Efficacy and Safety of Intravenous Neridronic Acid in CRPS
Complex Regional Pain Syndrome (CRPS)
About this trial
This is an interventional treatment trial for Complex Regional Pain Syndrome (CRPS) focused on measuring Neridronic Acid, Neridronate, CRPS, reflex sympathetic dystrophy (RSD)
Eligibility Criteria
Inclusion Criteria:
- Informed consent signed.
- Male or female participant at least 18 years of age at Visit 1.
- A diagnosis of CRPS according to the clinical diagnostic criteria recommended by the International Association for the Study of Pain (IASP; "Budapest clinical criteria"), assessed at Visit 1. Signs and symptoms of CRPS must apply to an affected limb (arm or leg) and must demonstrate asymmetry with respect to the contralateral limb. The CRPS duration must be 2 years or less since onset of symptoms.
- A baseline average pain intensity score of greater than or equal to 4 using an 11-point numerical rating scale (NRS), referring to the CRPS-affected limb (average of pain recorded over 7 days). The baseline average pain intensity score will be calculated automatically by the electronic diary, which must be checked prior to allocation at Visit 2. A participant who has not met average baseline pain intensity requirements (at least 4 average pain intensity ratings) due to lack of compliance with the electronic diary may be rescheduled for Visit 2 (1 time only), with appropriate re-training to ensure compliance with use of the electronic diary.
- In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment (Visit 2). Participants must have failed attempts with at least 2 available treatments for CRPS, 1 of which must have been a pharmacologic treatment.
- Women of child-bearing potential must have a negative urine Beta-human chorionic gonadotropin (ß-HCG) pregnancy test at Visit 1 and must be using 2 forms of medically acceptable contraception, including at least 1 highly effective method of contraception with a low failure rate, defined as less than 1% per year, and a second medically acceptable method such as use of condoms with spermicide by their male partner. A barrier method alone is not acceptable. Highly effective methods of contraception must be used for at least 1 month prior to Visit 2 and for the duration of 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 (assistance in filling out the questionnaires may be provided, if required due to motor or other physical impairment).
Exclusion Criteria:
- Evidence of severe renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30 mL/min/1.73 m2 using the 2009 Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine equation [Levey et al. 2009] or a urinary albumin to creatinine ratio [ACR] greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2. Note: a single repeat laboratory test is allowed.
- Serum calcium or magnesium outside of the central laboratory's reference range, based on central safety laboratory data obtained prior to Visit 2 (2 repeat laboratory tests are allowed); a history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia (e.g., hypoparathyroidism); anticipated need for any new drug with known potential to cause hypocalcemia (e.g., aminoglycosides, new treatment with or dose adjustment of loop diuretics) during the trial. Participants on a stable dose of loop diuretics may receive treatment with IMP as long as no dosage increases in the diuretic medication are anticipated and calcium levels are in the reference range.
- Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on central safety laboratory data obtained prior to Visit 2 (up to 4 repeat laboratory tests are allowed). Participants with vitamin D deficiency should receive appropriate supplementation during the Enrollment Period. A vitamin D level of at least 30 ng/mL (75 nmol/L) must be documented prior to allocation to IMP.
- Corrected QT interval (according to Fridericia's formula; QTcF) greater than 470 ms (average of 3 Electrocardiogram (ECGs) obtained at Visit 1) according to central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 2 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 1(a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; history of Long QT Syndrome or a relative with this condition; or any history of or other known risk factor for torsade de pointes.
- Participants receiving medications with a known risk of torsades de pointes within 7 days prior to allocation. Participants receiving selective serotonin re-uptake inhibitor antidepressants (e.g., citalopram, escitalopram) are eligible if the QT interval values do not meet the exclusion criteria, the medication was started at least 1 month prior to Visit 1, the dose is stable, and the dose is anticipated to remain stable throughout the trial.
- Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of a bisphosphonate within the previous year, anticipated requirement for treatment with a bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or other bone turnover suppressing drugs within 6 months prior to Visit 1.
- History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, acetaminophen, or to vitamin D or calcium supplements.
- Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 1), 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. Participants with indeterminate, suspicious or unreliable dental history, in the opinion of the investigator, must undergo a dental examination prior to receiving treatment.
- Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
- Prior radiation therapy of the head or neck (within 1 year of Visit 1).
- History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.
- 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 Visit 1.
- Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1, 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 participants safety during trial participation.
- Women who are pregnant or breastfeeding.
- Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 1, or current evidence of chronic liver disease. Safety laboratory testing may be repeated prior to Visit 2, and participants will be allowed in the trial if results of 2 consecutive tests, at least 3 days apart, are less than or equal to 2-fold upper limit of normal.
- Participation in another investigational drug trial within 3 months prior to Visit 1, or any previous trial involving neridronic acid.
- 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.
- Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
- Participants incapable of giving informed consent.
Criteria to continue into Treatment Period B
- A value of at least 4 on the pain intensity question (question number 29, GLOBAL07) of the Patient-Reported Outcomes Measurement Information System (PROMIS®) (PROMIS-29 profile) at Visit 11.
