E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complex Regional Pain Syndrome (CRPS) |
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E.1.1.1 | Medical condition in easily understood language |
Complex regional pain syndrome is a chronic, severely painful disabling condition. It can develop after a minor injury (fracture, sprain), usually in a distal extremity (hand, wrist, ankle, and foot). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064334 |
E.1.2 | Term | Complex regional pain syndrome Type I |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064335 |
E.1.2 | Term | Complex regional pain syndrome Type II |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superior efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo for the treatment of CRPS-related pain. |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo for the treatment of CRPS-related pain.
To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on the dynamic mechanical allodynia (DMA).
To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on the pressure pain threshold (PPT).
To assess the efficacy of a cumulative dose of 400 mg intravenous neridronic acid versus placebo on edema of the hand or foot. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed consent signed.
2. Male or female subjects at least 18 years of age at Visit 1.
3. 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.
4. A baseline average pain intensity score of greater than or equal to 4 using an 11-point 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 subject 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.
5. In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment (Visit 2). Subjects must have failed attempts with at least 2 available treatments for CRPS, 1 of which must have been a pharmacologic treatment.
6. Women of child-bearing potential must have a negative urine 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 (e.g., oral contraceptives or intrauterine device), 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.
7. Subjects 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). |
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E.4 | Principal exclusion criteria |
1. 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.
2. Serum calcium or magnesium outside of the central laboratory’s reference range, based on central safety laboratory data obtained prior to Visit 2; (2 repeated laboratory tests are allowed); a history of hypocalcemia or a metabolic disorder anticipated to increase risk for hypocalcemia; anticipated need for any new drug with known potential to cause hypocalcemia during the trial.
3. 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. Subjects 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.
4. Corrected QT interval (according to Fridericia’s formula; QTcF) greater than 470 ms (average of 3 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; clinically unstable cardiac disease.
5. Subjects receiving medications with a known risk of torsades de pointes within 7 days prior to allocation. Subjects receiving selective serotonin re-uptake inhibitor antidepressants 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.
6. 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.
7. History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, acetaminophen, or to vitamin D or calcium supplements.
8. 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. Subjects with indeterminate, suspicious or unreliable dental history, in the opinion of the investigator, must undergo a dental examination prior to receiving treatment.
9. Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
10. Prior radiation therapy of the head or neck (within 1 year of Visit 1).
11. History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.
12. 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.
13. Current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1, based on subject history and physical examination and according to the investigator’s judgment.
14. 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 subject’s safety during trial participation.
15. Women who are pregnant or breastfeeding.
16. Elevated AST or ALT 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 subjects 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.
17. Participation in another investigational drug trial within 3 months prior to Visit 1, or any previous trial involving neridronic acid.
18. Subject 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.
19. Subjects taking forbidden concomitant medications/therapies or not being able to follow the rules of use of concomitant treatment.
20. Subjects incapable of giving informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Week 12 in the average pain intensity score (weekly average of pain values recorded daily in the electronic diary). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The change from the baseline phase (Day -7 to Day -1) to Week 12 will be analyzed. |
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E.5.2 | Secondary end point(s) |
1. Change from baseline to Week 26 in the average pain intensity recorded on the tablet computer.
2. 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.
3. 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.
4. Change from baseline to Week 12 in the pain intensity level of DMA.
5. Change from baseline to Week 12 in the PPT ratio for the thenar muscle/abductor hallucis muscle.
6. Change from baseline to Week 12 in the ratio of the figure of eight measurements of the affected limb versus the unaffected limb. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The change from baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) will be analyzed.
2. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
3. The change from baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) will be analyzed.
4. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
5. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed.
6. The change from baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) will be analyzed. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Canada |
Czech Republic |
Poland |
Serbia |
Slovakia |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |