NHR Jan-Mar 2019: Research Protocol: Efficacy of Dioscorea villosa 6CH in treatment of dyslipidaemia: A double-blind, randomized, placebo-controlled clinical trial

Efficacy of Dioscorea villosa 6CH in treatment of dyslipidaemia: A double-blind, randomized, placebo-controlled clinical trial


Kisor Kumar Naskar*1, Ompriya Mishra2, Abhijit Chattopadhyay3, Aniruddha Banerjee4, Ashutosha Kumar4, Jasleen Luthra5, Laijun Nahar5, Mohammad Karim6, Ritika Asthana5, Seeta Singh4, Tirthankar Banerjee6, Anamika Basu7, Sk. Swaif Ali7, Munmun Koley8, Subhranil Saha9

  1. Reader, Dept. of Homoeopathic Materia Medica, D N De Homoeopathic Medical College and Hospital, Govt. of West Bengal
  2. Reader, Dept. of Obstetrics and Gynaecology, National Institute of Homoeopathy, Govt. of India
  3. Professor and Head, Dept. of Homoeopathic Materia Medica, National Institute of Homoeopathy, Govt. of India
  4. Postgraduate Trainees, Dept. of Repertory, National Institute of Homoeopathy, Govt. of India
  5. Postgraduate Trainees, Homoeopathic Materia Medica, National Institute of Homoeopathy, Govt. of India
  6. Postgraduate Trainees, Dept. of Homoeopathic Materia Medica, D N De Homoeopathic Medical College and Hospital, Govt. of West Bengal
  7. Interns, Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, Govt. of West Bengal
  8. Independent Researcher, Champsara, Baidyabati, Hooghly, West Bengal
  9. Independent Researcher, Shibpur, Howrah, West Bengal

*Correspondence: drkisorkumarnaskar@gmail.com


ABSTRACT:

Background: Keeping in view the current scenario of increasing risk of dyslipidemia leading to Coronary Heart Diseases in Indian population and dearth of conclusive evidence in support of beneficial role of homoeopathy, we intend to evaluate the efficacy of Dioscorea villosa 6CH in comparison with placebo in treatment of dyslipidemia.

Methods/Design: In this prospective, double-blind, randomized, parallel arm, placebo-controlled trial, patients diagnosed with dyslipidemia will be randomized in 1:1 ratio to one of the two interventions – Dioscorea villosa 6CH or identical looking Placebo. The outcome measure being used is the blood lipid profile (triglyceride, cholesterol total, LDLc, VLDLc, and HDLc). The study endpoint is 2 months. Lipid profile will be assessed at baseline, and 2 months after intervention. The trial will require 100 patients in order to achieve 80% power for the specified endpoint keeping a provision for 20% attrition rate. In accordance with CONSORT/ReDHoT guidelines, all comparative analyses will be conducted on intention-to-treat basis using SPSS.

Discussion: The outcomes from this trial will generate efficacy data of Dioscorea villosa 6CH in treatment of dyslipidemia. Trial registration: CTRI/2018/04/013511

Keywords: Dyslipidemia; Dioscorea villosa; Homoeopathy; Placebo; Randomized Controlled Trial


INTRODUCTION

Of late, in a short review [1] of published homoeopathy research evidences on dyslipidemia identified four preclinical, three observational studies, and two case records. There were positive leads in managing patients suffering from dyslipidemia. However, more well-designed studies were warranted to generate effectiveness/efficacy of homoeopathy. An observational study conducted by Govekar JP, et al, 2009 [2] on hyperlipoproteinemia on 322 patients showed improvement in 290 patients with a reduction in TC and TGL levels in 100 and 37 patients respectively. Though the study had been carried out on a large number of patients and throws light on the role of indicated homoeopathic medicines on patients with lipoproteinemia, it was methodologically and statistically compromised. Another cohort study [3] with 57 patients of hypercholesterolemia treated with complex homeopathy showed a significant reduction in lipid parameters. There were few promising case series and case reports also [4-6]. A preclinical study on chickens [7] showed reduction in lipid parameters with homoeopathic medicine Baryta carbonicum and Baryta muriaticum. Another study [8] highlighted the remedial effect of homoeopathic drug Syzygium jambolanum on carbohydrate and lipid metabolic disorders in streptozotocin induced diabetic rats. The lipid lowering effect of Cholesterinum has also been found [9]. A multicentric, open-label, randomized, placebo-controlled exploratory trial [CTRI/2014/12/005257] has been undertaken by CCRH [10] on 120 patients, randomized to either homeopathy or placebo. Outcome measure is to evaluate the changes in LDL-cholesterol levels at 3rd and 6th month from baseline. In a recent review [11] conducted by the investigator himself, Diosgenin, the active ingredient of Dioscorea villosa, was

found to have definite lipid-lowering properties in material doses and was hypothesized to have promising potential as homoeopathic medicine in dyslipidaemia.

