Safety of Intravenous Neridronic Acid in CRPS

Complex Regional Pain Syndrome Clinical Trial

Official title:

Open-label Safety Trial of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02972359
• Other study ID #: KF7013-03
• Secondary ID: 2016-001164-11U1
• Status: Completed
• Phase: Phase 3
• Start date: December 20, 2016
• Est. completion date: January 9, 2019

Study information

• Verified date: November 2019
• Source: Grünenthal GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 580
• Est. completion date: January 9, 2019
• Est. primary completion date: January 9, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (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 (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.

• 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 (e.g., citalopram, escitalopram) or tricyclic 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 until at least 4 days after the last infusion of IMP.

• 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.

Related Conditions & MeSH terms

• Complex Regional Pain Syndrome
• Complex Regional Pain Syndromes
• Reflex Sympathetic Dystrophy
• Syndrome

Intervention

Drug:
• Neridronic acid
Neridronic acid administered as intravenous infusion.

Locations

Country	Name	City	State
Germany	DE001: Klinische Forschung Hannover-Mitte GmbH	Hannover
Germany	DE004: Schmerzambulanz Medizinishe Hochschule Hannover	Hannover
Germany	DE006: AmBeNet GmbH	Leipzig
Germany	DE002: Schmerztagesklinik der Anästhesiologie Universitätsklinikum Würzburg	Würzburg
United States	US048: Albany Medical College	Albany	New York
United States	US012: Orange County Research Institute	Anaheim	California
United States	US019: Austin Center for Clinical Research	Austin	Texas
United States	US015: Northwest Clinical Research Center	Bellevue	Washington
United States	US018: Washington Center for Pain Management	Bellevue	Washington
United States	US022: Core Healthcare Group	Cerritos	California
United States	US020: Clinical Trials of South Carolina	Charleston	South Carolina
United States	US004: Northwestern University - Feinberg School of Medicine - Rehabilitation Institute of Chicago (RIC)	Chicago	Illinois
United States	US029: Great Lakes Clinical Trials LLC	Chicago	Illinois
United States	US036: University Anesthesiologists, S.C.	Chicago	Illinois
United States	US032: South Lake Pain Institute	Clermont	Florida
United States	US034: Mountain View Clinical Research, Inc.	Denver	Colorado
United States	US008: Pioneer Research Solutions	Houston	Texas
United States	US033: Alliance Research Centers	Laguna Hills	California
United States	US027: The Helm Center for Pain Management	Laguna Woods	California
United States	US045: Woodland International Research Group	Little Rock	Arkansas
United States	US003: Samaritan Center for Medical Research	Los Gatos	California
United States	US001: Sunrise Research Institute, Inc	Miami	Florida
United States	US046: AMPM Research Clinic	Miami	Florida
United States	US016: North Star Medical Research, LLC	Middleburg Heights	Ohio
United States	US010: Catalina Research Institute, LLC	Montclair	California
United States	US038: Vanderbilt University Medical Center	Nashville	Tennessee
United States	US026: Better Health Clinical Research Inc.	Newnan	Georgia
United States	US007: Medical Research International	Oklahoma City	Oklahoma
United States	US051: Creighton University, Osteoporosis Research Center	Omaha	Nebraska
United States	US035: Compass Research	Orlando	Florida
United States	US005: International Clinical Research Institute	Overland Park	Kansas
United States	US017: Cactus Clinical Research, Inc.	Phoenix	Arizona
United States	US031: Gold Coast Research, LLC	Plantation	Florida
United States	US002: Princeton Medical Institute	Princeton	New Jersey
United States	US043: Translational Pain Research, University of Rochester	Rochester	New York
United States	US044: Woodland Research Northwest	Rogers	Arkansas
United States	US014: Northern California Research	Sacramento	California
United States	US037: St. Louis Clinical Trials, LC	Saint Louis	Missouri
United States	US023: Axios Research, LLC	Salt Lake City	Utah
United States	US013: Swedish Pain Services/ Research Institute	Seattle	Washington
United States	US049: Premier Pain Centers, LLC	Shrewsbury	New Jersey
United States	US011: Clinical Research of West Florida, Inc.	Tampa	Florida
United States	US028: Quality of Life Medical and Research Centers LLC	Tucson	Arizona
United States	US040: Palm Beach Research Center	West Palm Beach	Florida
United States	US006: Abington Neurological Associates, LTD.	Willow Grove	Pennsylvania
United States	US009: The Center for Clinical Research, LLC	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Grünenthal GmbH

Countries where clinical trial is conducted

United States,  Germany, 

References & 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. Erratum in: Ann Intern Med. 2011 Sep 20;155(6):408. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE)	The primary endpoint of this trial was a binary endpoint assessing whether or not a participant experienced any TEAE.	Day 1 to Week 52
Secondary	Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event	The investigator could choose to permanently discontinue a participant from treatment if continued exposure of the participant to neridronic acid could have posed an undue risk to the participant.	Day 1 to Day 10
Secondary	Change From Baseline in the Current Pain Intensity Score	The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine", a higher score indicates more pain.	Baseline to Week 12 and Week 26
Secondary	Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score	Participants with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment.	Baseline, at Week 12 and Week 26
Secondary	Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score	Participants with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment.	Baseline, at Week 12 and Week 26
Secondary	Patient Global Impression of Change (PGIC) at Week 12	The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.	at Week 12
Secondary	Patient Global Impression of Change (PGIC) at Week 26	The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from "very much improved" to "very much worse". A response of "very much improved" or "much improved" is generally regarded as a clinically important improvement.	at Week 26
Secondary	Change in the Pain Interference Score of the Brief Pain Inventory (BPI)	The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities.	Baseline to Week 12 and Week 26