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Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (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. Male participants must use condom and spermicide during intercourse and must take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as above, starting with Visit 2 until at least 4 weeks after the last Investigational medicinal product (IMP) infusion.
  • 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 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 (a single repeat laboratory test is 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 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 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, with the exception of participants participating in study KF7013-01 who were assigned to placebo and did not receive 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 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 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. Two repeat laboratory tests are 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.
    • 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

  • US446 - Clinical Trial Connection
  • US453 - Physicians Research Group II, LLC
  • US428 - Quality of Life Medical and Research Center LLC
  • US422 - Woodland International Research Group
  • US454 - Alliance Research Institute
  • US415 - Clearview Medical Research LLC
  • US410 - Alliance Research Centers
  • US432 - Torrance Clinical Research Institute Inc.
  • Us414 - Alexander Ford Md
  • US441 - Samaritan Center for Medical Research
  • US406 - CI Trials
  • US411 - Syrentis Clinical Research
  • US420 - Mountain View Clinical Research, INC
  • US447 - ASCLEPES Research Centers
  • US457 - Florida Spine Institute
  • US430 - South Lake Pain Institute
  • US434 - Finlay Medical Research
  • US407 - Oceane 7 Medical and Research Center, Inc.
  • US436 - Cordova Research Institute
  • US417 - Tampa Pain Relief Center
  • US403 - Palm Beach Research Center
  • US404 - Infinite Clinical Trials
  • US424 - Georgia Neurology and Sleep Medicine Assoc.
  • US431 - Injury Care Research, LLC
  • US437 - Great Lakes Clinical Trials LLC
  • US435 - Centex Studies Inc
  • US448 - The Center for Rheumatology and Bone Research
  • US450 - SRI International
  • US449 - Michigan Pain Consultants
  • US433 - Creighton University - Osteoporosis Research Center
  • US419 - Manhattan Behavioral Medicine
  • US440 - OnSite Clinical Solutions LLC
  • US405 - OnSite Clinical Solutions LLC
  • US416 - Medical Research International
  • US429 - Lehigh Valley Health
  • US438 - Abington Neurological Associates, LTD.
  • US425 - PCPMG Clinical Research Unit LLC
  • US423 - Biopharma Informatic Inc. Research Center
  • US443 - Centex Studies Inc
  • US421 - Northwest Clinical Research Center
  • US445 - Exemplar Research Inc
  • CA404 - Jeffrey Weinberg Medicine Professional Corporation c/o Jacobs Pain Center
  • CA406 - Malton Medical Centre (attn: Vrijender Singh)
  • CA402 - SKDS Research Inc
  • CA407 - King Street Medical Clinic
  • CA403 - Bluewater Clinical Research Group
  • CA405 - Canadian Centre for Clinical TrialsCCCT
  • CZ403 - CCBR Ostrava
  • CZ402 - CCR Czech a,s.
  • CZ401 - FORBELI s.r.o.
  • PL405 - Medical Solutions
  • PL404 - Zagiel Med Sp Zoo
  • PL403 - Alergo-Med Specjalistyczna Przychodnia Lekarska Sp.z o.o
  • RS401 - Clinical Center of Serbia, Clinic for physical medicine and rehabilitation
  • RS403 - Clinical Center Kragujevac, Department of Physical Medicine and rehabilitation
  • RS404 - Clinical Center Nis, Clinic for Physical Medicine and Rehabilitation
  • RS405 - Clinical Center of Vojvodina, Medical Rehabilitation Clinic
  • SK402 - MUDr. Beata Dupejova, neurologicka ambulancia sro
  • SK404 - Medical Center Konzilium
  • SK403 - NEURES, s.r.o.
  • SK401 - MUDr. Viliam Cíbik, PhD, Algeziologická ambulancia
  • GB413 - MAC Clinical Research
  • GB412 - MAC Clinical Research
  • GB415 - MAC Clinical Research
  • GB416 - Royal Devon and Exeter Hospital
  • GB410 - MAC Clinical Research
  • GB409 - MAC Clinical Research
  • GB407 - Pain and Neuromodulation Centre Ground Floor, Gassiot House, St Thomas Hospital
  • GB402 - St Pancras Clinical Research
  • GB408 - MAC Clinical Research
  • GB414 - MAC Clinical Research

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
NCT03560986
Brief Title
Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)
Official Title
Placebo-controlled Efficacy and Safety Trial 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 31, 2018 (Actual)
Primary Completion Date
August 1, 2019 (Actual)
Study Completion Date
August 1, 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 100 mg or placebo) over 10 days, and a Follow-up Period 1 until Week 26. At Week 26, 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. Participants not meeting the pre-specified criteria to continue into Treatment Period B continued in Follow-up Period 2 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
267 (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. Male participants must use condom and spermicide during intercourse and must take care that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as above, starting with Visit 2 until at least 4 weeks after the last Investigational medicinal product (IMP) infusion. 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 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 (a single repeat laboratory test is 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 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 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, with the exception of participants participating in study KF7013-01 who were assigned to placebo and did not receive 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 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 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. Two repeat laboratory tests are 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. 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
US446 - Clinical Trial Connection
City
Cottonwood
State/Province
Arizona
ZIP/Postal Code
86326
Country
United States
Facility Name
US453 - Physicians Research Group II, LLC
City
Tempe
State/Province
Arizona
ZIP/Postal Code
85284
Country
United States
Facility Name
US428 - Quality of Life Medical and Research Center LLC
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85712
Country
United States
Facility Name
US422 - Woodland International Research Group
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72211
Country
United States
Facility Name
US454 - Alliance Research Institute
City
Canoga Park
State/Province
California
ZIP/Postal Code
91304
Country
United States
Facility Name
US415 - Clearview Medical Research LLC
City
Canyon Country
State/Province
California
ZIP/Postal Code
91351
Country
United States
Facility Name
US410 - Alliance Research Centers
City
Laguna Hills
State/Province
California
ZIP/Postal Code
92653
Country
United States
Facility Name
US432 - Torrance Clinical Research Institute Inc.
