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Efficacy and Safety of Intravenous Neridronic Acid in CRPS
Randomized, Double-blind, Placebo-controlled Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
3 other identifiers
interventional
182
7 countries
71
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started May 2018
Shorter than P25 for phase_3
71 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 7, 2018
CompletedFirst Posted
Study publicly available on registry
May 21, 2018
CompletedStudy Start
First participant enrolled
May 30, 2018
CompletedPrimary Completion
Last participant's last visit for primary outcome
July 31, 2019
CompletedStudy Completion
Last participant's last visit for all outcomes
July 31, 2019
CompletedResults Posted
Study results publicly available
August 6, 2020
CompletedAugust 6, 2020
July 1, 2020
1.2 years
May 7, 2018
June 23, 2020
July 20, 2020
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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.
From the Baseline Phase (Day -7 to Day -1) to Week 12
Secondary Outcomes (6)
Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer.
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
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.
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
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.
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA).
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle.
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
- +1 more secondary outcomes
Study Arms (2)
Neridronic acid
EXPERIMENTALNeridronic 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.
Placebo
PLACEBO COMPARATORMatching 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.
Interventions
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
Eligibility Criteria
You may qualify if:
- 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).
You may not qualify if:
- 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.
- 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.
- +15 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Grünenthal GmbHlead
Study Sites (71)
US015 - Tennessee Valley Pain Consultants
Huntsville, Alabama, 35801, United States
US043 - Horizon Research Partners
Mobile, Alabama, 36605, United States
US045 - Holland Center for Family Health
Peoria, Arizona, 85381, United States
US003 - HealthStar Research
Hot Springs, Arkansas, 71913, United States
US049 - Orange County Research Institute
Anaheim, California, 92801, United States
US053 - Core Healthcare Group
Cerritos, California, 90703, United States
US013 - Inland Pain Medicine
Colton, California, 92324, United States
US044 - The Helm Center for Pain Management
Laguna Woods, California, 92637, United States
US052 - Providere' Research Inc.
West Covina, California, 91790, United States
US036 - Denver Back Pain Specialists
Greenwood Village, Colorado, 80111, United States
US007 - Neurology Offices of South Florida
Boca Raton, Florida, 33428, United States
US030 - Gulfcoast Clinical Research Center
Fort Myers, Florida, 33912, United States
US004 - The Chappel Group Research
Kissimmee, Florida, 34744, United States
US023 - AGR Research
Lake Worth, Florida, 33462, United States
US020 - SIMEDHealth
Ocala, Florida, 34474, United States
US012 - NeuroMedical Research Center
Panama City, Florida, 32405, United States
US046 - Clinical Research of West Florida, Inc.
Tampa, Florida, 33603, United States
US027 - Drug Studies America
Marietta, Georgia, 30060, United States
US041 - Better Health Clinical Research, Inc.
