Low-Dose Naltrexone for the Treatment of Painful Diabetic Neuropathy, a Small, Randomized, Double-blind, Placebo-controlled Crossover Trial

The study design is a randomized, double-blind, placebo-controlled, crossover trial. The subjects and investigators will remain blinded for the duration of the study. Subjects will be randomized under the direction of investigational pharmacy and will be randomized in groups of 6 subjects with 3 being assigned to Group A and the other 3 being assigned to Group B. The randomization information will remain under the purview of Investigational Pharmacy until the conclusion of the study, who will be unblinded during the study for management of appropriate medication dispersal following randomization. As a crossover trial, all subjects will be exposed to both the investigational agent as well as placebo for 8 and 4 weeks, respectively. There will be no washout period in order to help maintain blinding.

The investigational agent in this study is naltrexone. Naltrexone is currently FDA approved for treatment of alcohol and opioid dependence at doses of 50mg daily or higher. Two placebo controlled trials involving 93 patients taking REVIA (naltrexone) 50mg daily reported no serious adverse events during the course of the trials. In this study, the drug will be used in an off-label capacity at lower doses to treat pain associated with diabetic neuropathy. Placebo will be used for this study as a control. The maximum duration of time a patient will receive placebo is 4 weeks. No prior and/or concomitant medical therapies will be collected during the study. The following criteria outline which concomitant medicines/therapies (including rescue therapies) are permitted/not permitted during the study:

• Opioid based medicines (including rescue therapies) are not permitted during the study.
• New pharmacologic therapies for pain not previously taken by the subject are not permitted during the study period.
• Any baseline (stable use at initiation of the study) non-opioid medication (including rescued therapies) are permitted during the study.
• Pre-study concomitant medications will be recorded via chart review prior to enrollment.

The drug and placebo will be administered orally via identical capsules and filler rendering them indistinguishable. Patients will take the investigational agent once daily for eight weeks. The agent will be administered following the titration regimen consisting of one week at 1.5mg daily, followed by one week of 3mg daily, then 4.5mg daily for the remaining six weeks. The dose titration for naltrexone was developed in clinical use and was the basis for our previous retrospective analysis (Retrospective Analysis for Safety and Tolerability of Low Dose Naltrexone with a Novel Dosing Regimen) that was accepted for a poster presentation at the American Society of Regional Anesthesiology and Pain Medicine in 2018. This regimen was developed in order to reduce the chance of a patient developing a particular side effect with their particular dose as well as with the intent to identify what dose worked best for any particular patient. Clinical trials have tested LDN at either 3mg/day or 4.5mg/day. No study, to our knowledge, has looked at having a patient be able to identify a dose response and titrate the medication to effect. This titration regimen allows patients to control their own dose of medication without needing to call their provider's office to change their regimen. Simply, the patient starts taking the smallest dose which is a 1.5mg capsule each evening for one week. If the patient experiences disruption of sleep or vivid dreams, they may switch from the evening to the morning. If no side effects develop, the patient may escalate their dose to two capsules (3.0mg) per evening during the second week of the trial and again switch to morning dosing if they develop any side effects. Lastly, the patient may increase their dose to the maximum of 3 capsules (4.5mg) per evening at the start of the third week of the trial and may transition to morning dosing if they develop side effects of the drug. The flexibility inherent in this dosing regimen is to optimize the potential effect of the medication and tolerance during this clinical trial as it has been found to be flexible and well-tolerated in clinical use at our institution where this regimen has been adapted by the majority of our providers.

Placebo will be administered once daily for four weeks for a total of 12 weeks including the active drug. The order of placebo and drug will be determined by randomization of subjects into one of two crossover timelines, one starting with the drug, the other starting with the placebo and switching at 8 and 4 weeks, respectively. The drug/placebo will be dispensed by investigational pharmacy and mailed in a packet directly to the subjects every 4 weeks. The first packet will contain 4 pill bottles with 7 capsules each, bottles will be clearly labeled week 1, week 2, week 3, week 4, to be taken in that order. The second packet will contain bottles labeled weeks 5 through 8 and the third packet with bottles labeled weeks 9 through 12.