A Study of Phyllanthus Niruri and Sida Cordifolia in Diabetic Peripheral Polyneuropathy

Diabetic Neuropathies Clinical Trial

— VEDICINE  

Official title:

A Randomized Placebo-compared Study on Efficiency of Two Different Administration Forms of Phyllanthus Niruri and Sida Cordifolia in Patients With Diabetic Peripheral Polyneuropathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02107469
• Other study ID #: NADIAD 2014
• Status: Completed
• Phase: N/A
• First received: April 3, 2014
• Last updated: February 23, 2016
• Start date: June 2014
• Est. completion date: February 2016

Study information

• Verified date: February 2016
• Source: Rosenberg European Academy of Ayurveda
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Indian Board of Alternative Medicine
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to determine whether phyllanthus niruri and sida cordifolia are effective in treatment of diabetic polyneuropathy compared to placebo. Also two different administration forms (extract capsules and crude herbs) are used to find out whether there are differences in efficiency and compliance.

Description:

This study will explore the difference in therapeutic efficiency between modern extracts and whole drug powder of Phyllanthus niruri plus Sida cordifolia root decoction in diabetic neuropathy compared to placebo. The difference in compliance regarding medicine and food recommendations will be additionally documented.

Design - Study in two parts:

Part I: prospective, placebo-controlled, partly double-blinded (regarding 2 of the arms- all arms are investigator-blinded), 3 arm-parallel group study for 3 weeks Part II: prospective, investigator-blinded, long-term-study for 8 weeks. The active groups of part I will continue with their assigned medication and the placebo-patients of part I will be randomized again for the 2 groups of active medication.

Methods:

Symptoms will be assessed using Neuropathy total symptom score 6 (NTSS-6) as main primary parameter. Additional quantitative sensory testing will be done with the Neuropathy Analyzer Vibrotherm Dx from Diabetic Footcare India for detection of vibration and thermal sensation threshold. Tolerability, adverse drug reactions, Compliance regarding medication intake and dietary recommendations will be documented by an additional questionnaire.

Three randomized groups of 30 outpatients each (powder/decoction ; extract ; placebo) will be created for the part I of the study for the first 3 weeks.

At part I placebo group will be double blinded compared to extract group and investigator-blinded to powder/decoction group.

After 3 weeks the patients of the placebo group will be randomly assigned into both active treatment groups for part II to describe the course of treatment with both administration forms with 45 patients each.

Study visits will be prior and after 1,2,3,5 and 8 weeks.

Statistical plan: The primary parameter will be compared by Mann Whitney-U-Test.

Secondary Parameters will be descriptively analysed.

Implication:

A new herbal formulation will be tested for diabetic neuropathy with modern randomized placebo controlled study design in Part I. The outcome of the observation in part II will bring us closer to evidence based selection of different ayurvedic preparations in an upraising marked of new extraction technologies.

Registry procedures and other quality factors:

Data checks to compare data entered into the registry against predefined rules for range or consistency with other data fields in the registry.

Source data verification to assess the accuracy, completeness, or representativeness of registry data by comparing the data to external data sources (medical records, paper case report forms).

Standard Operating Procedures to address registry operations and analysis activities, such as patient recruitment, data collection, data management, data analysis, reporting for adverse events, and change management.

Sample size assessment to specify the number of participants or participant years necessary to demonstrate an effect.

Statistical analysis plan describing the analytical principles and statistical techniques to be employed in order to address the primary and secondary objectives, as specified in the study protocol or plan.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 80 Years

Eligibility

Inclusion Criteria:

• Signed consent form

• positive history of type 1 or 2 diabetes mellitus having the symptoms of diabetic neuropathy (sensory, peripheral) will be selected.

• Only outpatient setting will be included.

• Patients with =2 symptoms having at least one symptom with moderate severity in occasional frequency (3 points in NTSS-6) are included if they additionally show an impaired vibration detection threshold.

Exclusion Criteria:

• suffering from any other associated clinical conditions influencing peripheral nerve function, for example:

• peripheral vascular disease if reason for nerve damage

• vitamin deficiency (FOL,B12,E)

• heavy metal intoxication (especially with lead, cadmium and thallium)

• other intoxications (alcohol, medicine)

• infectious disease (like HIV, typhus, syphilis, lyme disease, mononucleosis,...)