City
Lomita
State/Province
California
ZIP/Postal Code
90717
Country
United States
Facility Name
Us414 - Alexander Ford Md
City
Los Angeles
State/Province
California
ZIP/Postal Code
90035
Country
United States
Facility Name
US441 - Samaritan Center for Medical Research
City
Los Gatos
State/Province
California
ZIP/Postal Code
95032
Country
United States
Facility Name
US406 - CI Trials
City
Santa Ana
State/Province
California
ZIP/Postal Code
92705
Country
United States
Facility Name
US411 - Syrentis Clinical Research
City
Santa Ana
State/Province
California
ZIP/Postal Code
92705
Country
United States
Facility Name
US420 - Mountain View Clinical Research, INC
City
Denver
State/Province
Colorado
ZIP/Postal Code
80209
Country
United States
Facility Name
US447 - ASCLEPES Research Centers
City
Brooksville
State/Province
Florida
ZIP/Postal Code
34613
Country
United States
Facility Name
US457 - Florida Spine Institute
City
Clearwater
State/Province
Florida
ZIP/Postal Code
33765
Country
United States
Facility Name
US430 - South Lake Pain Institute
City
Clermont
State/Province
Florida
ZIP/Postal Code
34711
Country
United States
Facility Name
US434 - Finlay Medical Research
City
Miami
State/Province
Florida
ZIP/Postal Code
33126
Country
United States
Facility Name
US407 - Oceane 7 Medical and Research Center, Inc.
City
Miami
State/Province
Florida
ZIP/Postal Code
33144
Country
United States
Facility Name
US436 - Cordova Research Institute
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Facility Name
US417 - Tampa Pain Relief Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33603
Country
United States
Facility Name
US403 - Palm Beach Research Center
City
West Palm Beach
State/Province
Florida
ZIP/Postal Code
33409
Country
United States
Facility Name
US404 - Infinite Clinical Trials
City
Riverdale
State/Province
Georgia
ZIP/Postal Code
30274
Country
United States
Facility Name
US424 - Georgia Neurology and Sleep Medicine Assoc.
City
Suwanee
State/Province
Georgia
ZIP/Postal Code
30024
Country
United States
Facility Name
US431 - Injury Care Research, LLC
City
Boise
State/Province
Idaho
ZIP/Postal Code
83713
Country
United States
Facility Name
US437 - Great Lakes Clinical Trials LLC
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60640
Country
United States
Facility Name
US435 - Centex Studies Inc
City
Lake Charles
State/Province
Louisiana
ZIP/Postal Code
70601
Country
United States
Facility Name
US448 - The Center for Rheumatology and Bone Research
City
Wheaton
State/Province
Maryland
ZIP/Postal Code
20902
Country
United States
Facility Name
US450 - SRI International
City
Plymouth
State/Province
Michigan
ZIP/Postal Code
48170
Country
United States
Facility Name
US449 - Michigan Pain Consultants
City
Wyoming
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
US433 - Creighton University - Osteoporosis Research Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68122
Country
United States
Facility Name
US419 - Manhattan Behavioral Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10036
Country
United States
Facility Name
US440 - OnSite Clinical Solutions LLC
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28210
Country
United States
Facility Name
US405 - OnSite Clinical Solutions LLC
City
Hickory
State/Province
North Carolina
ZIP/Postal Code
28601
Country
United States
Facility Name
US416 - Medical Research International
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73109
Country
United States
Facility Name
US429 - Lehigh Valley Health
City
Allentown
State/Province
Pennsylvania
ZIP/Postal Code
18103
Country
United States
Facility Name
US438 - Abington Neurological Associates, LTD.
