Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)

NCT03560986 | Terminated Phase 3 Results FDA Drug

• 3 other identifiers: KF7013-042017-004244-37U1111-1203-5020
• Study Type: interventional
• Target: 267
• Locations: 7 countries
• Sites: 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 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.

Conditions

Complex Regional Pain Syndrome (CRPS)

Keywords

Neridronic Acid; Neridronate; CRPS; Reflex sympathetic dystrophy (RSD)

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)

Study Arms (2)

Neridronic acid

EXPERIMENTAL

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.

Drug: Neridronic acid 100 mg

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Neridronic acid 100 mg DRUG

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

Neridronic acid

Placebo DRUG

Glass vials with matching placebo.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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. 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).

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Grünenthal GmbH: lead

Study Sites (71)

US446 - Clinical Trial Connection

Cottonwood, Arizona, 86326, United States

Location

US453 - Physicians Research Group II, LLC

Tempe, Arizona, 85284, United States

Location

US428 - Quality of Life Medical and Research Center LLC

Tucson, Arizona, 85712, United States

Location

US422 - Woodland International Research Group

Little Rock, Arkansas, 72211, United States

Location

US454 - Alliance Research Institute

Canoga Park, California, 91304, United States

Location

US415 - Clearview Medical Research LLC

Canyon Country, California, 91351, United States

Location

US410 - Alliance Research Centers

Laguna Hills, California, 92653, United States

Location

US432 - Torrance Clinical Research Institute Inc.

Lomita, California, 90717, United States

Location

Us414 - Alexander Ford Md

Los Angeles, California, 90035, United States

Location

US441 - Samaritan Center for Medical Research

Los Gatos, California, 95032, United States

Location

US406 - CI Trials

Santa Ana, California, 92705, United States

Location

US411 - Syrentis Clinical Research

Santa Ana, California, 92705, United States

Location

US420 - Mountain View Clinical Research, INC

Denver, Colorado, 80209, United States

Location

US447 - ASCLEPES Research Centers

Brooksville, Florida, 34613, United States

Location

US457 - Florida Spine Institute

Clearwater, Florida, 33765, United States

Location

US430 - South Lake Pain Institute

Clermont, Florida, 34711, United States

Location

US434 - Finlay Medical Research

Miami, Florida, 33126, United States

Location

US407 - Oceane 7 Medical and Research Center, Inc.

Miami, Florida, 33144, United States

Location

US436 - Cordova Research Institute

Miami, Florida, 33155, United States

Location

US417 - Tampa Pain Relief Center

Tampa, Florida, 33603, United States

Location

US403 - Palm Beach Research Center

West Palm Beach, Florida, 33409, United States

Location

US404 - Infinite Clinical Trials

Riverdale, Georgia, 30274, United States

Location

US424 - Georgia Neurology and Sleep Medicine Assoc.

Suwanee, Georgia, 30024, United States

Location

US431 - Injury Care Research, LLC

Boise, Idaho, 83713, United States

Location

US437 - Great Lakes Clinical Trials LLC

Chicago, Illinois, 60640, United States

Location

US435 - Centex Studies Inc

Lake Charles, Louisiana, 70601, United States

Location

US448 - The Center for Rheumatology and Bone Research

Wheaton, Maryland, 20902, United States

Location

US450 - SRI International

Plymouth, Michigan, 48170, United States

Location

US449 - Michigan Pain Consultants

Wyoming, Michigan, 49503, United States

Location

US433 - Creighton University - Osteoporosis Research Center

Omaha, Nebraska, 68122, United States

Location

US419 - Manhattan Behavioral Medicine

New York, New York, 10036, United States

Location

US440 - OnSite Clinical Solutions LLC

Charlotte, North Carolina, 28210, United States

Location

US405 - OnSite Clinical Solutions LLC

Hickory, North Carolina, 28601, United States

Location

US416 - Medical Research International

Oklahoma City, Oklahoma, 73109, United States

Location

US429 - Lehigh Valley Health

Allentown, Pennsylvania, 18103, United States

Location

US438 - Abington Neurological Associates, LTD.

