Safety of Intravenous Neridronic Acid in CRPS

NCT ID: NCT02972359

Last Updated: 2019-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 580 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-20
• Study Completion Date: 2019-01-09

Brief Summary

The aim of this trial was to investigate the safety of intravenous neridronic acid in patients with complex regional pain syndrome (CRPS).

The trial was divided into 3 periods: a 60-day enrollment period, a treatment period consisting of 4 infusions over 10 days, and a follow-up period of approximately 50 weeks (with visits at Week 2, Week 6, Week 12, Week 26, Week 39, and Week 52).

Detailed Description

At the Enrollment Visit the trial objectives, procedures, and risks were explained to the participants and the informed consent form was signed. Medical history was obtained, a physical examination was conducted, and other safety assessments were performed. Signs and symptoms of CRPS were assessed to confirm the diagnosis of CRPS according to the Budapest clinical criteria. Participants were trained to report their pain. Calcium and vitamin D supplementation were initiated to ensure sufficient vitamin D levels prior to treatment.

Participants meeting all eligibility criteria received infusions of investigational medicinal product (IMP) during visits on Day 1, Day 4, Day 7, and Day 10. Flexibility of ±1 day was allowed for Day 4, Day 7, and Day 10 whilst ensuring a minimum period of 48 hours between infusions. During the treatment period and follow-up period, pain intensity ratings were captured at the site visits in a patient reported-outcome system.

Conditions

Complex Regional Pain Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Neridronic acid

Neridronic acid 100 mg administered on Day 1, Day 4, Day 7, and Day 10, resulting in a total dose of neridronic acid 400 mg.

Group Type: EXPERIMENTAL

Neridronic acid

Intervention Type: DRUG

Neridronic acid administered as intravenous infusion.

Interventions

Neridronic acid

Neridronic acid administered as intravenous infusion.

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 complex regional pain syndrome 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.
• Ongoing moderate to severe chronic pain, including a baseline current pain intensity score of greater than or equal to 4 using an 11-point Numerical Rating Scale, referring to the CRPS-affected limb, at Visit 2 (prior to dosing).
• 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 trials of at least 2 treatments for CRPS, one of which must be a pharmacologic treatment.
• Women of child-bearing potential must have a negative urine beta-human chorionic gonadotropin (β-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 (e.g., oral contraceptives or intrauterine device), 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 impairment).

Exclusion Criteria

• Evidence of renal impairment (estimated glomerular filtration rate [eGFR] less than 60 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 creatinine ratio greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2, or a history of chronic kidney disease. 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); concomitant use of drug(s) with known potential to cause hypocalcemia (e.g., aminoglycosides).
• Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL, 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 must be documented prior to allocation to investigational medicinal product (IMP).
• Corrected QT interval (according to Fridericia's formula; QTcF) greater than 470 ms (average of 3 electrocardiograms [ECGs] obtained at Visit 1); serum potassium outside the central laboratory's reference range at Visit 1; 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 other known risk factor for torsade de pointes.
• Anticipated requirement for treatment with oral or intravenous bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia®) or other drugs affecting bone turnover or bone metabolism 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 (e.g., impacted molars, severe tooth decay, foci of infection) that may predispose 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 2.
• 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 participant's 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 with neridronic acid, with the exception of participants of 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 signing the informed consent.

• 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

Study Director

Role: STUDY_DIRECTOR

Grünenthal GmbH

Locations

US017: Cactus Clinical Research, Inc.

Phoenix, Arizona, United States

US028: Quality of Life Medical and Research Centers LLC

Tucson, Arizona, United States

US045: Woodland International Research Group

Little Rock, Arkansas, United States

US044: Woodland Research Northwest

Rogers, Arkansas, United States

US012: Orange County Research Institute

Anaheim, California, United States

US022: Core Healthcare Group

Cerritos, California, United States

US033: Alliance Research Centers

Laguna Hills, California, United States

US027: The Helm Center for Pain Management

Laguna Woods, California, United States

US003: Samaritan Center for Medical Research

Los Gatos, California, United States

US010: Catalina Research Institute, LLC

Montclair, California, United States

US014: Northern California Research

Sacramento, California, United States

US034: Mountain View Clinical Research, Inc.

Denver, Colorado, United States

US032: South Lake Pain Institute

Clermont, Florida, United States

US001: Sunrise Research Institute, Inc

Miami, Florida, United States

US046: AMPM Research Clinic

Miami, Florida, United States

US035: Compass Research

Orlando, Florida, United States

US031: Gold Coast Research, LLC

Plantation, Florida, United States

US011: Clinical Research of West Florida, Inc.

Tampa, Florida, United States

US040: Palm Beach Research Center

West Palm Beach, Florida, United States

US026: Better Health Clinical Research Inc.

Newnan, Georgia, United States

US004: Northwestern University - Feinberg School of Medicine - Rehabilitation Institute of Chicago (RIC)

Chicago, Illinois, United States

US036: University Anesthesiologists, S.C.

Chicago, Illinois, United States

US029: Great Lakes Clinical Trials LLC

Chicago, Illinois, United States

US005: International Clinical Research Institute

Overland Park, Kansas, United States

US037: St. Louis Clinical Trials, LC

St Louis, Missouri, United States

US051: Creighton University, Osteoporosis Research Center

Omaha, Nebraska, United States

US002: Princeton Medical Institute

Princeton, New Jersey, United States

US049: Premier Pain Centers, LLC

Shrewsbury, New Jersey, United States

US048: Albany Medical College

Albany, New York, United States

US043: Translational Pain Research, University of Rochester

Rochester, New York, United States

US009: The Center for Clinical Research, LLC

Winston-Salem, North Carolina, United States

US016: North Star Medical Research, LLC

Middleburg Heights, Ohio, United States

US007: Medical Research International

Oklahoma City, Oklahoma, United States

US006: Abington Neurological Associates, LTD.

Willow Grove, Pennsylvania, United States

US020: Clinical Trials of South Carolina

Charleston, South Carolina, United States

US038: Vanderbilt University Medical Center

Nashville, Tennessee, United States

US019: Austin Center for Clinical Research

Austin, Texas, United States

US008: Pioneer Research Solutions

Houston, Texas, United States

US023: Axios Research, LLC

Salt Lake City, Utah, United States

US018: Washington Center for Pain Management

Bellevue, Washington, United States

US015: Northwest Clinical Research Center

Bellevue, Washington, United States

US013: Swedish Pain Services/ Research Institute

Seattle, Washington, United States

DE001: Klinische Forschung Hannover-Mitte GmbH

Hanover, , Germany

DE004: Schmerzambulanz Medizinishe Hochschule Hannover

Hanover, , Germany

DE006: AmBeNet GmbH

Leipzig, , Germany

DE002: Schmerztagesklinik der Anästhesiologie Universitätsklinikum Würzburg

Würzburg, , Germany

Countries

United States; Germany

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: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-001164-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1180-8099

Identifier Type: OTHER

Identifier Source: secondary_id

KF7013-03

Identifier Type: -

Identifier Source: org_study_id