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 Table of Contents  
RESEARCH PROTOCOL
Year : 2013  |  Volume : 7  |  Issue : 4  |  Page : 145-152

Efficacy of homoeopathic treatment for diabetic distal symmetric polyneuropathy: A multicentric randomised double-blind placebo-controlled clinical trial


1 Director General, Central Council for Research in Homoeopathy, Janakpuri, New Delhi, India
2 Scientist-4, Central Council for Research in Homoeopathy, Janakpuri, New Delhi, India
3 Scientist 1, Central Council for Research in Homoeopathy, Janakpuri, New Delhi, India

Date of Web Publication26-Dec-2013

Correspondence Address:
Bindu Sharma
Scientist-4, Central Council for Research in Homoeopathy, 61-65, Institutional Area, Opposite D-Block, Janakpuri, New Delhi - 110 058
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-7168.123380

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  Abstract 

Background: There are limitations in the management of Diabetic Distal Symmetric Polyneuropathy (DDSP) in conventional system but in Homoeopathy the research studies have shown positive results. These studies were not robust enough to prove the efficacy of individualized homoeopathy, thus this protocol has been developed to assess the efficacy of these individualized homoeopathic drugs in this disease.
Material and Methods: It shall be a double blind randomised placebo controlled clinical trial. On the basis of earlier observational studies and repertorial anamnesis of DDSP symptoms, 15 homoeopathic medicines have been identified. The validated scales are being used for evaluating the outcomes post-intervention. The primary outcome is change in Neuropathy Total Symptom Score-6 (NTSS-6) from baseline to 12 months. The secondary outcomes include the changes in HbA1c, peripheral nerve conduction test, World Health Organization Quality Of Life BREF (WHOQOL-BREF) and Diabetic Neuropathy Examination (DNE) Score at 12 months post intervention.
Discussion: Results from this trial will help to construct a strategy for treating the patients with DDSP and for improving the quality of life of diabetic patients.
Trial Registration: Clinical Trial Registry - India: CTRI/2013/07/003818.

Keywords: Clinical trial, Diabetes mellitus, Homoeopathy, Medicine, Polyneuropathy


How to cite this article:
Manchanda RK, Sharma B, Mehra P. Efficacy of homoeopathic treatment for diabetic distal symmetric polyneuropathy: A multicentric randomised double-blind placebo-controlled clinical trial. Indian J Res Homoeopathy 2013;7:145-52

How to cite this URL:
Manchanda RK, Sharma B, Mehra P. Efficacy of homoeopathic treatment for diabetic distal symmetric polyneuropathy: A multicentric randomised double-blind placebo-controlled clinical trial. Indian J Res Homoeopathy [serial online] 2013 [cited 2019 Aug 18];7:145-52. Available from: http://www.ijrh.org/text.asp?2013/7/4/145/123380


  Background Top


Diabetic neuropathy is defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in a patient with diabetes, after the exclusion of other causes. In course of diabetes, some 20-90% of individuals eventually develop diabetic neuropathy. [1] Diabetes affects approximately 246 million people worldwide out after and of these about 20-30 million people worldwide are affected by symptomatic diabetic neuropathy. More than 80% of patients with clinical diabetic neuropathy have a distal symmetrical form of the disorder. [2],[3]

Blood sugar levels and duration of the disease are the main risk factors for development of this disease. [4],[5] So, it is essential to develop a strategy to stop the progression of this disabling condition to the extent possible.

The conventional treatment includes non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressants, etc., which are having side effects and are even contraindicated in certain conditions. [1] There are no specific guidelines for painful diabetic neuropathy and many patients remain untreated or undertreated. [6]

An observational comparative study by R. Pomposelli et al. on forty five type 2 diabetic patients with polyneuropathy showed substantial stability of the electro-neuro-physiological values and nerve conduction test, blood pressure and body weight in both groups. A slight decrease of fasting blood glucose, glycated haemoglobin, improvement in QOL scores, decrease in usage and per capita cost of allopathic drugs were found in homoeopathic group. [7] A prospective multi-centric open clinical trial carried out by CCRH also showed statistical improvement in all the symptoms of DDSP with the usage of 15 homoeopathic medicines on individual symptoms. [8]

Considering the positive outcome of these studies which are generally underpowered, this protocol has been developed to initiate new study with proper rigor and sample size. This document is a clinical research protocol designed for human research study which will be strictly adhered to while undertaking the trial. This study shall be conducted according to Declaration of Helsinki [9] and Good Clinical Practice in India.

