Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)

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 theInternational 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 orleg) and must demonstrate asymmetry with respect to the contralateral limb. The CRPSduration 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 ofpain recorded over 7 days). The baseline average pain intensity score will becalculated automatically by the electronic diary, which must be checked prior toallocation at Visit 2. A participant who has not met average baseline pain intensityrequirements (at least 4 average pain intensity ratings) due to lack of compliancewith the electronic diary may be rescheduled for Visit 2 (1 time only), withappropriate 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 toallocation to treatment (Visit 2). Participants must have failed attempts with atleast 2 available treatments for CRPS, 1 of which must have been a pharmacologictreatment.

• Women of child-bearing potential must have a negative urine Beta-human chorionicgonadotropin (ß-HCG) pregnancy test at Visit 1 and must be using 2 forms of medicallyacceptable contraception, including at least 1 highly effective method ofcontraception with a low failure rate, defined as less than 1% per year, and a secondmedically acceptable method such as use of condoms with spermicide by their malepartner. A barrier method alone is not acceptable. Highly effective methods ofcontraception must be used for at least 1 month prior to Visit 2 and for the durationof the trial. Male participants must use condom and spermicide during intercourse andmust take care that the female sexual partner uses at least 1 additional method ofcontraception with a low failure rate defined as above, starting with Visit 2 until atleast 4 weeks after the last Investigational medicinal product (IMP) infusion.

• Participants must be able to communicate meaningfully, be able to differentiate withregard to location and intensity of the pain, and be able to answer the questions inthe questionnaires used in this trial (assistance in filling out the questionnairesmay be provided, if required due to motor or other physical impairment).

Exclusion Criteria:

• Evidence of renal impairment (estimated Glomerular Filtration Rate [eGFR] less than 30mL/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 creatinineratio [ACR] greater than 150 mg/g), based on central safety laboratory data obtainedprior to Visit 2. Note: a single repeat laboratory test is allowed.

• Serum calcium or magnesium outside of the central laboratory's reference range, basedon central safety laboratory data obtained prior to Visit 2 (a single repeatlaboratory test is allowed); a history of hypocalcemia or a metabolic disorderanticipated to increase risk for hypocalcemia (e.g., hypoparathyroidism); anticipatedneed for any new drug with known potential to cause hypocalcemia (e.g.,aminoglycosides, new treatment with or dose adjustment of loop diuretics) during thetrial. Participants on a stable dose of loop diuretics may receive treatment with IMPas long as no dosage increases in the diuretic medication are anticipated and calciumlevels are in the reference range.

• Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL (75 nmol/L), basedon central safety laboratory data obtained prior to Visit 2 (up to 4 repeat laboratorytests are allowed). Participants with vitamin D deficiency should receive appropriatesupplementation 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 ECGreading facility evaluation or QTcF greater than 470 ms at pre-dose ECG at Visit 2according to the investigator's judgment; serum potassium outside the centrallaboratory'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 myocardialischemia, or an indwelling pacemaker; evidence of complete left bundle branch block;complete atrioventricular block; history of Long QT Syndrome or a relative with thiscondition; 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 7days prior to allocation. Participants receiving selective serotonin re-uptakeinhibitor antidepressants are eligible if the QT interval values do not meet theexclusion criteria, the medication was started at least 1 month prior to allocation,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 abisphosphonate within the previous year, anticipated requirement for treatment with abisphosphonate for another condition such as osteoporosis during the trial, oradministration 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 otherbisphosphonate, acetaminophen, or to vitamin D or calcium supplements.

• Recent tooth extraction or other invasive dental procedure (within 3 months prior toVisit 1), unhealed or infected extraction site, or significant dental/periodontaldisease that may pre-dispose to need for tooth extraction or other invasive dentalprocedures during the trial. Participants with indeterminate, suspicious or unreliabledental history, in the opinion of the investigator, must undergo a dental examinationprior 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 basalcell carcinoma.

• Use of nerve blocks, ketamine infusions, intravenous immunoglobulin, acupuncture,electromagnetic field treatment, or initiation/implementation of radiofrequencyablation or other sympathectomy procedures, or peripheral nerve stimulation within 6weeks 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 andaccording to the investigator's judgment.

• Any other severe medical condition, including severe depression, or any other severemood disorder, that in the opinion of the investigator may affect efficacy or safetyassessments or may compromise the participants safety during trial participation.

• Women who are pregnant or breastfeeding.

• Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-foldupper limit of normal, based on central safety laboratory data obtained at Visit 1, orcurrent evidence of chronic liver disease. Safety laboratory testing may be repeatedprior to Visit 2, and participants will be allowed in the trial if results of 2consecutive tests, at least 3 days apart, are less than or equal to 2-fold upper limitof normal.

• Participation in another investigational drug trial within 3 months prior to Visit 1,or any previous trial involving neridronic acid, with the exception of participantsparticipating in study KF7013-01 who were assigned to placebo and did not receiveneridronic acid.

• Participant is engaged in litigation related to their disability from CRPS in whichmonetary gain or loss (or other compensation) may affect their objective participationin the trial.

• Participants taking forbidden concomitant medications/therapies or not being able tofollow 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) ofthe Patient-Reported Outcomes Measurement Information System (PROMIS®) (PROMIS-29profile) at Visit 11.

• The following exclusion criteria are not met:

• Evidence of renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 2009CKD-EPI creatinine equation [Levey et al. 2009] or a urinary ACR greater than 150mg/g), based on central safety laboratory data obtained prior to Visit 11. Asingle repeat laboratory test is allowed.

• Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained atVisit 10) according to the central ECG reading facility evaluation or QTcFgreater than 470 ms at pre-dose ECG at Visit 11 according to the investigator'sjudgment; serum potassium outside the central laboratory's reference range atVisit 10 (a single repeat laboratory test is allowed); clinically unstablecardiac disease, including: unstable atrial fibrillation, symptomaticbradycardia, unstable congestive heart failure, active myocardial ischemia, or anindwelling pacemaker; evidence of complete left bundle branch block; completeatrioventricular block; any other known risk factor for torsade de pointes.

• Participants receiving medications with a known risk of torsades de pointeswithin 7 days prior to re-allocation.

• Participants taking forbidden concomitant medications/therapies or not being ableto follow the rules of use of concomitant treatment.

• Recent tooth extraction or other invasive dental procedure (within 3 months priorto Visit 11), unhealed or infected extraction site, or significantdental/periodontal disease that may pre-dispose to need for tooth extraction orother invasive dental procedures during the further course of the trial.

• Serum calcium outside of the central laboratory's reference range, despiteappropriate supplementation between Visit 10 and Visit 11, based on the lastcentral safety laboratory data obtained prior to Visit 11. Two repeat laboratorytests are allowed.

• Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level lessthan 30 ng/mL (75 nmol/L), based on the last central safety laboratory dataobtained prior to Visit 11, i.e., inability to normalize 25(OH)D levels to atleast 30 ng/mL (75 nmol/L) despite appropriate supplementation between Visit 10and Visit 11. Two repeat laboratory tests are allowed.

• Elevated aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal, based on central safety laboratory data obtained atVisit 10, or current evidence of chronic liver disease. A single repeatlaboratory test is allowed.

• No other criterion for trial and/or IMP discontinuation is met.