The following exclusion criteria are not met:
- Evidence of severe renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 2009 CKD-EPI creatinine equation [Levey et al. 2009] or a urinary ACR greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 11. A single repeat laboratory test is allowed.
- Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained at Visit 10) according to the central ECG reading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 11 according to the investigator's judgment; serum potassium outside the central laboratory's reference range at Visit 10 (a single repeat laboratory test is allowed); clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or an indwelling pacemaker; evidence of complete left bundle branch block; complete atrioventricular block; any other known risk factor for torsade de pointes.
- Participants receiving medications with a known risk of torsades de pointes within 7 days prior to re-allocation.
- Participants taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
- Recent tooth extraction or other invasive dental procedure (within 3 months prior to Visit 11), 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 further course of the trial.
- Serum calcium or magnesium outside of the central laboratory's reference range, despite appropriate supplementation between Visit 10 and Visit 11, based on the last central safety laboratory data obtained prior to Visit 11. One repeat laboratory test is allowed.
- Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), based on the last central safety laboratory data obtained prior to Visit 11, i.e., inability to normalize 25(OH)D levels to at least 30 ng/mL (75 nmol/L) despite appropriate supplementation between Visit 10 and Visit 11. Two repeat laboratory tests are allowed (with a minimum interval of 3 days).
- Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained at Visit 10, or current evidence of chronic liver disease. A single repeat laboratory test is allowed.
- No other criterion for trial and/or IMP discontinuation is met.
Sites / Locations
- US015 - Tennessee Valley Pain Consultants
- US043 - Horizon Research Partners
- US045 - Holland Center for Family Health
- US003 - HealthStar Research
- US049 - Orange County Research Institute
- US053 - Core Healthcare Group
- US013 - Inland Pain Medicine
- US044 - The Helm Center for Pain Management
- US052 - Providere' Research Inc.
- US036 - Denver Back Pain Specialists
- US007 - Neurology Offices of South Florida
- US030 - Gulfcoast Clinical Research Center
- US004 - The Chappel Group Research
- US023 - AGR Research
- US020 - SIMEDHealth
- US012 - NeuroMedical Research Center
- US046 - Clinical Research of West Florida, Inc.
- US027 - Drug Studies America
- US041 - Better Health Clinical Research, Inc.
- US032 - Millennium Pain Center
- US011 - Otrimed Corporation
- US040 - Regeneris Medical
- Us054 - Aa Mrc
- US025 - Oakland Medical Research
- US009 - Elite Clinical Research
- US017 - Jackson Anesthesia Pain Center
- US033 - Galen Research
- US050 - Premier Pain Centers
- US029 - Dent Neurologic Institute
- US038 - DiGiovanna Institute For Medical Education
- US022 - The Neurological Institute
- US047 - The Center for Clinical Research
- US005 - Hometown Urgent Care and Research
- US021 - SP Research PLLC
- US028 - Founders Research Corporation
- US018 - Carolinas Center for Advanced Management of Pain
- US055 - Diversified Medical Practices
- US048 - Axios Research
- US037 - Clinical Research Partners
- AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre
- AU005 - Port Kembla Public Hospital
- AU003 - Neuro Trials Victoria Pty Ltd
- AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital
- FR004 - Centre Hospitalier Universitaire Amiens Picardie
- FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur
- FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur
- DE006 - Center for Clinical Research Dr. med. I. Schoel
- DE011 - Klinische Forschung Berlin Mitte GmbH
- DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin
- DE002 - Klinische Forschung Hamburg GmbH
- DE010 - Klinische Forschung Hannover Mitte
- DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz
- DE005 - Klinische Forschung Schwerin GmbH
- KR008 - Chungnam National University Hospital
- KR003 - Seoul National University Bundang Hospital
- KR002 - Seoul National University Hospital
- KR005 - Samsung Medical Center
- KR007 - Konkuk University Medical Center
- KR004 - Seoul St Mary's Hospital
- KR006 - Korea University Guro Hospital
- KR001 - Ajou University Medical Center
- NZ004 - Optimal Clinical Trials
- Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board
- NZ002 - Southern Clinical Trials Group Ltd
- ES009 - General Hospital of Alicante
- ES002 - Hospital de la Santa Creu i Sant Pau
- ES005 - Hospital Sanitas La Moraleja Pain Unit
- ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia
- ES006 - Hospital Infanta Luisa Rheumatology
- ES007 - Hospital Clínico Universitario de Valencia
- ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit
Arms of the Study
Arm 1
Arm 2
Experimental
Placebo Comparator
Neridronic acid
Placebo
Neridronic acid 100 mg - 4 intravenous (i.v.) infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The investigational medicinal product (IMP) was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration. The maximum neridronic acid dose was 800 mg: 400 mg in Treatment Period A and 400 mg in Treatment Period B.
Matching placebo - 4 intravenous infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The IMP was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.