Dyslipidemia refers to the derangements of one or many of the lipoproteins; elevations of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and/or triglycerides (TGL), or low levels of high-density lipoprotein (HDL) cholesterol while the elevation of lipoproteins alone is labelled as “hyperlipidemia.” The term “atherogenic dyslipidemia” denotes a combination of elevated TGL and small-dense LDL particles and low levels of HDL-cholesterol. Dyslipidemia may result from overproduction or lack of clearance of the lipoprotein particles or may be related to other defects in the apolipoprotein or metabolic enzyme deficiencies. The pathways and means of lipid metabolism in the human body reflect interactions of genetics, complex biochemical processes influenced by medical disorders, medications, and environmental factors [12].

The role of high serum cholesterol, especially a high level of LDL-cholesterol, as a risk factor for coronary artery diseases is well-established [13]. Asian Indians have double the risk of coronary artery diseases than the whites; due to dyslipidemia that is characterized by borderline high TGL, elevated apolipoprotein-B, and reduced HDL in them. It is opined that although the TC levels in Asian Indians is similar or lower as compared to Caucasians, dyslipidemia is more common, which contributes to coronary heart disease (CHD).

The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) reinforces LDL as the primary target of cholesterol-lowering therapy with the optimal goal of its level below 100 mg/dL. The panel recommends treatment beyond LDL lowering for patients with triglyceride levels of 200 mg/dL and above. Non-HDL-cholesterol, representing the sum of all atherogenic lipoproteins, has been identified as a secondary target of therapy in patients with elevated triglyceride levels. Managing and monitoring non-HDL-cholesterol level is found particularly important for Asian Indians. Lifestyle changes such as maintenance in regular aerobic physical activity, increase intake of Omega-3 polyunsaturated fatty acids in diet, and therapeutic interventions such as statins (HMG-CoA reductase inhibitors), fibrates, or a combination of statins with fibrates or niacin have been suggested for their beneficial role in lowering LDL-cholesterol levels, TGL, and increasing HDL-cholesterol levels, but with their adverse effects [14].

Keeping in view the current scenario of increasing risk of dyslipidemia leading to CHD in Indian population and dearth of conclusive evidence suggesting a beneficial role of homoeopathy, there is a need to undertake a study for exploring the effectiveness of homoeopathic medicines, especially Dioscorea villosa in dyslipidemia along with lifestyle modifications (LSM).

Aims and objectives: To evaluate whether empirically selected Dioscorea villosa 6CH has any lipid lowering properties in comparison with placebo in treatment of dyslipidemia.

METHODS / DESIGN

Study design: Prospective, double-blind, randomized, placebo-controlled, two parallel arms trial with a 2 months’ duration for each patient.

Trial registration: The study protocol is registered prospectively in Clinical Trials Registry – India (CTRI) vides reg. no. CTRI/2018/04/013511.

Study setting: Outpatients of D N De Homoeopathic Medical College and Hospital (DNDHMCH) and National Institute of Homoeopathy (NIH).

Selection of samples: Samples will be selected as per below mentioned eligibility criteria from the patients visiting the outpatient departments of the said institutions. Formal effect size calculation was not possible on account of absence of any earlier study of similar design. In a recent multicenter RCT [15] conducted in India on dyslipidemic patients, the baseline mean (± standard deviation) of LDL-c level (mg/dL) in the verum group was reported to be 148.5 ± 24.0 and it was reduced by 29.4% over 3 months of treatment with one capsule of a proprietary bioactive phytonutrient formulation containing red yeast rice, grape-seed, niacinamide, and folic acid. Homoeopathy has never been experimented under controlled situation in dyslipidemia. Lifestyle modification (LSM; dietary restrictions and physical exercise) will be implemented in both arms. Hence, we expect mean reduction of LDLc by 20% (i.e. 118.8 ± 24.0) and 10% (133.65 ± 24.0) in the verum and control arm respectively over 2 months of therapy. Effect size (Cohen’s d) was estimated to be 0.619. With this assumed effect size, keeping α = 0.05, power (1 – β) = 80%, and allocation ratio of 1:1, to detect a significant difference between two independent means (two groups) of LDLc over 2 months of intervention through unpaired t test, calculated sample size becomes 84. Keeping a provision for 20% drop-outs, the target sample size becomes 100 (Dioscorea 6C + LSM: 50, Placebo + LSM: 50).

