinion of the investigators, would compromise the patient’s safe participation will also be excluded. The exclusion will be primarily based on the information provided by the patients. Menorrhagia will be excluded with the help of menstrual assessment chart ¹⁰.

Sample Size and Randomization: The Sample size was estimated that would be sufficient to detect significant differences in the quality of life improvement and the change of the size of fibroid by ultrasound scan between the experimental and control group. The sample size was calculated with the main outcome parameter as a reduction in uterine leiomyoma size ¹¹. For a quantitative outcome,

μ1 = Anticipated mean response for standard Rx

σ = Anticipated standard deviation of standard Rx

μ2 = Anticipated mean response for new Rx

α = Level of significance(to detect a treatment difference)

β = Degree of certainty that a difference in (P1-P2) if present would be detected

n = 2 σ² x f_{(α, β)}

(μ₁ - μ₂)²

f = (Z _α/2 + Z _β) ²

Control group µ1 = 0

Treatment group µ2 = 28% (assumed a µ2 = 10%)

SD = 10%

Z _α = 1.96 for α = 5%

Z _β = 1.28 for β = 90%

N = 20

Add loss to follow up = 30

Consecutive consenting sample method will be followed to select participants of the first two arms for the study. A blocked design will be used, using an online statistical computing web programming ¹² to generate the randomization schedule, 14 sets of 2 unique numbers per set range from 1 to 2 (representing arm I and arms II) were used. Arm III was selected by non-randomized purposive sampling method.

Treatment Protocol: Participant of Arm I and Arm II will receive a treatment regimen for twelve weeks. Oral administration and external administration will be performed according to the following method Table 1. Participants with uterine fibroids that fulfilled the recruitment criteria scheduled for myomectomy or hysterectomy after a minimum of three months from the day of recruitment will be recruited. They will be assessed at fortnightly intervals without drug intervention. All the participants of the treatment groups will be blind to treatments. The method of administration is described in Table 1.

TABLE 1: METHOD OF DRUG ADMINISTRATION

Study Drug Formulations and Dosage:

TABLE 2: STUDY DRUG FORMULATIONS AND DOSAGE

Packaging and Dispensing: Satakuppa powder and Krishnajeeraka powder, single ingredient drugs used for the study are prepared at the Department of Pharmacology and Pharmaceutics, Institute of Indigenous Medicine under standard GMP conditions.

Other drugs are purchased from Sri Lanka Ayurveda Drug Cooperation, Department of Ayurveda, Navinna, Sri Lanka. Liquid drugs (decoctions and oil) are bottled in sterilized glass bottles with sealed plastic lids. Tablets and powders are packed in light and waterproof sealed plastic containers.

Each drug is packed for 14 days and labeled indicating the batch number, arm, dose, time of administration, mode of administration (oral or external use), etc. Drugs are stored in the pharmacy and will dispense to the study participants at each visit with instructions, and a therapeutic diary is provided for all.

Treatment compliance will be assured by visual inspection of the drug containers, which will be carried by the patients at every clinic visit and questions by the investigator.

Arm III (control group) will be selected from De Soysa Hospital for Women (Teaching), Colombo 08, Sri Lanka. Participants with uterine fibroids who fulfill the recruitment criteria and scheduled for myomectomy or Hysterectomy on or after 03 months will be recruited. They will be assessed to evaluate associated features at four weekly intervals at the same clinic, but no drug intervention will be performed.

Follow Up: Study participants will be followed up for four weeks after drug administration period ones on a fortnightly basis. Associated features will be assessed in each visit and USS will be performed in the last visit (Visit 10).

Patient Safety: At the first visit a blood sample (5 ml) will be obtained under aseptic conditions into a sterile centrifuge tube via venous puncture by an experienced nurse and send immediately to a relevant laboratory for assessing. All patients will undergo routine testing that included FBC, AST/ALT, and serum creatinine/GFR), Estradiol (E₂), FSH Levels, urine full report before (Visit 1) and after the treatment (Visit 8) Table 3. Vital signs will be measured at each visit.

TABLE 3: DATA COLLECTION SCHEDULE

Primary Outcome Measures: USS will be used to determine the primary outcome. Change from baseline in volume of the largest fibroid will be measured. TVS/TAS will be done at the end of 12 weeks (Visit 8) and again after one month at follow up (Visit 10). Clinical improvement of the size of fibroid will be evaluated by comparing with baseline scan with the help of 2D Ultrasound scan. Measurements will be calculated by measuring ovoid volumes by using the longer and shorter diameter with the determination of their mean values ¹⁴. Necessary steps will be taken to blind the ultra-sonographer.

Secondary Outcome Measures: Symptom severity and their impact on (Health-Related Quality of Life) HRQL will be assessed by a Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QOL) ¹⁵ which is already validated in a small population at the same study centers.

Body constituent (Prakriti) is identifying of each at the screening with the help of a questionnaire ¹⁶. Effect of therapy according to the body constituent will be evaluated at the end of the study. Changes in the hormone levels; estrogen (E₂) and FSH will be studied by comparing before and after treatment values.

Statistical Analysis: Statistical analysis will be done using SPSS version 16. All statistical tests will be performed, two-tailed with significance determined by reference to the 5% level.

Data and Safety Monitoring: Monitoring will be conducted for quality control of the trial. Research subjects will be routinely questioned about adverse events at study visits. All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, regardless of a study group or suspected causal relationship to the study drug (s) will be recorded in the subjects’ case histories. Data will be reported to ERCIIM without undue delay.

Ethical Consideration: This study protocol was approved by the Institutional Review Board of the Faculty of Graduate study, Colombo University, Sri Lanka. Ethical clearance was obtained from the Ethical Review Committee of Institute of Indigenous Medicine, University of Colombo (ERC No: 17/68).

