Efficacy and Safety of Intravenous Neridronic Acid in CRPS

NCT ID: NCT03530345

Last Updated: 2020-08-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 182 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-05-30
• Study Completion Date: 2019-07-31

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.

Conditions

Complex Regional Pain Syndrome (CRPS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Neridronic acid

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.

Group Type: EXPERIMENTAL

Neridronic acid 100 mg

Intervention Type: DRUG

100 mg neridronic acid supplied in glass vials in 8 mL of excipients.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Glass vials with matching placebo.

Interventions

Neridronic acid 100 mg

100 mg neridronic acid supplied in glass vials in 8 mL of excipients.

Intervention Type: DRUG

Placebo

Glass vials with matching placebo.

Intervention Type: DRUG

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.
• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Grünenthal GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Grünenthal Study Director

Role: STUDY_DIRECTOR

Grünenthal GmbH

Locations

US015 - Tennessee Valley Pain Consultants

Huntsville, Alabama, United States

US043 - Horizon Research Partners

Mobile, Alabama, United States

US045 - Holland Center for Family Health

Peoria, Arizona, United States

US003 - HealthStar Research

Hot Springs, Arkansas, United States

US049 - Orange County Research Institute

Anaheim, California, United States

US053 - Core Healthcare Group

Cerritos, California, United States

US013 - Inland Pain Medicine

Colton, California, United States

US044 - The Helm Center for Pain Management

Laguna Woods, California, United States

US052 - Providere' Research Inc.

West Covina, California, United States

US036 - Denver Back Pain Specialists

Greenwood Village, Colorado, United States

US007 - Neurology Offices of South Florida

Boca Raton, Florida, United States

US030 - Gulfcoast Clinical Research Center

Fort Myers, Florida, United States

US004 - The Chappel Group Research

Kissimmee, Florida, United States

US023 - AGR Research

Lake Worth, Florida, United States

US020 - SIMEDHealth

Ocala, Florida, United States

US012 - NeuroMedical Research Center

Panama City, Florida, United States

US046 - Clinical Research of West Florida, Inc.

Tampa, Florida, United States

US027 - Drug Studies America

Marietta, Georgia, United States

US041 - Better Health Clinical Research, Inc.

Newnan, Georgia, United States

US032 - Millennium Pain Center

Bloomington, Illinois, United States

US011 - Otrimed Corporation

Edgewood, Kentucky, United States

US040 - Regeneris Medical

North Attleboro, Massachusetts, United States

Us054 - Aa Mrc

Flint, Michigan, United States

US025 - Oakland Medical Research

Troy, Michigan, United States

US009 - Elite Clinical Research

Jackson, Mississippi, United States

US017 - Jackson Anesthesia Pain Center

Jackson, Mississippi, United States

US033 - Galen Research

Chesterfield, Missouri, United States

US050 - Premier Pain Centers

Shrewsbury, New Jersey, United States

US029 - Dent Neurologic Institute

Amherst, New York, United States

US038 - DiGiovanna Institute For Medical Education

North Massapequa, New York, United States

US022 - The Neurological Institute

Charlotte, North Carolina, United States

US047 - The Center for Clinical Research

Winston-Salem, North Carolina, United States

US005 - Hometown Urgent Care and Research

Dayton, Ohio, United States

US021 - SP Research PLLC

Oklahoma City, Oklahoma, United States

US028 - Founders Research Corporation

Philadelphia, Pennsylvania, United States

US018 - Carolinas Center for Advanced Management of Pain

Spartanburg, South Carolina, United States

US055 - Diversified Medical Practices

Houston, Texas, United States

US048 - Axios Research

Salt Lake City, Utah, United States

US037 - Clinical Research Partners

Richmond, Virginia, United States

AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre

St Leonards, New South Wales, Australia

AU005 - Port Kembla Public Hospital

Wollongong, New South Wales, Australia

AU003 - Neuro Trials Victoria Pty Ltd

Noble Park, Victoria, Australia

AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital

St Kilda East, Victoria, Australia

FR004 - Centre Hospitalier Universitaire Amiens Picardie

Amiens, , France

FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur

Grenoble, , France

FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur

Nantes, , France

DE006 - Center for Clinical Research Dr. med. I. Schoel

Bad Homburg, , Germany

DE011 - Klinische Forschung Berlin Mitte GmbH

Berlin, , Germany

DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin

Cottbus, , Germany

DE002 - Klinische Forschung Hamburg GmbH

Hamburg, , Germany

DE010 - Klinische Forschung Hannover Mitte

Hanover, , Germany

DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz

Mainz, , Germany

DE005 - Klinische Forschung Schwerin GmbH

Schwerin, , Germany

NZ004 - Optimal Clinical Trials

Grafton, Auckland, New Zealand

Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board

Tauranga, Bay of Plenty, New Zealand

NZ002 - Southern Clinical Trials Group Ltd

Christchurch, Canterbury, New Zealand

KR008 - Chungnam National University Hospital

Daejeon, , South Korea

KR003 - Seoul National University Bundang Hospital

Seongnam-si, , South Korea

KR002 - Seoul National University Hospital

Seoul, , South Korea

KR005 - Samsung Medical Center

Seoul, , South Korea

KR007 - Konkuk University Medical Center

Seoul, , South Korea

KR004 - Seoul St Mary's Hospital

Seoul, , South Korea

KR006 - Korea University Guro Hospital

Seoul, , South Korea

KR001 - Ajou University Medical Center

Suwon, , South Korea

ES009 - General Hospital of Alicante

Alicante, , Spain

ES002 - Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

ES005 - Hospital Sanitas La Moraleja Pain Unit

Madrid, , Spain

ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia

Puerto Real, , Spain

ES006 - Hospital Infanta Luisa Rheumatology

Seville, , Spain

ES007 - Hospital Clínico Universitario de Valencia

Valencia, , Spain

ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit

Xàtiva, , Spain

Countries

United States; Australia; France; Germany; New Zealand; South Korea; Spain

References

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.

Reference Type: BACKGROUND

PMID: 19414839 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan: Pooled-Interim-Analysis-KF7013-02-KF7013-04

View Document

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: Final-Analysis-KF7013-02

View Document

Other Identifiers

2016-003833-91

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1187-8036

Identifier Type: OTHER

Identifier Source: secondary_id

KF7013-02

Identifier Type: -

Identifier Source: org_study_id