Newnan, Georgia, 30265, United States
US032 - Millennium Pain Center
Bloomington, Illinois, 61704, United States
US011 - Otrimed Corporation
Edgewood, Kentucky, 41017, United States
US040 - Regeneris Medical
North Attleboro, Massachusetts, 02760, United States
Us054 - Aa Mrc
Flint, Michigan, 48504, United States
US025 - Oakland Medical Research
Troy, Michigan, 48085, United States
US009 - Elite Clinical Research
Jackson, Mississippi, 39202, United States
US017 - Jackson Anesthesia Pain Center
Jackson, Mississippi, 39202, United States
US033 - Galen Research
Chesterfield, Missouri, 63005, United States
US050 - Premier Pain Centers
Shrewsbury, New Jersey, 07702, United States
US029 - Dent Neurologic Institute
Amherst, New York, 14226, United States
US038 - DiGiovanna Institute For Medical Education
North Massapequa, New York, 11758, United States
US022 - The Neurological Institute
Charlotte, North Carolina, 28204, United States
US047 - The Center for Clinical Research
Winston-Salem, North Carolina, 27103, United States
US005 - Hometown Urgent Care and Research
Dayton, Ohio, 45424, United States
US021 - SP Research PLLC
Oklahoma City, Oklahoma, 73112, United States
US028 - Founders Research Corporation
Philadelphia, Pennsylvania, 19152, United States
US018 - Carolinas Center for Advanced Management of Pain
Spartanburg, South Carolina, 29303, United States
US055 - Diversified Medical Practices
Houston, Texas, 77057, United States
US048 - Axios Research
Salt Lake City, Utah, 84106, United States
US037 - Clinical Research Partners
Richmond, Virginia, 23235, United States
AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre
St Leonards, New South Wales, 2065, Australia
AU005 - Port Kembla Public Hospital
Wollongong, New South Wales, 2502, Australia
AU003 - Neuro Trials Victoria Pty Ltd
Noble Park, Victoria, 3174, Australia
AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital
St Kilda East, Victoria, 3183, Australia
FR004 - Centre Hospitalier Universitaire Amiens Picardie
Amiens, 80054, France
FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur
Grenoble, 38043, France
FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur
Nantes, 44277, France
DE006 - Center for Clinical Research Dr. med. I. Schoel
Bad Homburg, 61348, Germany
DE011 - Klinische Forschung Berlin Mitte GmbH
Berlin, 10117, Germany
DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin
Cottbus, 03046, Germany
DE002 - Klinische Forschung Hamburg GmbH
Hamburg, 20253, Germany
DE010 - Klinische Forschung Hannover Mitte
Hanover, 30159, Germany
DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz
Mainz, 55131, Germany
DE005 - Klinische Forschung Schwerin GmbH
Schwerin, 19055, Germany
NZ004 - Optimal Clinical Trials
Grafton, Auckland, 1010, New Zealand
Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board
Tauranga, Bay of Plenty, 3112, New Zealand
NZ002 - Southern Clinical Trials Group Ltd
Christchurch, Canterbury, 8013, New Zealand
KR008 - Chungnam National University Hospital
Daejeon, 35015, South Korea
KR003 - Seoul National University Bundang Hospital
Seongnam-si, 13620, South Korea
KR002 - Seoul National University Hospital
Seoul, 03080, South Korea
KR005 - Samsung Medical Center
Seoul, 06351, South Korea
KR007 - Konkuk University Medical Center
Seoul, 5030, South Korea
KR004 - Seoul St Mary's Hospital
Seoul, 6591, South Korea
KR006 - Korea University Guro Hospital
Seoul, 8308, South Korea
KR001 - Ajou University Medical Center
Suwon, 16499, South Korea
ES009 - General Hospital of Alicante
Alicante, 03010, Spain
ES002 - Hospital de la Santa Creu i Sant Pau
Barcelona, 08041, Spain
ES005 - Hospital Sanitas La Moraleja Pain Unit
Madrid, 28050, Spain
ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia
Puerto Real, 11510, Spain
ES006 - Hospital Infanta Luisa Rheumatology
Seville, 41010, Spain
ES007 - Hospital Clínico Universitario de Valencia
Valencia, 46010, Spain
ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit
Xàtiva, 46800, Spain
Related Publications (1)
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.
PMID: 19414839BACKGROUND
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Limitations and Caveats
A pre-specified interim analysis was conducted on pooled primary endpoint data of studies KF7013-02 and KF7013-04 (NCT03560986). The interim analysis indicated futility (neridronate unlikely to be superior to placebo) and both studies were stopped.
Results Point of Contact
- Title
- Director Clinical Trials
- Organization
- Grünenthal GmbH
Study Officials
- STUDY DIRECTOR
Grünenthal Study Director
Grünenthal GmbH
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Masking Details
- Blinded treatment in Treatment Period A, open-label infusion in Treatment Period B.
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 7, 2018
First Posted
May 21, 2018
Study Start
May 30, 2018
Primary Completion
July 31, 2019
Study Completion
July 31, 2019
Last Updated
August 6, 2020
Results First Posted
August 6, 2020
Record last verified: 2020-07
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP
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.