Study Aims

Primary


To evaluate the efficacy of homoeopathic treatment using pre-identified medicines in the management of DDSP.

Secondary

  • To assess the change in QOL of patients using WHO QOL BREF questionnaire
  • To assess the change in diabetic neuropathy examination (DNE) score post intervention.
Study Design and Setting

It shall be a double-blind randomised placebo-control clinical trial in which patients will be enrolled for 6 months or till sample size is complete whichever is earlier + one year of follow up. The patients will be enrolled at the outpatient department (OPD) of six research centres spread all over India. These Institutes/Units have been selected for carrying out the research study keeping in view prevalence of the disease, adequacy of the manpower, facilities of laboratory investigations and the willingness of the research personnel at the centres.

Following validated scales are being used during this trial at different times during data collection:

Diabetic neuropathy symptom score (DNS score)

It is a four-item validated symptom score, with high predictive value to screen for peripheral neuropathy (PNP) in diabetes. [10],[11]

Diabetic neuropathy examination score (DNE score)

The DNE score is a sensitive and validated hierarchical physical examination scoring system, which contains two items concerning muscle strength, one concerning reflexes and five concerning sensation, for a total of eight items. [12],[13]

Neuropathy Total Symptom Score (NTSS-6) - Healthcare Professional administered version

The evaluating healthcare professional will complete a score of frequency times intensity by asking patients about their symptoms of deep aching pain, burning pain, and prickling sensation as well as numbness in their lower extremities. [14]

WHO QOL-BREF

This is a questionnaire asked from the patient as how he/she feels about their QOL, health or other areas of life within last 4 weeks. The questions along with the options will be read out by the investigator or read by the patient himself/herself and appropriate answer will be marked at three months interval. [15]

The risk group patients shall be screened with DNS score and other laboratory parameters. Consent will be obtained from the patients during screening. The subjects qualifying inclusion criteria shall be subjected to intervention. The cases have been randomised to receive either of interventions, that is homoeopathic medicine or placebo. 15 homoeopathic medicines have been identified on the basis of earlier observational studies and repertorial anamnesis of DDSP symptoms. These medicines have been blinded at the headquarter level and have been sent to the centres to be prescribed as per the randomisation. The process of randomization, investigation and follow up has been detailed in [Figure 1].
Figure 1: Consort flow diagram
*See Study Eligibility Criteria


Click here to view


As the study is double blind, it has been ensured that the investigator prescribes the intervention as per the randomisation code provided to him and the pharmacist has sole access to medication to be dispensed as per the instructions.

Unblinding of the study will be done only after the study is completed in all the centres and the final data will be analysed statistically by the team at headquarters. However, in case of any serious adverse event, the particular participant will be unblinded after reporting to the co-ordinator/co-co-ordinator as early as possible and at CCRH headquarters within 24 working hours by phone or fax followed by written narration of the event within 48 hours. The same will be mentioned in the Case Recording Format of the patient at the centre.

Ethical Approval

The intervention drugs are known homoeopathic pharmacopoeial preparations. The study has been approved by the Ethical Committee vide letter 1-169/2011-12/CCRH/CR/DDSP/858/July 2013.

Sample Size

The sample size was calculated with NTSS-6 as the primary outcome variable. Assuming mean ± SD NTSS-6 during 12 months period post-intervention in the control arm as 10 ± 4 and in the intervention arm 8 ± 4, to detect this difference with 95% confidence level, 90% power, 10 post-intervention measurements, and correlation in repeated value of NTSS-6 as 0.7, we would require 30 evaluable patients in each group. Considering some loss to follow up, at least 42 patients in each group will be taken. However, sample size calculation will be revisited based on the data accumulated by 6 months time.

Study Eligibility Criteria *

Eligible participants comprise males and females, aged 30-70 years, suffering from type 2 diabetes but stable with allopathic treatment for past 3 months. Patients will be selected for the study as per the detailed screening, which includes the signs (DNE score ≥3), symptoms (DNS score ≥1), abnormal nerve conduction test, HbA1c ≤8%, controlled hypertension and those who provide the written informed consent.

