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Efficacy and Safety of Intravenous Neridronic Acid in CRPS

Primary Purpose

Complex Regional Pain Syndrome (CRPS)

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Neridronic acid 100 mg
Placebo
Sponsored by
Grünenthal GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Complex Regional Pain Syndrome (CRPS) focused on measuring Neridronic Acid, Neridronate, CRPS, reflex sympathetic dystrophy (RSD)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • US015 - Tennessee Valley Pain Consultants
  • US043 - Horizon Research Partners
  • US045 - Holland Center for Family Health
  • US003 - HealthStar Research
  • US049 - Orange County Research Institute
  • US053 - Core Healthcare Group
  • US013 - Inland Pain Medicine
  • US044 - The Helm Center for Pain Management
  • US052 - Providere' Research Inc.
  • US036 - Denver Back Pain Specialists
  • US007 - Neurology Offices of South Florida
  • US030 - Gulfcoast Clinical Research Center
  • US004 - The Chappel Group Research
  • US023 - AGR Research
  • US020 - SIMEDHealth
  • US012 - NeuroMedical Research Center
  • US046 - Clinical Research of West Florida, Inc.
  • US027 - Drug Studies America
  • US041 - Better Health Clinical Research, Inc.
  • US032 - Millennium Pain Center
  • US011 - Otrimed Corporation
  • US040 - Regeneris Medical
  • Us054 - Aa Mrc
  • US025 - Oakland Medical Research
  • US009 - Elite Clinical Research
  • US017 - Jackson Anesthesia Pain Center
  • US033 - Galen Research
  • US050 - Premier Pain Centers
  • US029 - Dent Neurologic Institute
  • US038 - DiGiovanna Institute For Medical Education
  • US022 - The Neurological Institute
  • US047 - The Center for Clinical Research
  • US005 - Hometown Urgent Care and Research
  • US021 - SP Research PLLC
  • US028 - Founders Research Corporation
  • US018 - Carolinas Center for Advanced Management of Pain
  • US055 - Diversified Medical Practices
  • US048 - Axios Research
  • US037 - Clinical Research Partners
  • AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre
  • AU005 - Port Kembla Public Hospital
  • AU003 - Neuro Trials Victoria Pty Ltd
  • AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital
  • FR004 - Centre Hospitalier Universitaire Amiens Picardie
  • FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur
  • FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur
  • DE006 - Center for Clinical Research Dr. med. I. Schoel
  • DE011 - Klinische Forschung Berlin Mitte GmbH
  • DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin
  • DE002 - Klinische Forschung Hamburg GmbH
  • DE010 - Klinische Forschung Hannover Mitte
  • DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz
  • DE005 - Klinische Forschung Schwerin GmbH
  • KR008 - Chungnam National University Hospital
  • KR003 - Seoul National University Bundang Hospital
  • KR002 - Seoul National University Hospital
  • KR005 - Samsung Medical Center
  • KR007 - Konkuk University Medical Center
  • KR004 - Seoul St Mary's Hospital
  • KR006 - Korea University Guro Hospital
  • KR001 - Ajou University Medical Center
  • NZ004 - Optimal Clinical Trials
  • Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board
  • NZ002 - Southern Clinical Trials Group Ltd
  • ES009 - General Hospital of Alicante
  • ES002 - Hospital de la Santa Creu i Sant Pau
  • ES005 - Hospital Sanitas La Moraleja Pain Unit
  • ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia
  • ES006 - Hospital Infanta Luisa Rheumatology
  • ES007 - Hospital Clínico Universitario de Valencia
  • ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Neridronic acid

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
May 7, 2018
Last Updated
July 20, 2020
Sponsor
Grünenthal GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT03530345
Brief Title
Efficacy and Safety of Intravenous Neridronic Acid in CRPS
Official Title
Randomized, Double-blind, Placebo-controlled Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Terminated
Why Stopped
Sponsor decision
Study Start Date
May 30, 2018 (Actual)
Primary Completion Date
July 31, 2019 (Actual)
Study Completion Date
July 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grünenthal GmbH

