CREATE-1 Study: CRPS Treatment Evaluation 1 Study. A Randomized, Double-blind, Placebo-controlled Study to

INTERVENTION: Product Name: Disodium Zoledronate Tetrahydrate Product Code: AXS‐02 Pharmaceutical Form: Tablet INN or Proposed INN: Disodium Zoledronate Tetrahydrate CAS Number: 165800‐07‐7 Current Sponsor code: AXS‐02 Other descriptive name: Disodium (1‐Hydroxy‐2‐(1H‐Imidazol‐1‐yl)‐1‐ Phosphonoethyl)Phosphonic Acid Tetrahydrate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use CONDITION: Complex regional pain syndrome (CRPS‐I). ; MedDRA version: 20.1 Level: LLT Classification code 10064334 Term: Complex regional pain syndrome Type I System Organ Class: 100000004852 Therapeutic area: Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] ‐ Anesthesia and Analgesia [E03] PRIMARY OUTCOME: ; Main Objective: To assess the effect of AXS‐02 versus placebo on the mean of the Pain Intensity Difference (PID) from Baseline to Week 12, where pain intensity is measured by the weekly average daily pain intensity using the NRS.; ; Primary end point(s): The primary efficacy endpoint will be the mean of the Pain Intensity Difference (PID) from Baseline to Week 12, where pain intensity is measured by the weekly average daily pain intensity using the NRS.; ; Secondary Objective: Effect of AXS‐02 vs placebo on; ‐PGI‐C at Week 12 (key secondary).; ‐CGI‐C at Week 12.; ‐mPID(week 6‐12), (mean of the PIDs measured over the interval from Week 6 to Week 12. Proportion of responders with =50% reduction from Baseline in NRS score at Week 12); ‐PID over time.; ‐Proportion of responders with =50% reduction from Baseline in NRS score over time.; ‐Proportion of responders with =30% reduction from Baseline in NRS score over time.; ‐Change from Baseline in the BPI Pain Intensity score and BPI Pain Interference score over time.; ‐Change from Baseline in the EQ‐5Dâ„¢ over time.; ‐PGI‐C and CGI‐C scores at Week 12.; ‐Change from Baseline in SF‐MPQ‐2 and pain on motion over time.; ‐Proportion of subjects with resolution of baseline disease symptoms of allodynia wk 12,hyperalgesia, skin color changes, and local edema.; ‐Use of rescue medication; ‐Bone turnover markers (s‐CTX, s‐P1NP).; ‐Safety as assessed by AEs, vital signs, and laboratory assessments.; ‐Disease recurrence.; ; ; Timepoint(s) of evaluation of this end point: The NRS scores will be collected from Screening (Visit 1) and daily through Week 12 via a PRO diary.; SECONDARY OUTCOME: ; Secondary end point(s): The key secondary endpoint is:; ‐Patients’ Global Impressions of Change (PGI‐C) at Week 12; ; ; Other secondary endpoints are:; ‐Clinicians’ Global Impressions of Change (CGI‐C) scores at Week 12.; ‐Proportion of subjects with resolution of allodynia at Week 12.; ‐mPID(week 6‐12), defined as the mean of the PIDs measured over the interval from Week 6 to Week 12; Proportion of responders with =50% reduction from Baseline in NRS score at Week 12.; ‐Proportion of responders with a =30% reduction from baseline in NRS score at week 4.; Other Exploratory Endpoints:; ‐PID over time.; ‐Proportion of responders with a =30% reduction from baseline in NRS score over time.; ‐Proportion of responders with a =50% reduction from baseline in NRS score over time.; ‐Change from Baseline in the BPI Pain Intensity score (average of Questions 3, 4, 5, and 6) and BPI Pain Interference score (average of Questions 9A‐9G) over time.; ‐Change from Baseline in the EQ‐5Dâ„¢ over time.; ‐Change from Baseline in the SF‐MPQ‐2 over time.; ‐Change from Baseline in pain on motion over time.; ‐Proportion of subjects with resolution of baseline disease symptoms of hyperalgesia, skin color changes, and local edema.; ‐Use of rescue medication.; ‐Bone turnover markers (s‐CTX and s‐P1NP).; ‐Disease recurrence.; ; Safety endpoints include the following:; ‐Incidence of TEAEs.; ‐Clinical laboratory test results.; ‐Vital sign measurements.; ‐Physical examination findings.; ; Timepoint(s) of evaluation of this end point: At screening, baseline, throughout treatment and follow‐up.; INCLUSION CRITERIA: A subject will be eligible for study participation if the subject meets all of the following criteria: 1. Is male or female at least 18 years of age. 2. Has a confirmed diagnosis of CRPS‐I according to the new criteria from the IASP (Budapest clinical diagnostic criteria [Appendix C]). 3. Has CRPS‐I in one upper or lower limb. 4. Has a baseline weekly average (the average of the daily pain intensity scores from the 7 days before Day 1 dosing) pain intensity score =5 based on an 11‐point (0‐10) NRS in the affected limb. 5. Has been diagnosed with CRPS‐I within 6 months at the time of screening. 6. Has a history of a traumatic event inciting CRPS symptoms (eg, fracture, crushing injury, orthopedic surgery) within 12 months of Screening. 7. Has failed trials of at least 2 availabl