Participants shall be excluded if they have diabetic mononeuropathy, diabetic polyradiculopathy, diabetic amyotrophy , diabetic autonomic neuropathy, abnormalities of gait, development of typical Charcot's joints, particularly in the feet , loss of arch with multiple fractures of tarsal bones, wrist and/or foot drop, paralysis of III, IV or VI cranial nerves, myocardial infarction less than 6 months, unstable angina, neuropathy due to other causes, for example vitamin B12 deficiency, alcohol addiction or dependence, cases presenting with long-term complication of diabetes such as severe retinopathy, severe renal involvement or with history of recurrent acute complications like hypoglycaemia, ketoacidosis, etc., cases with other systemic diseases like cardiovascular, endocrinal diseases like thyroid dysfunction or systemic infections or on other treatment therapies (Except for hypertensive and dyslipidaemic patients on standard care).

Data Collection

Data collection shall start with the screening procedures, which involve a two stage screening as mentioned below:

Stage I

'Preliminary verbal screening'


OPD doctor looks for the presence of signs and symptoms (DNS score) and/or diagnosed cases of diabetic polyneuropathy. Screened subjects will be sent to the investigating officer who will perform detailed screening after taking the written informed consent from the patient for taking part in the study.

Stage II

Detailed screening


The investigator and the consultant from conventional system will examine the patient and advise for relevant investigations to confirm fulfilment of inclusion criteria and rule out the factors mentioned in the exclusion criteria to enrol the patient in the study.

Randomisation

All enrolled patients are allocated the intervention as per the Block randomisation. This is done for each centre separately. Random generated codes are made available from computer-based software, RALLOC. Enrolment number of the patient is used for the purpose for randomisation. Initial randomisation is maintained for all follow up visits.

The measurement domains, tools and time points at which data are collected are shown in [Table 1].
Table 1: Data collection at baseline, 3, 6 and 12 months

Click here to view


Data Management

The information of all patients screened and enrolled is to be recorded. The case history of each case is to be recorded in the Case Recording Format and the relevant annexure pertaining to base line assessment, NTSS-6, DNE, WHOQOL BREF, Acute Phase Information Sheet, Adverse Event Reporting Form and details of medicine dispensing are to be filled and maintained.

The patients who stop taking the allopathic medicines or stop taking the intervention on his/her own, will be considered under as Protocol Violation. So these patients will not be considered for analysis 'as per protocol'. Similarly the cases that suffer from any intercurrent/concurrent or acute complaint and are subjected to acute homoeopathic medicine or conventional therapy will not be considered for analysis 'as per protocol'. Such cases will be considered for sub-group analysis and also can be considered for analysis under the principle for 'intention to treat'.

Study Arms

Intervention arm


The homoeopathic medicines shortlisted are to be prescribed to the patients enrolled in this group. The shortlisted medicines are: Arsenic alb, Calcarea carb, Carbo veg, Conium mac, Kali carbonica, Lycopodium, Phosphorus, Pulsatilla, Plumbum, Mercurius, Sulphur, Phosphoric acid, Natrum muraticum, Nitric acid and Zincum met. The medicine is to be selected through a process of constructing the symptom totality for the case followed by repertorisation and consulting the homoeopathic materia medica.

Control arm

Patients to be given placebo in this group, which is prepared with same liquid solvent as used for preparation of medicine but without any medicinal substance. The placebo is identical to the medicine dispensed to the other group.

Treatment and Follow-up

In both the groups the patients will continue with the standard care as per the conventional system of medicine, which will be monitored by the consultant attached at each centre for the study. Homoeopathic medicines will be prescribed serially beginning with 6C, followed by 30C, 200C and 1M as per the need of the case. As this is a pathological condition and is affecting the nervous system the starting potency has been kept low with frequent repetition.

Dosage and Repetition

The dosage of the medicine to be administered and its repetition are mentioned in [Table 2].
Table 2: Potency, dosage and repetition of the medicine

Click here to view


Follow-up Assessment

It shall be done considering the following parameters:

  1. Any change in the score
  2. Any change in prescribing totality
  3. General well being of patient
  4. Any other change or observation in the case
  5. Any change in laboratory reports.
Acute Phase

In case of acute exacerbation of diabetic neuropathy or any other acute disease arising during the course of treatment, prescription will be changed and selection of the medicine will be based on the characteristic attributes of the chronic phase. Investigators will select a new medicine as per the acute totality of the case or refer for conventional treatment as the case may be. Previously prescribed medicines/placebo are to be discontinued till acute phase is over. Record to be maintained in follow up sheet for acute phase.

