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1 Clinical Trial Details (PDF Generation Date :- Sat, 03 Nov :24:50 GMT) CTRI Number Last Modified On 10/06/2013 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2013/06/ [Registered on: 11/06/2013] - Trial Registered Retrospectively No Interventional Drug Randomized, Crossover Trial Low dose naltrexone in foot pain of diabetes A randomized, double-blinded and active-comparison cross-over clinical trial comparing efficacy and safety of low dose naltrexone and amitriptyline in painful diabetic neuropathy Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) DH-LDN.v /1 Protocol Number Details of Principal Investigator 4040 Pharmacology Deptt Sector-12 Details Contact Person (Scientific Query) Room no , Level 4, P.N. Chhuttani Block,, Sector 12, Details Contact Person (Public Query) Room no , Level 4, P.N.Chhuttani Block,, Sector12, page 1 / 5

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Inclusion Criteria Source of Monetary or Material Support > Postgraduate Institute of Medical Education and Research, Type of Sponsor NIL List of Countries of Principal Investigator Dr Primary Sponsor Details Postgraduate Institute of Medical Education and Research Kairon Administrative Block, Sector 12 (Opposite to Panjab University), -, Research institution and hospital NIL of Site Site Phone/Fax/ Postgraduate Institute of Medical Education and Research, 4040, Dept of Pharmacology, Level 4, P.N.Chhuttani Block,, Sector 12, of Committee Approval Status Date of Approval Is Independent Ethics Committee? Institute Ethics Committee, Postgraduate Institute of Medical Education and Research Status Not Applicable Health Type Patients Approved 02/01/2010 No Date No Date Specified Condition Diabetic Neuropathy Type Details Comparator Agent Amitriptyline Drugs used in the treatment of diabetic neuropathic pain 10 or 25 mg orally once per day for a total duration of 6 weeks Intervention Low-dose naltrexone Low-dose naltrexone is compared with Amitriptyline for efficacy and safety in painful diabetic neuropathy 2 mg orally once per day for a total duration of 6 weeks Age From Age To Gender Details Year(s) Year(s) Both Inclusion Criteria - Presence of type 2 diabetes mellitus - No change in anti-diabetic medication for the last 1 month - Evidence of diabetic neuropathy by page 2 / 5

3 Exclusion Criteria Method of Generating Random Sequence Method of Concealment Blinding/Masking Details Computer generated randomization Case Record Numbers Participant and Investigator Blinded - Diabetic Neuropathy Symptom Score >1 point - Diabetic Neuropathy Examination Score >4 point - Vibration perception test and monofilament test - Neuropathic pain present for at least 1 month. - Mean pain intensity of more than 50% by patient assessment by VAS Exclusion Criteria - Age below 18 or above 75 years - Evidence of renal disease (S. creatinine > 1.5) - Evidence of liver disease (deranged LFT with clinical evidence) - Pregnant and lactating mothers and women intending pregnancy. - Evidence of other causes for neuropathy and painful conditions - Epilepsy, psychiatric and cardiac diseases, hypertensives not on treatment, peripheral vascular disease and substance abuse. - Intake of anticonvulsants, antidepressants, membrane stabilizers and opioids. - Participation in any other clinical trial with in the last 30 days Primary Outcome Outcome Timepoints VAS scoring of diabetic neuropathic pain Every 2 weeks from 2 to 16 weeks Secondary Outcome Outcome Timepoints Target Sample Size Improvement on Likert scale, PGIC and neuropathy score Total Sample Size=60 Sample Size from =60 Phase of Trial Phase 2/ Phase 3 Date of First Enrollment () Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial () Publication Details Brief Summary 01/03/2012 No Date Specified Years=1 Months=2 Days=0 Not Applicable Closed to Recruitment of Participants Not yet published every 2 weeks from 2 to 16 weeks Diabetes mellitus is a syndrome with disordered metabolism and hyperglycemia due to inappropriate insulin secretion characterized by chronic complications affecting nervous system, kidney, eye and foot besides acute complications. Diabetic neuropathy has a prevalence of more than 50% among diabetics of more than 25 years duration. page 3 / 5

