Efficacy and Safety of Intravenous Neridronic Acid in CRPS-I

Study Overview
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Brief Summary
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This clinical trial is being conducted to demonstrate the efficacy of neridronic acid in the treatment of pain associated with complex regional pain syndrome type I (CRPS-I). The trial is divided into 3 periods: a 60-day enrollment period, a 12-week trial period, and an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period will be terminated for all participants after the last participant enrolled completes their Month 6 visit (Visit 9). The double-blind will be maintained throughout the 12-week trial period and extended follow-up period.

Official Title
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A Randomized, Double-blind Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome Type I (CRPS-I)

Conditions
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Complex Regional Pain Syndrome, Type I

Intervention / Treatment
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* Drug: Placebo
* Drug: Neridronic acid 62.5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed. Male or female participant between 18 years and 80 years of age. A diagnosis of complex regional pain syndrome type I according to the clinical diagnostic criteria using the International Association for the Study of Pain clinical diagnostic criteria (Budapest criteria). Baseline Pain Intensity Score of 4 or greater using an 11-point Numerical Rating Scale referring to the CRPS-affected limb. In stable treatment and follow-up therapy for CRPS type I for at least 1 month. Participant has undergone a recent regular dental examination. Women of child-bearing potential must have a negative urine ß-HCG pregnancy test at enrollment. Women of child-bearing potential must practice protocol defined acceptable methods of birth control during the trial. Participants must be able to communicate meaningfully, be able to differentiate with regard to location and intensity of the pain, and be able to answer the questions in the questionnaires used in this trial. Compliance with the use of electronic diary assessed prior to allocation to treatment. Exclusion Criteria: A diagnosis of complex regional pain syndrome type II. Documented history or diagnosis of peripheral neuropathy, including diabetic peripheral neuropathy or other metabolic or toxic neuropathy, or any other chronic pain condition that would significantly affect a participant's ability to report CRPS-related pain. Body weight less than 40 kg. Evidence of renal impairment or a history of chronic kidney disease. Serum calcium or magnesium outside of the central laboratory's reference range; history of hypocalcemia; any metabolic disorder anticipated to increase risk for hypocalcemia. Vitamin D deficiency. Participants with vitamin D deficiency prior to enrollment may be enrolled with appropriate supplementation during the enrollment period. Corrected QT interval greater than 470 milliseconds; treatment with medications within the last 30 days prior to allocation to IMP that have potential to prolong the QT interval or anticipated need for such medications during the course of the trial. Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of intravenous bisphosphonate, administration of oral bisphosphonate within the previous year, anticipated requirement for treatment with oral or intravenous bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia) or other bone turnover suppressing drugs within the past 6 months. History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, or to vitamin D or calcium supplements. Recent tooth extraction, unhealed or infected extraction site, or significant dental/periodontal disease that may pre-dispose to need for tooth extraction or other invasive dental procedures during the trial. Evidence of denture-related gum trauma or improperly fitting dentures causing injury. Prior radiation therapy of the head or neck (within 1 year of enrollment). Recent treatment with high doses of systemic steroids or anticipated need for concomitant high-dose steroid treatment during the trial. History of malignancy within 2 years before enrollment with the exception of basal cell carcinoma. Daily intake of long- and short-acting or controlled-release opioid analgesics of more than 200 mg morphine equivalents, regimens combining high-dose opioids and benzodiazepines, or any other treatment regimen considered unstable, unsafe, or have potential to affect the interpretation of the trial. Use of nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture, electromagnetic field treatment, or initiation/implementation of radiofrequency ablation or other sympathectomy procedures, or peripheral nerve stimulation within 6 weeks prior to allocation to investigational medicinal product. Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of enrollment, based on participant history and physical examination and according to the investigator's judgment. Any other severe medical condition, including severe depression, or any other severe mood disorder, that in the opinion of the investigator may affect efficacy or safety assessments or may compromise the participant's safety during trial participation. Participant is engaged in litigation related to their disability from CRPS in which monetary gain or loss (or other compensation) may affect their objective participation in the trial. Women who are pregnant or breastfeeding. Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2-fold upper limit of normal (ULN), or evidence or history of liver disease. Participation in an investigational drug trial within 3 months prior to enrollment, or prior participation in this trial with receipt of any infusion of IMP, even a partial infusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10 | Drug: Placebo<br>* Matching placebo administered as intravenous infusion.<br>|
| Experimental: 125 mg Neridronic acid<br>Neridronic acid 62.5 mg administered as intravenous infusion on Day 1 and Day 4; matching placebo administered as intravenous infusion on Day 7 and Day 10 | Drug: Placebo<br>* Matching placebo administered as intravenous infusion.<br>Drug: Neridronic acid 62.5 mg<br>* Neridronic acid administered as intravenous infusion.<br>|
| Experimental: 250 mg Neridronic acid<br>Neridronic acid 62.5 mg administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10 | Drug: Neridronic acid 62.5 mg<br>* Neridronic acid administered as intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Pain Intensity Score to Week 12. | The Pain Intensity Score is the mean value of current pain intensity ratings, obtained twice-daily for 1 week, using an 11-point numerical rating scale where 0 = no pain and 10 = pain as bad as you can imagine. All pain intensity ratings for the primary endpoint will be in reference to the CRPS-affected limb. | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to treatment: Proportion of Participants With at Least 30 Percent Reduction in the Pain Intensity Score | Participants with at least a 30 percent decrease in the Pain Intensity Score will be considered to have responded to treatment. The Pain Intensity Score is determined as for the primary endpoint. | Baseline; Week 12 | 
| Response to treatment: Proportion of Participants With at Least 50 Percent Reduction in the Pain Intensity Score | Participants with at least a 50 percent decrease in the Pain Intensity Score will be considered to have responded to treatment. The Pain Intensity Score is determined as for the primary endpoint. | Baseline; Week 12 | 
| Change in the Brief Pain Inventory (BPI) Interference Score | The BPI Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants will rate their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities. | Baseline; Week 12 | 
| Patient Global Impression of Change (PGIC) | The PGIC is a self-reported measure of perceived change in overall condition since the start of the study. Participants will select one of seven responses ranging from very much improved to very much worse. A response of very much improved or much improved is generally regarded as a clinically important outcome. | Baseline; Week 12 | 
| Change in the EuroQol-5 Dimension 5 Level (EQ-5D-5L) Index Score | The EQ-5D-5L Index Score describes the participant's overall health status and is derived from self-reported scores in 5 health dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Participants will rate each dimension at one of 5 levels, with level 1 indicating the best health state (no problems) and level 5 indicating worst health state (e.g., unable to walk about). The EQ-5D-5L Index Score ranges from 0 to 1, with 0 representing death and 1.0 representing perfect health. | Baseline; Week 12 | 
| Change in the EuroQol Visual Analog Scale (EQ VAS) | The EQ VAS is a self-reported measure of the participant's overall health today. Participants will place a mark on a 20 cm vertical scale numbered from 0 to 100, with 0 labeled as the worst health you can imagine and 100 labeled as the best health you can imagine. The EQ VAS ranges from 0 to 100, with higher scores representing better overall health. | Baseline; Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RSD, Neridronic Acid, Neridronate, CRPS