Outcome Measures

The primary outcome measure is change in NTSS-6 from baseline to 12 months. The secondary outcomes include the changes in DNE score, HbA1c, Peripheral nerve conduction test and WHO QOL BREF between the groups post-intervention.


  Treatment Assessment Top


Assessment of improvement will be done after all the potencies (6C, 30C, 200C and 1M) of the selected medicine have been used; clinically improved patients will be put on periodic observation till they complete one year follow up for final assessment. A patient will be labelled as failure if the complaints persist or worsen after the medicine has been tried in all potencies during the period of one year.


  Data Analysis Top


Statistical Method

Data obtained from all the study centres would be verified and analysed using following statistical methods:

Baseline characteristics will be compared between the two groups. Repeated measures analysis using Generalised Estimating Equation (GEE) will be used to compare difference in NTSS-6 during 12 months intervention period. Following would be considered as potential confounders in diabetes mellitus - hereditary factor, diet, smoking, obesity, stress, etc., In case there is imbalance in the distribution of these potential confounders between the two treatment arms, multivariate analysis will be used to adjust for the effect of these confounders on the effect size. For the primary outcome and each of the secondary outcomes, both per protocol and intention to treat analysis will be done. Effect size and 95% confidence interval will be computed. O'Brien and Fleming Stopping Rule will be used for one interim analysis at 6 months and final analysis at 18 months. After the final analysis group code will be broken. SPSS software will be used for data analysis.


  Discussion Top


The results which will be obtained from the study will be compared with the previous studies. It is hoped that the outcome of the study will be useful to the profession in general and researchers in particular.


  Trial Status Top


The trial is currently in the recruitment phase.


  Acknowledgements Top


This project is being taken up as part of intra mural research program of Central Council for Research in Homoeopathy. The authors are grateful to the experts namely Dr. V. K. Gupta, Dr. A. C. Amini, Dr. Manjeet Singh, Dr. Ajay Ajmani, Dr. R. M. Pandey and Dr. Kusum Chand who helped in refining the protocol and imparted training to the investigators. We are also thankful to the members of Ethical Committee and Scientific Advisory Committee who advised certain modifications for bringing out more clarity in the protocol and finally approved it for implementing at the respective research centres. The authors also express their gratitude to Dr. Alok Kumar, former Director General Incharge and Dr. Vikram Singh, Deputy Director (H), CCRH for thier constant support and help in implementing this protocol at the respective centres. The authors acknowledge the contribution of the investigators at these centres where this study has been initiated. Mrs. Maya Padmanabhan, Statistical assistant at the headquarters is acknowledged for her contribution. We thank the participants for their participation in this study.

Other Literature Referred

  1. Available from: www.who.int/mediacentre/factsheets/fs312/en/ [Last accessed on 2011 Oct 23].
  2. Powers AC. Diabetes mellitus. Harrison's Principless of Internal Medicine, 16 th ed., Vol II. New York: McGraw-Hill, Medical Publishing Division; 2005. p. 2165.
  3. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States (Key Facts), 1990-1997: Results of a follow-up national survey. JAMA 1998;280:1569-75.
  4. England JD, Gronseth GS, Franklin G, Miller RG, Asbury AK, Carter GT, et al. Neurology-Distal symmetric polyneuropathy: A definition for clinical research: Report of American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2005;64:199-207. Avialable from: www.neurology.org/content/64/2/199.full.html [Last accessed on 2011 Aug 11].
  5. Frier BM and Fisher BM. Diabetes mellitus. Davidson's Principles and Practice of Medicine. 19 th ed. London: Churchill Livingstone; 2002. p. 673-5.
  6. Pradeepa R, Rema M, Vignesh J, Deepa M, Deepa R, Mohan V. Prevalence and risk factors for diabetic neuropathy in an urban south Indian population: The Chennai Urban Rural Epidemiology study (Cures-55). Diabet Med 2008;25:407-12.
  7. Ashok S, Ramu M, Deepa R, Mohan V. Prevalence of Neuropathy in Type 2 Diabetic patients attending a diabetic centre in South India. J Assoc Physicians India 2002;50:546-50.
  8. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-65.
  9. Simmons Z and Feldman EL. Update on diabetic neuropathy. Curr Opin Neurol 2002;5:595-603.
  10. Available from: www.genome.gov/.../Deviation_Violation_examples 8-07.pdf [Last accessed on 2012 Sep 13].
  11. Available from: http://www.consort-statement.org/resources/glossary /e---l/loss-to-follow-up/ [Last accessed on 2012 Sep 14].
  12. Available from: http://www.medicalcriteria.com/site/index.php [Last accessed on 2012 Sep 14].
  13. Tiwari NL and Tamboli P. Diabetes mellitus-Defining scope and clinical approach for homoeopathic management. Indian Journal of Research in Homoeoapthy 2008;2:28-36.