• cancer

• autoimmune disease

• hepatitis

• vasculitis

• amyloidosis

• severe kidney failure

• pregnancy

• disorder of connective tissue

• steroids taken up to 1 month prior to study

• the likely need for insulin therapy

Regarding prior medication patients are advised not to start additional therapy during the study as long as symptoms are not worsening, antihyperglycaemic drugs will only be adjusted by study physicians if necessary.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Neuralgia
• Diabetic Neuropathies
• Diabetic Neuropathy
• Diabetic Polyneuropathy
• Neuralgia
• Polyneuropathies

Intervention

Drug:
• Sida cordifolia roots
Sida cordifolia roots, crude drug (coarse powder) a plant product 7g (packages prepared) are soaked in 112ml water (measurement cup provided) for 12 hours and then boiled until the level is reduced to 1/4 of hight. Fluid is filtered an drunk after cooling down to room temperature - orally 2 times a day before breakfast and dinner
• Phyllanthus niruri
Phyllanthus niruri (whole plant) fine powder 3g three times a day with warm water before meals taken orally.
• Sida cordifolia roots extract
gelatine capsule with 300mg Sida cordifolia roots spraydry extract 12:1 concentrated normalized to alkaloids (alcoholic/aqueous extract) - 2 capsules taken orally 2 times a day with warm water before meal
• Phyllanthus niruri extract
gelatine capsule with 300mg Phyllanthus niruri spray dry extract 5:1 concentrated normalized to bitters (alcohol/aqueous extract) - 2 capsules taken orally 3 times a day with warm water before meal

Other:
• Sida cordifolia placebo
300mg inert Maltodextrin in gelatine capsule. 2 capsules given 2 times a day orally with warm water before meals
• Phyllanthus niruri placebo
300mg inert Maltodextrin in gelatine capsule. 2 capsules given 3 times a day orally with warm water before meals

Locations

Country	Name	City	State
India	P.D. Patel Ayurveda Hospital	Nadiad	Gujarat

Sponsors (2)

Lead Sponsor	Collaborator
Rosenberg European Academy of Ayurveda	EUROPEAN PROFESSIONAL ASSOCIATION OF AYURVEDA PRACTITIONERS AND THERAPISTS

Country where clinical trial is conducted

India, 

References & Publications (18)

Asare GA, Addo P, Bugyei K, Gyan B, Adjei S, Otu-Nyarko LS, Wiredu EK, Nyarko A. Acute toxicity studies of aqueous leaf extract of Phyllanthus niruri. Interdiscip Toxicol. 2011 Dec;4(4):206-10. doi: 10.2478/v10102-011-0031-9. — View Citation

Bastyr EJ 3rd, Price KL, Bril V; MBBQ Study Group. 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 Aug;27(8):1278-94. — View Citation

Boulton AJ. The diabetic foot: from art to science. The 18th Camillo Golgi lecture. Diabetologia. 2004 Aug;47(8):1343-53. Epub 2004 Jul 28. Review. — View Citation

Cornblath, DR. Diabetic neuropathy: Diagnostic methods. Advanced Studies in Medicine 4(8a):650-661, 2004.

Dettori J. The random allocation process: two things you need to know. Evid Based Spine Care J. 2010 Dec;1(3):7-9. doi: 10.1055/s-0030-1267062. — View Citation

Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol. 2002 Jun;81(1):81-100. Review. — View Citation

Huber CS, Levett JM, Atkinson JM. A Tool to Assess Compliance in Anticoagulation Management. In: Henriksen K, Battles JB, Keyes MA, Grady ML, editors. Advances in Patient Safety: New Directions and Alternative Approaches (Vol. 3: Performance and Tools). Rockville (MD): Agency for Healthcare Research and Quality (US); 2008 Aug. — View Citation

Kanth VR, Diwan PV. Analgesic, antiinflammatory and hypoglycaemic activities of Sida cordifolia. Phytother Res. 1999 Feb;13(1):75-7. — View Citation

Kästenbauer T, Sauseng S, Brath H, Abrahamian H, Irsigler K. The value of the Rydel-Seiffer tuning fork as a predictor of diabetic polyneuropathy compared with a neurothesiometer. Diabet Med. 2004 Jun;21(6):563-7. — View Citation

Konaté K, Bassolé IH, Hilou A, Aworet-Samseny RR, Souza A, Barro N, Dicko MH, Datté JY, M'Batchi B. Toxicity assessment and analgesic activity investigation of aqueous acetone extracts of Sida acuta Burn f . and Sida cordifolia L. (Malvaceae), medicinal plants of Burkina Faso. BMC Complement Altern Med. 2012 Aug 11;12:120. doi: 10.1186/1472-6882-12-120. — View Citation

Kudom AA, Mensah BA, Botchey MA. Aqueous neem extract versus neem powder on Culex quinquefasciatus: implications for control in anthropogenic habitats. J Insect Sci. 2011;11:142. doi: 10.1673/031.011.14201. — View Citation

Kumar P. S., et al. Immediate effects of nerve sliders and nerve massage on vibration and thermal perception thresholds in patients with painful diabetic peripheral neuropathy- a pilot randomized clinical trial. Physiotherapy and Occupational Therapy Journal 3(3):5-19, July - Sept 2010

Neeraj, T., & Parul, S. (2011). Quality standards of indian medicinal plants. New Delhi: Indian Council of Medical Research, Medicinal Plants Unit.