Inclusion criteria:

  1. Newly diagnosed dyslipidemia patients not undergoing any therapy
  2. Age 18-65 years
  3. Both sexes
  4. Providing written informed consent to participate

Exclusion criteria:

  1. Self reported familial hypertryglyceridaemia
  2. Patients who are too sick for consultation, unable to read patient information sheet, unwilling to take part or not giving consent to join the study
  3. Diagnosed cases of systemic diseases, unstable mental or psychiatric illness or other uncontrolled or life-threatening illness affecting quality of life or any organ failure
  4. Pregnancy and lactation
  5. Substance abuse and/or dependence
  6. Self-reported immune-compromised state, and
  7. Undergoing homoeopathic treatment for chronic disease within last 6 months

Criteria for discontinuing or modifying allocated interventions: Patients can be excluded from further participation within the study or withdraw themselves without having to provide any further reasons. Possible reasons for this therapy dropout are expected to be:

  1. Withdrawal of the patient’s consent
  2. Consumption of drugs or, rather, medications which are not permitted during the duration of the clinical study
  3. Deficient compliance of patients after the evaluation of the examining physician (regular and specified consumption of study medication)
  4. A newly occurring condition which influences the efficacy of the study investigation or is contra-indicative to the intake of study medication or which needs to be treated with a medication which is not permitted as a concurrent medication during the study
  5. Retroactive appraisal of either unfulfilled inclusion criteria or fulfilled exclusion criteria after the decision of the examining physician/leader of the clinical study
  6. Medically necessary transfer of the patient to a different department or hospital during the study phase
  7. Unexpected findings which make the continuation of therapy from an ethical or medical point of view unjustifiable; the decision will be made by the concerned physician

The complete study can be discontinued prematurely if it is perceptible early on that it cannot fulfill the aforementioned inclusion criteria. This includes:

  1. The necessary recruiting numbers cannot be achieved
  2. There are serious violations of the protocol
  3. The documentation is incomplete or was deliberately filled out incorrectly and legal or ethical instructions are not met

Randomization: Permuted block randomization method has been adopted to generate 10 blocks of 10 random numbers [10 × 10 = 100] to maintain 1:1 distribution. Random sequence (1 and 2 for either of medicine or placebo) will be generated by a third party, not allowed to influence the study in any way. This chart has been made available to the pharmacist in strict confidentiality and will never be disclosed to the patients or doctors under any circumstances. The allocated code will be maintained till the end of the trial.

Blinding: Participants, the principal investigator and the co-investigators, the outcome assessors, and the pharmacist will remain blinded to the identity of the two treatment groups until the end of the study. Concealment will be maintained by identically coded containers having alike vials of either medicine or placebo. Unblinding of individual participants through the investigator will occur in cases of SAEs.

Intervention:

  • Experimental arm: Intervention is planned as administering Dioscorea villosa 6CH, two doses orally everyday for consecutive 2 months. Each dose will consist of 4 medicated globules no. 30 (moistened adequately with Dioscorea 6CH preserved in 90% v/v ethanol), to be taken orally on clean tongue with empty stomach. Dietary restrictions and physical activity will continue uninterrupted. Duration of therapy: 2 months
  • Comparator arm: Placebo, indistinguishable from verum, will be administered orally on clean tongue with empty stomach for 2 months. Each placebo dose will consist of 4 cane sugar globules no. 30 moistened with 90% v/v ethanol. Dietary restrictions and physical activity will continue uninterrupted. Duration of therapy: 2 months.

The homoeopathic medicine Dioscorea villosa 6CH was manufactured by Dr. Reckeweg & Co. GmbH, v1114, D-64625 Bensheim, Germany, Lot No. 3257IN42411D, Mfg. 05/2017, Exp. 02/2022. Identical glass vials were filled with cane sugar globules no. 10 and were moistened with either Dioscorea 6CH or rectified spirit and labeled with code, name of medicine and potency. These were dispended according to the randomization list provided to the pharmacist.

Selection of tools:

  1. Standardized data recording proforma
  2. Blood lipid profile reports

Brief of procedure: Following preliminary screening using inclusion criteria and detailed screening using specified exclusion criteria, eligible patients are being recruited into the trial. Following that, outcome data (baseline lipid profile) is being recorded. Following that, intervention is continued for two consecutive months. Following that, outcome measure is being recorded again.