 
  References Top

1.Kochar DK, Rawat N, Agrawal RP, Vyas A, Beniwal R, Kochar SK, et al. Sodium valproate for painful diabetic neuropathy: A randomized double blind placebo controlled study. QJM 2004;97:33-8.  Back to cited text no. 1
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2.Said G. Diabetic neuropathy: A review. Nat Clin Pract Neurol 2007;3:331-40. [Cited 2011 October 31]. Available from: www.connote.org/user/natureClinicalPractice/tag/proximaldiabetic neuropathy.  Back to cited text no. 2
    
3.Available from: http://www.nature.com/nrneurol/journal/v3/n6/full/ncpneuro0504.html [Last accessed on 2011 Oct 31].  Back to cited text no. 3
    
4.Hovaguimian A, Gibbons CH. Clinical approach to the treatment of painful diabetic neuropathy. Ther Adv Endocrinol Metab 2011;2:27-38.  Back to cited text no. 4
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5.Baig H, Singh K, Sharma A, Obera P, Kaushik S, Nayak D, et al. Role of Cephlandra indica Ø in the management of Diabetes mellitus as an add on medicine along with conventional anti-diabetics. Clinical Research Studies Series II. Central Council for Research in Homoeopathy, New Delhi; 2009:15-20.  Back to cited text no. 5
    
6.Baig H, Singh K, Sharma A, Obera P, Kaushik S, Mishra A. Rhus aromaticus in the management of Diabetes mellitus. Clinical Research Studies Series II. Central Council for Research in Homoeopathy, New Delhi; 2009:21-7.  Back to cited text no. 6
    
7.R. Pomposelli et al. Observational study of homoeopathic and conventional therapies in patients with diabetic Polyneuropathy. Homeopathy (2009) 98:17-25.  Back to cited text no. 7
[PUBMED]    
8.Nayak C, Oberai P, Varanasi R, Baig H, Ch R, Reddy GR, et al. A prospective multi-centric open clinical trial to evaluate usefulness of homoeopathic medicines in the management of diabetic distal symmetric Polyneuropathy. Homeopathy 2013;102:130-8.  Back to cited text no. 8
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9.World medical association declaration of Helsinki - Ethical Principles for Medical Research involving Human subjects. Bulletin of World Health Organisation, 2001. [Cited 2011 March 25]. Available from: www.who.int.bulliten.  Back to cited text no. 9
    
10.Masharani U, Karam JH. Diabetes mellitus and Hypoglycemia. Current Medical Diagnosis and Treatment 2001, 40 th ed. New York: Lange Medical Books/McGraw-Hill Medical Publishing Division. p. 1191.  Back to cited text no. 10
    
11.Lavery LA, Armstrong DG, Boulton A. Screening for Diabetic Peripheral Neuropathy. Diabetic Microvascular Complications Today 2004:17-9.  Back to cited text no. 11
    
12.Meijer JWG, Bosma E, Lefrandt JD, Links TP, Smit AJ, Stewart RE, et al. Clinical diagnosis of Diabetic Poly neuropathy with the diabetic neuropthy symptom and diabetic neuropthy examination score. Diabetes Care, March 2003; Volume 26, Number 3:697-701.  Back to cited text no. 12
    
13.Meijer JW, Sonderen EV, Blaauwwiekel EE, Smit AJ, Groothoff JW, Eisma WH, et al. Diabetic Neuropathy Examination - A hierarchical scoring system to diagnose distal Polyneuropathy in diabetes. Diabetes Care, June 2000; Volume 23, Number 6:750-753.  Back to cited text no. 13
    
14.Bastyr EJ, Price KL, Bril V. Development and Validity Testing of the Neuropathy Total Symptom Score - 6: Questionnaire for the study of sensory symptoms of Diabetic Peripheral Neuropathy. Clin Ther 2005;27:1278-94.  Back to cited text no. 14
    
15.World Health Organization. Manual for WHOQOL-BREF - Introduction, administration, scoring and generic version of assessment. Switzerland: WHO, December 1996:1-18.  Back to cited text no. 15
    


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