City
Willow Grove
State/Province
Pennsylvania
ZIP/Postal Code
19090
Country
United States
Facility Name
US425 - PCPMG Clinical Research Unit LLC
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29601
Country
United States
Facility Name
US423 - Biopharma Informatic Inc. Research Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77043
Country
United States
Facility Name
US443 - Centex Studies Inc
City
Houston
State/Province
Texas
ZIP/Postal Code
77058
Country
United States
Facility Name
US421 - Northwest Clinical Research Center
City
Bellevue
State/Province
Washington
ZIP/Postal Code
98007
Country
United States
Facility Name
US445 - Exemplar Research Inc
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26505
Country
United States
Facility Name
CA404 - Jeffrey Weinberg Medicine Professional Corporation c/o Jacobs Pain Center
City
Markham
State/Province
Ontario
ZIP/Postal Code
L3R 9W9
Country
Canada
Facility Name
CA406 - Malton Medical Centre (attn: Vrijender Singh)
City
Mississauga
State/Province
Ontario
ZIP/Postal Code
L4V 1P1
Country
Canada
Facility Name
CA402 - SKDS Research Inc
City
Newmarket
State/Province
Ontario
ZIP/Postal Code
L3Y 5G8
Country
Canada
Facility Name
CA407 - King Street Medical Clinic
City
Oshawa
State/Province
Ontario
ZIP/Postal Code
L1H 1G6
Country
Canada
Facility Name
CA403 - Bluewater Clinical Research Group
City
Sarnia
State/Province
Ontario
ZIP/Postal Code
N7T 4X3
Country
Canada
Facility Name
CA405 - Canadian Centre for Clinical TrialsCCCT
City
Thornhill
State/Province
Ontario
ZIP/Postal Code
L4J 1W3
Country
Canada
Facility Name
CZ403 - CCBR Ostrava
City
Ostrava
ZIP/Postal Code
70 200
Country
Czechia
Facility Name
CZ402 - CCR Czech a,s.
City
Pardubice
ZIP/Postal Code
53 002
Country
Czechia
Facility Name
CZ401 - FORBELI s.r.o.
City
Prague 6
ZIP/Postal Code
16 000
Country
Czechia
Facility Name
PL405 - Medical Solutions
City
Elblag
ZIP/Postal Code
82-300
Country
Poland
Facility Name
PL404 - Zagiel Med Sp Zoo
City
Lublin
ZIP/Postal Code
20-362
Country
Poland
Facility Name
PL403 - Alergo-Med Specjalistyczna Przychodnia Lekarska Sp.z o.o
City
Tarnów
ZIP/Postal Code
33-100
Country
Poland
Facility Name
RS401 - Clinical Center of Serbia, Clinic for physical medicine and rehabilitation
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
RS403 - Clinical Center Kragujevac, Department of Physical Medicine and rehabilitation
City
Kragujevac
ZIP/Postal Code
34000
Country
Serbia
Facility Name
RS404 - Clinical Center Nis, Clinic for Physical Medicine and Rehabilitation
City
Nis
ZIP/Postal Code
18000
Country
Serbia
Facility Name
RS405 - Clinical Center of Vojvodina, Medical Rehabilitation Clinic
City
Novi Sad
ZIP/Postal Code
21000
Country
Serbia
Facility Name
SK402 - MUDr. Beata Dupejova, neurologicka ambulancia sro
City
Banska Bystrica
ZIP/Postal Code
97404
Country
Slovakia
Facility Name
SK404 - Medical Center Konzilium
City
Dubnica nad Vahom
ZIP/Postal Code
018 41
Country
Slovakia
Facility Name
SK403 - NEURES, s.r.o.
City
Krompachy
ZIP/Postal Code
5342
Country
Slovakia
Facility Name
SK401 - MUDr. Viliam Cíbik, PhD, Algeziologická ambulancia
City
Pruske
ZIP/Postal Code
1852
Country
Slovakia
Facility Name
GB413 - MAC Clinical Research
City
Barnsley
ZIP/Postal Code
S75 3DL
Country
United Kingdom
Facility Name
GB412 - MAC Clinical Research
City
Blackpool
ZIP/Postal Code
FY2 0JH
Country
United Kingdom
Facility Name
GB415 - MAC Clinical Research
City
Cannock
ZIP/Postal Code
WS11 0BN
Country
United Kingdom
Facility Name
GB416 - Royal Devon and Exeter Hospital
City
Exeter
ZIP/Postal Code
EX2 5DW
Country
United Kingdom
Facility Name
GB410 - MAC Clinical Research
City
Leeds
ZIP/Postal Code
LS10 1DU
Country
United Kingdom
Facility Name
GB409 - MAC Clinical Research
City
Liverpool
ZIP/Postal Code
L34 1BH
Country
United Kingdom
Facility Name
GB407 - Pain and Neuromodulation Centre Ground Floor, Gassiot House, St Thomas Hospital
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
GB402 - St Pancras Clinical Research
City
London
ZIP/Postal Code
WC1X 8QD
Country
United Kingdom
Facility Name
GB408 - MAC Clinical Research
City
Manchester
ZIP/Postal Code
M13 9NQ
Country
United Kingdom
Facility Name
GB414 - MAC Clinical Research
City
Stockton-on-Tees
ZIP/Postal Code
TS17 6EW
Country
United Kingdom

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 Complex Regional Pain Syndrome (CRPS)

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