Efficacy and Safety of Intravenous Neridronic Acid in CRPS-I

Phase 2

Completed

Conditions: Complex Regional Pain Syndrome, Type I

Interventions: Drug: Placebo
Drug: Neridronic acid 62.5 mg

Registration Number: NCT02402530

Lead Sponsor: Grünenthal GmbH

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 459

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matching placebo administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10
125 mg Neridronic acid	Neridronic acid 62.5 mg	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
125 mg Neridronic acid	Placebo	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
250 mg Neridronic acid	Neridronic acid 62.5 mg	Neridronic acid 62.5 mg administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10

Primary Outcome Measures

Name	Time	Method
Change in the Pain Intensity Score to Week 12.	Baseline; 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.

Secondary Outcome Measures

Name	Time	Method
Response to treatment: Proportion of Participants With at Least 50 Percent Reduction in the Pain Intensity Score	Baseline; Week 12	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.
Change in the EuroQol-5 Dimension 5 Level (EQ-5D-5L) Index Score	Baseline; Week 12	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.
Response to treatment: Proportion of Participants With at Least 30 Percent Reduction in the Pain Intensity Score	Baseline; Week 12	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.
Change in the Brief Pain Inventory (BPI) Interference Score	Baseline; Week 12	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.
Patient Global Impression of Change (PGIC)	Baseline; Week 12	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.
Change in the EuroQol Visual Analog Scale (EQ VAS)	Baseline; Week 12	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.

Trial Locations

Locations (59): Site US119 - G & L Research
🇺🇸
Foley, Alabama, United States
Site US117 - Valley Pain Consultants
🇺🇸
Scottsdale, Arizona, United States
Site US172 - Core Healthcare Group
🇺🇸
Cerritos, California, United States
Site US110 - Orange County Research Institute
🇺🇸
Anaheim, California, United States
Site US124 - Quality of Life Medical and Research Centers LLC
🇺🇸
Tucson, Arizona, United States
Site US175 - Inland Pain Medicine
🇺🇸
Colton, California, United States
Site US108 - Catalina Research Institute
🇺🇸
Chino, California, United States
Site US152 - UC San Diego Healthcare Systems, Center for Pain Medicine
🇺🇸
La Jolla, California, United States
Site US102 - Samaritan Center for Medical Research
🇺🇸
Los Gatos, California, United States
Site US162 - South Lake Pain Institute
🇺🇸
Clermont, Florida, United States
Site US153 - Clinical Research of West Florida Inc - Clearwater
🇺🇸
Clearwater, Florida, United States
Site US143 - Florida Pain Institute
🇺🇸
Merritt Island, Florida, United States
Site US133 - Gold Coast Research LLC
🇺🇸
Plantation, Florida, United States
Site US122 - Precision Research Organization, LLC
🇺🇸
Miami Lakes, Florida, United States
Site US171 - Florida Medical Pain Management
🇺🇸
Saint Petersburg, Florida, United States
Site US165 - Palm Beach Research
🇺🇸
West Palm Beach, Florida, United States
Site US131 - Better Health Clinical Research, Inc
🇺🇸
Newnan, Georgia, United States
Site US103 - Great Lakes Clinical Trials
🇺🇸
Chicago, Illinois, United States
Site US127 - Advance Clinical Research, Inc
🇺🇸
Saint Louis, Missouri, United States
Site US151 - Premier Pain Centers
🇺🇸
Shrewsbury, New Jersey, United States
Site US137 - Montefiore Medical Center
🇺🇸
Bronx, New York, United States
Site US166 - Albany Medical College
🇺🇸
Albany, New York, United States
Site US145 - University of Rochester
🇺🇸
Rochester, New York, United States
Site US157 - North Star Medical Research
🇺🇸
Middleburg Heights, Ohio, United States
Site US114 - Abington Neurological Associates
🇺🇸
Willow Grove, Pennsylvania, United States
Site US149 - Founders Research Corporation
🇺🇸
Philadelphia, Pennsylvania, United States
Site US134 - Lovelace Scientific Resources, Inc
🇺🇸
Austin, Texas, United States
Site US107 - Austin Center for Clinical Research
🇺🇸
Austin, Texas, United States
Site US164 - Advanced Clinical Research
🇺🇸
West Jordan, Utah, United States
Site US144 - Bellevue Surgery Center
🇺🇸
Bellevue, Washington, United States
Site US173 - Bellevue Surgery Center
🇺🇸
Bellevue, Washington, United States
Site US123 - Northwest Clinical Research Center
🇺🇸
Bellevue, Washington, United States
Site DE101 - Klinische Forschung Hannover Mitte GmbH
🇩🇪
Hannover, Germany
Site GB104 - The Royal Victoria Infirmary
🇬🇧
Cambridge, United Kingdom
Site GB108 - Darlington Memorial Hospital, Centre for Research and clinical Intervention
🇬🇧
Darlington, United Kingdom
Site DE103 - Algesiologikum Studienzentrum und Algesiologikum MVZ
🇩🇪
Munich, Germany
Site DE107 - Studienzentrum A. Schwittay
🇩🇪
Böhlen, Germany
Site DE104 - Schmerzzentrum Dr. med. C. Wachter & T. Tusker
🇩🇪
Fellbach, Germany
Site DE102 - Universitätsklinikum Würzburg Neurologische Klinik
🇩🇪
Würzburg, Germany
Site GB109 - Royal Devon Exeter Hospital
🇬🇧
Exeter, United Kingdom
Site GB101 - Guys and St. Thomas NHS Foundation Trust - St Thomas Hospital
🇬🇧
London, United Kingdom
Site GB111 - Chelsea and Westminster Hospital - NHS Foundation Trust
🇬🇧
London, United Kingdom
Site US116 - Arizona Pain Specialists
🇺🇸
Scottsdale, Arizona, United States
Site US154 - Woodland International Research Group
🇺🇸
Little Rock, Arkansas, United States
Site US101 - Princeton Medical Institute
🇺🇸
Princeton, New Jersey, United States
Site US156 - University Clinical Research Center
🇺🇸
Somerset, New Jersey, United States
Site US129 - International Clinical Research Institute
🇺🇸
Overland Park, Kansas, United States
Site US111 - Sunrise Research Institute
🇺🇸
Miami, Florida, United States
Site US169 - Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Site US105 - Advanced Biomedical Research of America
🇺🇸
Las Vegas, Nevada, United States
Site US113 - Pioneer Research Solutions, Inc
🇺🇸
Houston, Texas, United States
Site US118 - Omega International Pain Clinic
🇺🇸
Salt Lake City, Utah, United States
Site US161 - Swedish Pain and Headache Center
🇺🇸
Seattle, Washington, United States
Site US106 - Mountain View Clinical Research
🇺🇸
Denver, Colorado, United States
Site US126 - Northern California Research
🇺🇸
Sacramento, California, United States
Site US104 - Discovery Clinical Trials
🇺🇸
Orlando, Florida, United States
Site US121 - Clinical Research of West Florida
🇺🇸
Tampa, Florida, United States
Site US135 - The Center for Clinical Research
🇺🇸
Winston-Salem, North Carolina, United States
Site US112 - Clinical Trials of South Carolina
🇺🇸
Charleston, South Carolina, United States