4 Diabetic neuropathy has been classified in to generalized symmetric polyneuropathies as well as focal and multiple neuropathies. Generalized symmetric polyneuropathies are divided in to acute sensory, chronic sensorimotor and autonomic neuropathies. Focal and multifocal neuropathies are classified in to cranial, truncal, focal limb, proximal motor and coexisting chronic inflammatory demyelinating polyneuropathy. Though exact pathogenesis of diabetic neuropathy is unknown, different mechanisms have been suggested. Polyol pathway hyperactivity, non-enzymatic glycation, oxidative stress, neurotrophic factor deficiency, protein kinase-c activation and microvascular compromise are the mechanisms suggested for the occurrence of diabetic neuropathy. Clinically, sensorimotor neuropathy is characterized by affection of sensory and motor nervous systems. Sensory fibers first affected are the small non-myelinated nerve fibers followed by larger ones. It usually affects the distal lower limb and upper limb first, the reason being postulated to be due to the longer length of these neurons. Most patients are asymptomatic or have only mild symptoms initially. The diagnosis is often overlooked. Paresthesia, dysesthesias, neuropathic pain which may be burning, stabbing or aching types, loss of vibration and proprioception senses, sensory ataxia, predisposition to foot injury and foot ulceration and slowing of nerve conduction are the common features. Motor involvement is usually minor and is restricted to the distal extremities. It can cause foot deformity leading to callus and ulcer formation. Reflexes may also be altered. In acute painful diabetic neuropathy, patients complain of severe pain which is worse at night. They feel intense pain when bed sheet or clothing touches their foot which is termed allodynia. There might be negligible other sensory or motor symptoms and signs. This can occur when the sugar control is poor and is seen in new diabetics, during metabolic disruption following ketoacidosis or eating disorders. This may be associated with weight loss and may improve over 6 to 24 months. Such pain occasionally is seen with improved diabetes control too. Painful diabetic neuropathy is diagnosed by detailed history and symptom assessment. Vibration perception threshold (VPT) alteration, monofilament test, electrophysiology, nerve biopsy, skin punch biopsy, quantitative sensory testing, peripheral nerve imaging and composite measures though can be advocated for early diagnosis of diabetic neuropathy, none of them are fully confirmatory. They help in prognostic assessment of diabetic neuropathy. But in the case of painful diabetic neuropathy detailed history along with assessment of signs and symptoms is the most reliable method since all the above tests may be normal. Painful neuropathic symptoms are present in up to 53% of patients who suffer from diabetic neuropathy. The present management of painful diabetic neuropathy include control of sugar level followed by drugs for control of pain. It is currently thought that pharmacologic therapy for PDN is most effective when it targets mechanisms that contribute to neuropathic pain signals. Neuropathic page 4 / 5

5 Powered by TCPDF ( PDF of Trial pain may result from hyperexcitability of peripheral and central pain pathways, including changes in the type, degree of expression, or function of sodium and calcium channels. Aberrant peripheral nerve activity also may drive alterations in central pain processing via the excitatory neurotransmitter glutamate and reduced?-aminobutyric acid (GABA) inhibitory control. Drugs belonging to the group of antidepressants, anticonvulsants, membrane stabilizing agents, electrical stimulation and capsaicin are the agents that have been tried for treatment in painful diabetic neuropathy and different mechanisms for their benefit in the condition are described. Though amitriptyline is considered the first choice, it causes sedation in considerable number of patients. Anti-cholinergic side effects of amitriptyline can further worsens the situation if diabetes is associated with autonomic neuropathy. Naltrexone hydrochloride is a potential novel treatment for chronic pain. The drug is a competitive antagonist of opioid receptors, and has been used clinically for over 30 years mainly for the treatment of opioid addiction. However, when naltrexone is given at a lower dose, equal to or less than 5 mg/day [low-dose naltrexone (LDN)], its opiate antagonist activity turns into an agonist one so as to trigger a prolonged release of endogenous opioids such as?-endorphins (BE). Naltrexone has also been found to attenuate the production of pro-inflammatory cytokines and neurotoxic superoxides via suppressive effects on central nervous system microglia cells. Naltrexone has also been proposed to exert neuroprotective effects via modulation of mitochondrial apoptotic pathways. More recently, the drug has been used in dosages ranging from 3 mg to 4.5 mg per day to treat chronic pain and autoimmune disorders Naltrexone used in this dosage range is typically referred to as low-dose naltrexone (LDN). Pilot trials for LDN in Crohn s disease, multiple sclerosis, cancer related pain and fibromyalgia have recently been conducted. Given the naltrexone s demonstrated efficacy in suppressing effect on centrally produced proinflammatory cytokine activity and the overlap in symptoms between painful diabetic neuropathy and above mentioned conditions, we hypothesized that LDN would successfully reduce the symptoms of PDN. To test these hypotheses, we plan to conduct a clinical trial of LDN for the treatment of painful diabetic neuropathy, using a placebo-controlled, double-blind, cross-over design with amitriptyline as active comparator. page 5 / 5