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Complex Regional Pain Syndrome (CRPS)
Keywords
Neridronic Acid, Neridronate, CRPS, reflex sympathetic dystrophy (RSD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Blinded treatment in Treatment Period A, open-label infusion in Treatment Period B.
Allocation
Randomized
Enrollment
182 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Neridronic acid
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Neridronic acid 100 mg
Intervention Description
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Glass vials with matching placebo.
Primary Outcome Measure Information:
Title
Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
Description
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.
Time Frame
From the Baseline Phase (Day -7 to Day -1) to Week 12
Secondary Outcome Measure Information:
Title
Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer.
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Title
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.
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Title
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.
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Title
Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA).
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Title
Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle.
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Title
Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb.
Description
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.
Time Frame
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Grünenthal Study Director
Organizational Affiliation
Grünenthal GmbH
Official's Role
Study Director
Facility Information:
Facility Name
US015 - Tennessee Valley Pain Consultants
City
Huntsville
State/Province
Alabama
ZIP/Postal Code
35801
Country
United States
Facility Name
US043 - Horizon Research Partners
City
Mobile
State/Province
Alabama
ZIP/Postal Code
36605
Country
United States
Facility Name
US045 - Holland Center for Family Health
City
Peoria
State/Province
Arizona
ZIP/Postal Code
85381
Country
United States
Facility Name
US003 - HealthStar Research
City
Hot Springs
State/Province
Arkansas
ZIP/Postal Code
71913
Country
United States
Facility Name
US049 - Orange County Research Institute
City
Anaheim
State/Province
California
ZIP/Postal Code
92801
Country
United States
Facility Name
US053 - Core Healthcare Group
City
Cerritos
State/Province
California
ZIP/Postal Code
90703
Country
United States
Facility Name
US013 - Inland Pain Medicine
City
Colton
State/Province
California
ZIP/Postal Code
92324
Country
United States
Facility Name
US044 - The Helm Center for Pain Management
City
Laguna Woods
State/Province
California
ZIP/Postal Code
92637
Country
United States
Facility Name
US052 - Providere' Research Inc.
City
West Covina
State/Province
California
ZIP/Postal Code
91790
Country
United States
Facility Name
US036 - Denver Back Pain Specialists
City
Greenwood Village
State/Province
Colorado
ZIP/Postal Code
80111
Country
United States
Facility Name
US007 - Neurology Offices of South Florida
City
Boca Raton
State/Province
Florida
ZIP/Postal Code
33428
Country
United States
Facility Name
US030 - Gulfcoast Clinical Research Center
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33912
Country
United States
Facility Name
US004 - The Chappel Group Research
City
Kissimmee
State/Province
Florida
ZIP/Postal Code
34744
Country
United States
Facility Name
US023 - AGR Research
City
Lake Worth
State/Province
Florida
ZIP/Postal Code
33462
Country
United States
Facility Name
US020 - SIMEDHealth
City
Ocala
State/Province
Florida
ZIP/Postal Code
34474
Country
United States
Facility Name
US012 - NeuroMedical Research Center
City
Panama City
State/Province
Florida
ZIP/Postal Code
32405
Country
United States
Facility Name
US046 - Clinical Research of West Florida, Inc.
City
Tampa
State/Province
Florida
ZIP/Postal Code
33603
Country
United States
Facility Name
US027 - Drug Studies America
City
Marietta
State/Province
Georgia
ZIP/Postal Code
30060
Country
United States
Facility Name
US041 - Better Health Clinical Research, Inc.
City
Newnan
State/Province
Georgia
ZIP/Postal Code
30265
Country
United States
Facility Name
US032 - Millennium Pain Center
City
Bloomington
State/Province
Illinois
ZIP/Postal Code
61704
Country
United States
Facility Name
US011 - Otrimed Corporation
City
Edgewood
State/Province
Kentucky
ZIP/Postal Code
41017
Country
United States
Facility Name
US040 - Regeneris Medical
City
North Attleboro
State/Province
Massachusetts
ZIP/Postal Code
02760
Country
United States
Facility Name
Us054 - Aa Mrc
City
Flint
State/Province
Michigan
ZIP/Postal Code
48504
Country
United States
Facility Name
US025 - Oakland Medical Research
City
Troy
State/Province
Michigan
ZIP/Postal Code
48085
Country
United States
Facility Name
US009 - Elite Clinical Research
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39202
Country
United States
Facility Name
US017 - Jackson Anesthesia Pain Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39202
Country
United States
Facility Name
US033 - Galen Research
City
Chesterfield
State/Province
Missouri
ZIP/Postal Code
63005
Country
United States
Facility Name
US050 - Premier Pain Centers
City
Shrewsbury
State/Province
New Jersey
ZIP/Postal Code
07702
Country
United States
Facility Name
US029 - Dent Neurologic Institute
City
Amherst
State/Province
New York
ZIP/Postal Code
14226
Country
