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 |
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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 | 20.0 |
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 | 100000014344 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 | 100000014344 |
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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 assess the safety and tolerability of neridronic acid in subjects with complex regional pain syndrome. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of neridronic acid in subjects with complex regional pain syndrome.
To assess the efficacy of neridronic acid in treatment of complex regional pain syndrome. |
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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”).
4. Ongoing moderate to severe chronic pain, including a baseline current pain intensity score of 4 or greater using an 11-point NRS, referring to the CRPS-affected limb.
5. In stable treatment and follow-up therapy for CRPS for at least 1 month prior to allocation to treatment.
6. Women of child-bearing potential must have a negative urine (β-HCG) pregnancy test and must be using 2 forms of medically
acceptable contraception.
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. |
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E.4 | Principal exclusion criteria |
1. Evidence of renal impairment (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2 or a urinary albumin creatinine ratio greater than 30 mg/g). Note: If 2 consecutive laboratory tests indicate eGFR levels greater or equal to 60 mL/min/1.73 m2 or a single repeat laboratory test of the urinary albumin creatinine ratio is less than 30 mg/g during the enrollment period, the subject is eligible.
2. Serum calcium or magnesium outside of the central laboratory’s reference range.
3. Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL.
4. Corrected QT interval (QTcF) greater than 470 ms; serum potassium outside the central laboratory’s reference range; clinically unstable cardiac disease; evidence of complete left bundle branch block; complete atrioventricular block; history of Long QT Syndrome or a relative with this condition; or any other known risk factor for torsade de pointes.
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 (e.g., citalopram, escotalopram) or tricyclic antidepressants are eligible if the QT-interval
values do not meet the exclusion criteria, the medication was started at least 1 month prior to allocation, the dose is stable, and the dose is anticipated to remain stable until at least 4 days after the last infusion of IMP.
6. Anticipated requirement for treatment with oral or intravenous bisphosphonate for another condition, or administration of denosumab, or other drugs affecting bone turnover or bone metabolism 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, unhealed or infected extraction site, or significant dental/periodontal disease that may predispose to need for tooth extraction or other invasive dental procedures during the trial.
9. Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
10. Prior radiation therapy of the head or neck.
11. History of malignancy within 2 years prior to Visit 1, with the exception of basal cell carcinoma.
12. 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.
13. Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of Visit 1.
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 aspartate aminotransferase or alanine aminotransferase greater than 2-fold upper limit of normal or current evidence of chronic liver disease.
17. Participation in another investigational drug trial within 3 months prior to Visit 1.
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Occurrence of any treatment emergent adverse event (TEAE). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
TEAE occurrence from baseline to Week 52. |
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E.5.2 | Secondary end point(s) |
1) Occurrence of permanent discontinuation from treatment due to an adverse event.
2) Change in the current pain intensity score, using a numerical rating scale (NRS).
3) Response to treatment, defined as at least 30% and at least 50% decrease from baseline in the current pain intensity score.
4) Patient Global Impression of Change (PGIC).
5) Change in the Pain Interference score of the Brief Pain Inventory (BPI). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 1 to Day 10
2) Baseline to Week 12 and Week 26
3) at Week 12 and Week 26
4) at Week 12 and Week 26
5) Baseline to Week 12 and Week 26 |
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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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 |
Germany |
Poland |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 10 |