Efficacy and Safety of Intravenous Neridronic Acid in CRPS

Study Overview
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Brief Summary
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The aim of this trial was to investigate the efficacy and safety of intravenous neridronic acid in subjects with Complex Regional Pain Syndrome (CRPS). The trial consisted of an Enrollment Period lasting up to 60 days, Treatment Period A consisting of 4 infusions (neridronic acid or placebo) over 10 days, and a Follow-up Period 1 until Week 26. At Week 26, participants not meeting the pre-specified criteria to continue into Treatment Period B continued in Follow-up Period 2 until Week 52. Participants meeting the pre-specified criteria entered the open-label Treatment Period B with 4 additional infusions (neridronic acid) over 10 days and follow-up visits until Week 52.

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

Conditions
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Complex Regional Pain Syndrome (CRPS)

Intervention / Treatment
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* Drug: Neridronic acid 100 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Neridronic acid<br>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. | Drug: Neridronic acid 100 mg<br>* 100 mg neridronic acid supplied in glass vials in 8 mL of excipients.<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Glass vials with matching placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary) | In the Baseline Phase and in Treatment Period A/Follow-up Period 1, participants were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = no pain to 10 = pain as bad as you can imagine and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated. | From the Baseline Phase (Day -7 to Day -1) to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer. | 11-point NRS - from 0 = no pain to 10 = pain as bad as you can imagine - reported at the visits on a tablet computer (24-hour recall). Changes from baseline to Week 26 were planned to be analyzed. | From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) | 
| Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 12, Recorded on the Tablet Computer. | 11-point NRS - from 0 = no pain to 10 = pain as bad as you can imagine - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 12 was planned to be determined. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 
| Pain Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Average Pain Intensity at Week 26, Recorded on the Tablet Computer. | 11-point NRS - from 0 = no pain to 10 = pain as bad as you can imagine - reported at the visits on a tablet computer (24-hour recall). The number of participants with response at Week 26 was planned to be determined. | From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) | 
| Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA). | Dynamic mechanical allodynia: a tactile stimulus is applied in a single sweeping motion (1 cm to 2 cm length) on the skin on the affected limb. The participants are asked to judge the stimulus intensity by means of an NRS (0 to 10). 0 in this case means no pain. Each pricking, stinging or burning sensation is defined as a painful sensation, which should always be evaluated by giving a value greater than 0. 10 corresponds to the individual maximum pain imaginable. Change from baseline was planned to analyzed. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 
| Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle. | Pressure pain threshold: using a pressure algometer (contact area 1 cm2), the threshold for pressure-induced pain is measured on the thenar muscle/abductor hallucis muscle in 3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The threshold is then determined as the arithmetic mean of the 3 series (in kPa). The ratio of the thresholds of the affected limb versus the unaffected limb was planned to be calculated. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 
| Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb. | In participants with the CRPS sign of edema on the CRPS severity score at baseline, circumference of the hand or foot will be measured by the investigator with measurement tape using the figure-of-eight method at both the affected limb and the contralateral unaffected limb. Each measurement will be performed 3 times. The average of the 3 measurements will be used for further analysis. The ratio of the averages of the affected limb versus the unaffected limb was planned to be calculated and used for the determination of the change from baseline. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRPS, Neridronic Acid, Neridronate, reflex sympathetic dystrophy (RSD)