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
Conditions
Interventions
Product Name: Disodium Zoledronate Tetrahydrate
Product Code: AXS-02
Pharmaceutical Form: Tablet
INN or Proposed INN: Disodium Zoledronate Tetrahydrate
Sponsors
Axsome Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 available treatment modalities for CRPS. If receiving treatments or follow-up for CRPS-I, has been on a stable regime, except for chronic opioid therapy, for at least 3 weeks. See Section 8.13 for details. 8. If female and of childbearing potential, is nonlactating and nonpregnant (has negative pregnancy test results at Screening and Baseline). 9. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 1 or more of the following medically acceptable methods of birth control: -Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject’s usual menstrual cycle period) before study drug administration. -Total abstinence from sexual intercourse since the last menses before study drug administration, abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. -Intrauterine device. -Vasectomized partner. -Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream). 10. Is willing and able to complete the pain evaluations and quality of life questionnaires. 11. Is willing to take supplemental calcium and Vitamin D during the study. 12. Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements. 13. Is willing to voluntarily sign and date an informed consent form that is approved by an institutional review board before the conduct of any study procedure. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 140 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: A subject will be excluded from the study if the subject meets any of the following criteria: 1. Has a documented history or diagnosis of peripheral neuropathy, including diabetic neuropathy or other metabolic or toxic neuropathy. 2. Has type I diabetes mellitus, or poorly controlled type II diabetes mellitus. 3. Has severe renal impairment (creatinine clearance of 2 times the upper limit of normal. 5. Has hypocalcemia. 6. Has an abnormality of the esophagus that delays esophageal emptying, such as stricture or achalasia. 7. Is unable to stand or sit upright for at least 30 minutes. 8. Has significant difficulty swallowing tablets or is unable to tolerate oral medication. 9. Has current sign or symptom of severe and/or progressive or uncontrolled hepatic, renal, gastrointestinal (including untreated gastroesophageal reflux disease [GERD]), endocrine, hematological, cardiac, pulmonary, or neurological disease. 10. Has a clinically significant psychiatric disorder (eg, treatment-refractory major depression, schizophrenia, bipolar disorder, panic disorder, or generalized anxiety disorder). 11. Has any other clinically significant medical or pain condition (eg, Parkinson’s disease, cognitive impairment, or fibromyalgia) or clinical laboratory abnormality that would in the investigator's judgment interfere with the subject's ability to participate in the study. 12. Is on chronic opioid therapy within 4 weeks of randomization. NOTE: NOTE: Chronic is defined as “daily or near daily use of opioids for at least 90 days”. For all other opioid use, the subject must not have received a dose of opioids within 10 days prior to randomization (Day 1). 13. Has had a previous allergic reaction or hypersensitivity to bisphosphonates. 14. Received prior treatment with zoledronic acid. 15. Received treatment with a bisphosphonate within 6 months before study entry. 16. Received treatment with calcitonin within 3 months before study entry. 17. Received a sympathetic nerve block within 3 weeks prior to Baseline (Day -7). 18. Received treatment with high-dose oral or parenteral steroids (eg, 0.5 to 1 mg/kg per day orally) within the last 3 months, or anticipates a need for concomitant high-dose steroid treatment during the study (use of steroids in treatment of mild asthma or allergic rhinitis or topically for skin conditions will be permitted). 19. Has a known or suspected history of alcoholism or drug abuse or misuse within 2 years of Screening. 20. Has active litigation or a pending workers' compensation decision. 21. Previously participated in another clinical study of AXS-02 or received any investigational drug or device or investigational therapy within 30 days before Screening. 22. Has elevated risk for osteonecrosis of the jaw with bisphosphonate treatment, including patients with recent tooth extraction, significant dental or periodontal disease, prior radiation to the head or neck (within 1 year of screening), or a history of malignancy within 2 years (exce
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. ; 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-5D™ 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. ; 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. ; 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
| Measure | Time frame |
|---|---|
| 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-5D™ 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. | — |
Countries
Australia, Canada, United Kingdom, United States
Contacts
Public ContactJeffrey Nelson
Axsome Therapeutics, Inc.
Outcome results
None listed