Willow Grove, Pennsylvania, 19090, United States

Location

US425 - PCPMG Clinical Research Unit LLC

Greenville, South Carolina, 29601, United States

Location

US423 - Biopharma Informatic Inc. Research Center

Houston, Texas, 77043, United States

Location

US443 - Centex Studies Inc

Houston, Texas, 77058, United States

Location

US421 - Northwest Clinical Research Center

Bellevue, Washington, 98007, United States

Location

US445 - Exemplar Research Inc

Morgantown, West Virginia, 26505, United States

Location

CA404 - Jeffrey Weinberg Medicine Professional Corporation c/o Jacobs Pain Center

Markham, Ontario, L3R 9W9, Canada

Location

CA406 - Malton Medical Centre (attn: Vrijender Singh)

Mississauga, Ontario, L4V 1P1, Canada

Location

CA402 - SKDS Research Inc

Newmarket, Ontario, L3Y 5G8, Canada

Location

CA407 - King Street Medical Clinic

Oshawa, Ontario, L1H 1G6, Canada

Location

CA403 - Bluewater Clinical Research Group

Sarnia, Ontario, N7T 4X3, Canada

Location

CA405 - Canadian Centre for Clinical TrialsCCCT

Thornhill, Ontario, L4J 1W3, Canada

Location

CZ403 - CCBR Ostrava

Ostrava, 70 200, Czechia

Location

CZ402 - CCR Czech a,s.

Pardubice, 53 002, Czechia

Location

CZ401 - FORBELI s.r.o.

Prague, 16 000, Czechia

Location

PL405 - Medical Solutions

Elblag, 82-300, Poland

Location

PL404 - Zagiel Med Sp Zoo

Lublin, 20-362, Poland

Location

PL403 - Alergo-Med Specjalistyczna Przychodnia Lekarska Sp.z o.o

Tarnów, 33-100, Poland

Location

RS401 - Clinical Center of Serbia, Clinic for physical medicine and rehabilitation

Belgrade, 11000, Serbia

Location

RS403 - Clinical Center Kragujevac, Department of Physical Medicine and rehabilitation

Kragujevac, 34000, Serbia

Location

RS404 - Clinical Center Nis, Clinic for Physical Medicine and Rehabilitation

Niš, 18000, Serbia

Location

RS405 - Clinical Center of Vojvodina, Medical Rehabilitation Clinic

Novi Sad, 21000, Serbia

Location

SK402 - MUDr. Beata Dupejova, neurologicka ambulancia sro

Banská Bystrica, 97404, Slovakia

Location

SK404 - Medical Center Konzilium

Dubnica nad Váhom, 018 41, Slovakia

Location

SK403 - NEURES, s.r.o.

Krompachy, 5342, Slovakia

Location

SK401 - MUDr. Viliam Cíbik, PhD, Algeziologická ambulancia

Pruské, 1852, Slovakia

Location

GB413 - MAC Clinical Research

Barnsley, S75 3DL, United Kingdom

Location

GB412 - MAC Clinical Research

Blackpool, FY2 0JH, United Kingdom

Location

GB415 - MAC Clinical Research

Cannock, WS11 0BN, United Kingdom

Location

GB416 - Royal Devon and Exeter Hospital

Exeter, EX2 5DW, United Kingdom

Location

GB410 - MAC Clinical Research

Leeds, LS10 1DU, United Kingdom

Location

GB409 - MAC Clinical Research

Liverpool, L34 1BH, United Kingdom

Location

GB407 - Pain and Neuromodulation Centre Ground Floor, Gassiot House, St Thomas Hospital

London, SE1 7EH, United Kingdom

Location

GB402 - St Pancras Clinical Research

London, WC1X 8QD, United Kingdom

Location

GB408 - MAC Clinical Research

Manchester, M13 9NQ, United Kingdom

Location

GB414 - MAC Clinical Research

Stockton-on-Tees, TS17 6EW, United Kingdom

Location

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: 19414839 BACKGROUND

MeSH Terms

Conditions

Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy

Interventions

6-amino-1-hydroxyhexane-1,1-diphosphonate

Condition Hierarchy (Ancestors)

Autonomic Nervous System Diseases; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases

Limitations and Caveats

A pre-specified interim analysis was conducted on pooled primary endpoint data of studies KF7013-04 and KF7013-02 (NCT03530345). 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

Clinical-Trials@grunenthal.com

+49 241 569

Study Officials

• Grünenthal Study Director

  Grünenthal GmbH

  STUDY DIRECTOR

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: June 19, 2018
• Study Start: May 31, 2018
• Primary Completion: August 1, 2019
• Study Completion: August 1, 2019
• Last Updated: August 5, 2020
• Results First Posted: August 5, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

CA (6); SE (4); GB (10); PL (3); SL (4); US (41); CZ (3)