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

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

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.

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.

Diabetic Polyneuropathy, Diabetic, Polyneuropathy, Ayurvedic, Ayurveda, Neuralgia, Diabetic Neuralgia, Sida cordifolia, Phyllanthus Niruri, Phyllanthus Amarus, Extracts, Extract, Crude Herb, Crude, Herb, Herbal, Herbal Extract, Decoction, Churna, Powder, Bala, Bhumyamalaki, Tamalaki

Phyllanthus niruri 3g fine dry powder 3 times a day with warm water before meals for 8 weeks Sida cordifolia 7g coarse dry powder 2 times a day prepared as traditional decoction before meals for 8 weeks. Decoction: Take provided measurement cup full of water (112ml) and soak one portion (pe-packed) of the powder for 12 hours, then boil it until the upper level has been reduced to 1/4, filter, cool down to room temperature, drink

Phyllanthus niruri extract 2 capsules 3 times a day with warm water before meals for 8 weeks Sida cordifolia roots extract 2 capsules 2 times a day with warm water before meals for 8 weeks

Phyllanthus niruri placebo 2 capsules 3 times a day with warm water before meals for 3 weeks Sida cordifolia placebo 2 capsules 2 times a day with warm water before meals for 3 weeks

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 (whole plant) fine powder 3g three times a day with warm water before meals taken orally.

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

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

300mg inert Maltodextrin in gelatine capsule. 2 capsules given 2 times a day orally with warm water before meals

300mg inert Maltodextrin in gelatine capsule. 2 capsules given 3 times a day orally with warm water before meals

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)

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)

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)

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.

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.

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