Outcome assessment: The outcome measure is the blood lipid profile (triglyceride, cholesterol total, LDLc, VLDLc, and HDLc), being assessed at baseline, and after 2 months. A specially designed Microsoft MS Office Excel 2007 spread sheet (master chart) will be used for data extraction and shall be subjected to statistical analysis.

Statistical techniques and data analysis: It will follow intention-to-treat (ITT) approach; i.e. every included patient will enter the final analyses. Missing values will be imputed and replaced. Descriptive data (categorical and continuous) will be presented in terms of absolute values, percentages, mean, standard deviations (sd), confidence intervals (CI), etc. as appropriate. The groups will be checked for comparability of socio-demographic characteristics at baseline. Parametric or non-parametric inferential tests will be used to detect group differences as per normality or non-normality of distribution of data respectively. P values will be set at less than 0.01 two-tailed as statistically significant. SPSS® IBM® Inc., version 20 for Windows shall be used for statistical analysis. Adjusted analyses will be done to address baseline differences, if any. Aside from the analysis of all randomized patients, a per-protocol analysis will also be carried out which is supposed to indicate which effect sizes can be reached under optimal circumstances. In the per-protocol sample, all patients will be included who fulfill all study requirements.

Ethical issues: Intercurrent illness, adverse or serious adverse event(s), if any, will be recorded and treated accordingly as per homoeopathic principles irrespective of the allocated codes, or if non-responding, then the patient shall be referred for conventional treatment. Prior to enrolment, each patient will be provided with a patient information sheet in local vernacular Bengali detailing the objectives, methods, risks and benefits of participating, and confidentiality issues. Subsequent to that, written informed consent shall be obtained. Approval is already taken from the respective institutional ethics committees (IECs) prior to initiation [DNDHMCH: DHC/Estt-175/15/403/2017; Oct. 12, 2017; and NIH: 5-23/NIH/PG/Ethical Comm. 2009/Vol 5/2685 (A/S); March 28, 2018]. The study shall be performed under the constant supervision of the IEC. This study is in compliance with the Helsinki Declaration and with the International Conference on Harmonization (ICH) – Good Clinical Practice. Protocol amendments, if necessary will be submitted to the ethics committee and implementation will be done after approval.

Study flow diagram:

DISCUSSION & CONCLUSION

Despite the fact that homoeopathy has a long tradition in the complementary treatment of patients and is part of the medical curriculum in many European universities, there is an ongoing debate on its efficacy, effectiveness and credibility. Thus, more robust clinical studies with clear and relevant endpoints are needed to substantiate the evidence base from primary to critical care. This study examines the efficacy of Dioscorea villosa 6CH in dyslipidemiain randomized design and prospectively for the first time toward generating clinical evidence. The use of homoeopathic medicines in dyslipidemia is quite popular; however, scientific papers are sparse. This is a multi-centric study in homoeopathy hospitals. The protocol adheres to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement [16] and TIDieR (Template for Intervention Description and Replication) checklist [17]. Reporting of the study results will adhere to the RedHot (homoeopathy specific CONSORT) statement [18] and model validity of homoeopathic treatment (MVHT) [19].

Should the main outcome of the trial be positive, the qualitative element of the study will provide insights into homoeopathic treatment of dyslipidemia. Publication of results in a peer-reviewed and indexed scientific journal and presentation at scientific meetings is planned. Due acknowledgement and/or authorship will be given to them who have participated in the proposal development and data analysis at the end of the paper with their specific contribution to the study. Authorship credit shall be based on substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and final approval of the version to be published.

Trial status: At the time of initial manuscript submission, recruitment had already started (April 2018); and is ongoing.

Conflict of interest: The authors declare that they have no competing interests.

Funding: We received no funding for the study. Infrastructural support has been provided by the study sites. Additional costs required for the project will be incurred by the authors themselves.

Authors’ contributions: KKN conceived and designed the study and remains the principal investigator. OM and AC are the co-investigators. MK and SS wrote the study protocol and are responsible for statistical analysis. AB and SSA are responsible for data compilation and management. AB, AK, JL, LN, MK, RA, SS, and TB are responsible for data collection. SS drafted the manuscript. All authors reviewed and approved the final manuscript.

Acknowledgements: We are thankful to the patients, pharmacists and staffs for their sincere participation in this ongoing project.

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