Patel K, Patel M, Gupta SN. Effect of Atibalamula and Bhumyamalaki on thirty-three patients of diabetic neuropathy. Ayu. 2011 Jul;32(3):353-6. doi: 10.4103/0974-8520.93913. — View Citation

Shy ME, Frohman EM, So YT, Arezzo JC, Cornblath DR, Giuliani MJ, Kincaid JC, Ochoa JL, Parry GJ, Weimer LH; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003 Mar 25;60(6):898-904. — View Citation

Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL. Clinical examination for the detection of protective sensation in the feet of diabetic patients. International Cooperative Group for Clinical Examination Research. J Gen Intern Med. 1999 Jul;14(7):418-24. — View Citation

Srividya N, Periwal S. Diuretic, hypotensive and hypoglycaemic effect of Phyllanthus amarus. Indian J Exp Biol. 1995 Nov;33(11):861-4. — View Citation

Sumanth M, Mustafa SS. Antistress, Adoptogenic Activity of Sida cordifolia Roots in Mice. Indian J Pharm Sci. 2009 May;71(3):323-4. doi: 10.4103/0250-474X.56027. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient Diary	With every distributed one-week-package of drug/placebo the patients will get a diary where they are supposed to fill in if medication has been taken (morning/lunch/dinner) and how there symptoms are like (non, mild, moderate, severe) for every single day.	From start to end of treatment (8 weeks, 11 weeks for placebo group)	No
Primary	Improvement of NTSS-6 SCORE in per cent from baseline	Validated symptom score containing 6 questions investigation severity (not present, mild, moderate, severe) and frequency (never or occasional, occasional but normal, often, almost continuous) of symptoms (aching pain, allodynia, burning pain, lancinating pain, numbness, prickling sensation).	Initially, after 1, 2, 3, 5, 8 weeks of treatment, where placebo group will start again in one of the herbal treatment groups after 3 weeks (9 instead of 6 assessments)	No
Secondary	Improvement from baseline in per cent of quantitative sensory testing of vibration and thermal (hot/cold) threshold (score)	Semi-automated Neuropathy Analyser Dx from Diabetic Footcare India used to detect vibration and thermal (hot/cold) threshold (both soles); Inability to feel vibration up to: Normal: 10Hz below age of 50a and 15Hz above age of 50a = scoring "0"; Mild: 11-15Hz below age of 50a and 16-20Hz above age of 50a = scoring "1"; Moderate: 16-20Hz below age of 50a and 21-25Hz above age of 50a = scoring "2"; Severe: 20Hz below age of 50a and 26Hz above age of 50a = scoring "3"; Inability to feel cold down to: Normal: 20°C = scoring "0"; Mild: 19-15°C = scoring "1"; Moderate: 14-10°C = scoring "2"; Severe: < 9°C = scoring "3"; Inability to feel hot up to: Normal: 42°C = scoring "0"; Mild: 43-45°C = scoring "1"; Moderate: 46-48°C = scoring "2"; Severe: > 49°C = scoring "3"; Temperature of the probe is to be reduced from 30°C to 0°C to record perception of cold sensation and temperature of the probe is to be increased from 30°C up to 50°C to record perception of heat sensations.	Initially, after 1, 2, 3, 5, 8 weeks of treatment, where placebo group will start again in one of the herbal treatment groups after 3 weeks (9 instead of 6 assessments)	No
Secondary	Assessment of compliance regarding medication and dietary recommendations (score).	The used questionaire is an adaption of the warfarin compliance-assessment scale from Community Anticoagulation Therapy Clinic in Iowa. (Huber, Levett, & Atkinson, 2008); Medication - Missed doses: No dose missed = score "0"; One dose in a week missed = score "1"; Two doses in a week missed = score "2"; Three or more doses missed = score "3"; Medication - Additional doses: No extra dose = score "0"; One extra dose = score "1"; Two extra doses = score "2"; Three or more extra doses in a week = score "3"; Food habits: Completely followed dietary recommendations = score "0"; One day a week I ignored dietary recommendations = score "1"; Two days a week I ignored dietary recommendations = score "2"; Three or more days a week I ignored recommendations = score "3"	After 1, 2, 3, 5, 8 weeks of treatment, where placebo group will start again in one of the herbal treatment groups after 3 weeks (8 instead of 5 assessments)	No

External Links

•   Funding society: European Professional Association of Ayurveda-Practitioners and -Therapists
•   Nadiad Ayurveda College and Hospital - Site of study
•   Sponsor - Rosenberg European Academy of Ayurveda