DISCUSSION: Uterine fibroids are treated with herbal medicine in many traditions and countries ¹⁷. The study conducted by Jian Ping et al., ¹⁸ says studies on the use of herbal preparations for the treatment of uterine fibroids are limited due to scientific validity as there is a limited number of studies that are of low in quality. The use of herbal medicines for uterine fibroids may not be warranted unless firm evidence of their efficacy and safety has proved. Therefore this type of trial protocol will be helpful to provide evidence-based scientific data on this subject area.

By this trial, it is expected to discover that, the comprehensive treatments of Ayurveda can be more helpful for improved quality of life compared with the control group. Again safety of drug regimens could also measure by the study. Ayurveda describes a unique concept, Prakriti (constitution), which is genetically determined, categorizing the population into several subgroups based on phenotypic characters like appearance, temperament, and habits. The concept is claimed to be useful in predicting an individual’s susceptibility to a particular disease, the prognosis of that illness and selection of therapy. Effect of therapy will be analyzed by an individual’s constitution. The strengths of the study are its randomized single-blinded design, protocol publication and the recording of patient-reported complications. The limitations of the study could be slow patient recruitment because of the eligibility criteria and a single study setting.

CONCLUSION: Outcome of this study will be to develop evidence based effective alternative to standard methods of treating uterine fibroids and to validate the current practice in Ayurveda for uterine fibroids. This trial could emphasize the importance of individualized treatment for participants with uterine fibroids on basis of body constituent (Prakriti).

Trial Status: Recruitment of participants will commence in May 2018, and final results are expected to be available in April 2019.

ACKNOWLEDGEMENT: This research is supported by the University Grant Commission, Sri Lanka (Grant Number: UGC/VCDRIC/PG2016 (II)/IIM/03). Authors acknowledge Dr. Dulani Samaranayake, Department of Community Medicine, Faculty of Medicine, University of Colombo, Sri Lanka for her expert opinion given in sample size determination.

CONFLICT OF INTEREST: The authors declare that they have no conflicts of interest regarding the publication of this manuscript.

REFERENCES:

1. Serdar E and Bulun MD: Uterine fibroids: N Engl J Med 2013; 369: 1344-55. Doi: 10.1056/NEJMra1209993
2. Donnez J: Efficacy and safety of repeated use of Uripristal acetate in uterine fibroids Fertility and Sterility® 2015; 103(2): 0015-0282.
3. Pritts EA, Vanness DJ, Berek JS and Parker W: The prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids: a meta-analysis. Gynecol Surg 2015; 12: 165-177. Doi: 10.1007/s10397-015-0894-4.
4. Ayurveda Pharmacopoeia Part One, Department of Ayurveda, Sri Lanka, Government press. First Edition 1976.
5. Devamitta G: Kashaya Sangraha. Samayawardhana Publishers, Maradana, Colombo, Second Edition 1994.
6. Nagodavithana P: Sharangadhara Samhita. Samayawardhana Publishers, Colombo, First Edition 2001.
7. Priyadarshani EPC, Karunagoda KPKR and Perera PK: Therapeutic effects of Sri Lankan Ayurveda treatment regimens for uterine fibroids, a case series, Ayurveda Sameeksha, Department of Ayurveda, Sri Lanka, Government press 2017.
8. Powell M and Dutta D: Esmya® and the PEARL studies: A review. Women’s Health 2016; 12: 544–548
9. Kirsty I, Munro I, Michael J, Thrippleton, Alistair RW and Williams: Quantitative Serial MRI of the Treated Fibroid Uterus. http://www.plosone.org 2014; 9(3) Accessed by 15 July 2017.
10. Donnez J: Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids N Engl J Med 2012; 366: 421-432.
11. Engman M, Granberg S, Williams ARW, Meng CX, Lalitkumar PGL and Gemzell-Danielsson K: Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo-controlled Human Reproduction 2009; 1: 1-10.
12. Research randomizer https://www.randomizer.org
13. Devamitta G: Kashayasangraha. 2^nd Samayawardhana Publishers, Maradana, Colombo 1994; 2: 15
14. Zivkovic N, Zvkovic K, Despot A, Paic J and Zelic A: Measuring the volume of uterine fibroids using 2- and 3-dimensional ultrasound and comparison with histopathology. ActaClin Croat 2012; 5: 1-4.
15. Spies JB, Coyne K, Guaou Guaou N, Boyle D, Skyrnarz-Murphy K and Gonzalves SM: The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol 2002; 99(2): 290-300.
16. Juyal RC: Potential of Ayurgenomics Approach in Complex Trait Research: Leads from a Pilot Study on Rheumatoid Arthritis PLOS, 2012 Doi: 10.1371/journal. pone.0045752
17. Fu P, He JL, Cui L and Chen XC: Clinical observation on effect of XuejieHualiu Granule in treating hysteromyoma. Chinese Archives of Traditional Chinese Medicine 2004; 22: 1082-1084.
18. Liu JP, Yang H, Xia Y and Cardini F: Herbal preparations for uterine fibroids. NIH Public https://www.ncbi.nlm.nih. gov/pubmed/23633329 2009 Accessed. 23 July 2017
    

    ---

    How to cite this article:

    Karunagoda K, Perera PK and Senanayake H: Efficacy of two Ayurveda drug regimens for uterine fibroids, a randomized, single blind, three-arm, clinical trial- study protocol. Int J Pharm Sci & Res 2019; 10(3): 1366-71. doi: 10.13040/IJPSR.0975-8232.10(3).1366-71.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---