United States
Facility Name
US038 - DiGiovanna Institute For Medical Education
City
North Massapequa
State/Province
New York
ZIP/Postal Code
11758
Country
United States
Facility Name
US022 - The Neurological Institute
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Name
US047 - The Center for Clinical Research
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27103
Country
United States
Facility Name
US005 - Hometown Urgent Care and Research
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45424
Country
United States
Facility Name
US021 - SP Research PLLC
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
US028 - Founders Research Corporation
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19152
Country
United States
Facility Name
US018 - Carolinas Center for Advanced Management of Pain
City
Spartanburg
State/Province
South Carolina
ZIP/Postal Code
29303
Country
United States
Facility Name
US055 - Diversified Medical Practices
City
Houston
State/Province
Texas
ZIP/Postal Code
77057
Country
United States
Facility Name
US048 - Axios Research
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84106
Country
United States
Facility Name
US037 - Clinical Research Partners
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23235
Country
United States
Facility Name
AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre
City
St Leonards
State/Province
New South Wales
ZIP/Postal Code
2065
Country
Australia
Facility Name
AU005 - Port Kembla Public Hospital
City
Wollongong
State/Province
New South Wales
ZIP/Postal Code
2502
Country
Australia
Facility Name
AU003 - Neuro Trials Victoria Pty Ltd
City
Noble Park
State/Province
Victoria
ZIP/Postal Code
3174
Country
Australia
Facility Name
AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital
City
St Kilda East
State/Province
Victoria
ZIP/Postal Code
3183
Country
Australia
Facility Name
FR004 - Centre Hospitalier Universitaire Amiens Picardie
City
Amiens Cedex 1
ZIP/Postal Code
80054
Country
France
Facility Name
FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur
City
Nantes Cedex 2
ZIP/Postal Code
44277
Country
France
Facility Name
DE006 - Center for Clinical Research Dr. med. I. Schoel
City
Bad Homburg
ZIP/Postal Code
61348
Country
Germany
Facility Name
DE011 - Klinische Forschung Berlin Mitte GmbH
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin
City
Cottbus
ZIP/Postal Code
03046
Country
Germany
Facility Name
DE002 - Klinische Forschung Hamburg GmbH
City
Hamburg
ZIP/Postal Code
20253
Country
Germany
Facility Name
DE010 - Klinische Forschung Hannover Mitte
City
Hannover
ZIP/Postal Code
30159
Country
Germany
Facility Name
DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
DE005 - Klinische Forschung Schwerin GmbH
City
Schwerin
ZIP/Postal Code
19055
Country
Germany
Facility Name
KR008 - Chungnam National University Hospital
City
Daejeon
ZIP/Postal Code
35015
Country
Korea, Republic of
Facility Name
KR003 - Seoul National University Bundang Hospital
City
Seongnam-si
ZIP/Postal Code
13620
Country
Korea, Republic of
Facility Name
KR002 - Seoul National University Hospital
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
KR005 - Samsung Medical Center
City
Seoul
ZIP/Postal Code
06351
Country
Korea, Republic of
Facility Name
KR007 - Konkuk University Medical Center
City
Seoul
ZIP/Postal Code
5030
Country
Korea, Republic of
Facility Name
KR004 - Seoul St Mary's Hospital
City
Seoul
ZIP/Postal Code
6591
Country
Korea, Republic of
Facility Name
KR006 - Korea University Guro Hospital
City
Seoul
ZIP/Postal Code
8308
Country
Korea, Republic of
Facility Name
KR001 - Ajou University Medical Center
City
Suwon
ZIP/Postal Code
16499
Country
Korea, Republic of
Facility Name
NZ004 - Optimal Clinical Trials
City
Grafton
State/Province
Auckland
ZIP/Postal Code
1010
Country
New Zealand
Facility Name
Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board
City
Tauranga
State/Province
BAY OF Plenty
ZIP/Postal Code
3112
Country
New Zealand
Facility Name
NZ002 - Southern Clinical Trials Group Ltd
City
Christchurch
State/Province
Canterbury
ZIP/Postal Code
8013
Country
New Zealand
Facility Name
ES009 - General Hospital of Alicante
City
Alicante
ZIP/Postal Code
03010
Country
Spain
Facility Name
ES002 - Hospital de la Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
ES005 - Hospital Sanitas La Moraleja Pain Unit
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Facility Name
ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia
City
Puerto Real
ZIP/Postal Code
11510
Country
Spain
Facility Name
ES006 - Hospital Infanta Luisa Rheumatology
City
Sevilla
ZIP/Postal Code
41010
Country
Spain
Facility Name
ES007 - Hospital Clínico Universitario de Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit
City
Xativa
ZIP/Postal Code
46800
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Information available on the Grünenthal Group Web Site (see URL below for details); according to the European Federation of Pharmaceutical Industries and Associations (EFPIA) Data Sharing Principles.
IPD Sharing URL
http://www.grunenthal.com/r-d-vision-mission/clinical-trials/data-sharing-clinical-trials
Citations:
PubMed Identifier
19414839
Citation
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. doi: 10.7326/0003-4819-150-9-200905050-00006. Erratum In: Ann Intern Med. 2011 Sep 20;155(6):408.
Results Reference
background

Learn more about this trial

Efficacy and Safety of Intravenous Neridronic Acid in CRPS

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