Clinical trial NCT02972359: Safety of Intravenous Neridronic Acid in CRPS
Official title: Open-label Safety Trial of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complex Regional Pain Syndrome
Keywords: Neridronic Acid
Neridronate
CRPS
RSD (reflex sympathetic dystrophy)
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
First posted: 2016-11-23
Enrollment: 580
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.
* 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.

Primary outcomes:
measure: Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE)
timeFrame: Day 1 to Week 52
Secondary outcomes:
measure: Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event
timeFrame: Day 1 to Day 10
measure: Change From Baseline in the Current Pain Intensity Score
timeFrame: Baseline to Week 12 and Week 26
measure: Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score
timeFrame: Baseline, at Week 12 and Week 26
measure: Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score
timeFrame: Baseline, at Week 12 and Week 26
measure: Patient Global Impression of Change (PGIC) at Week 12
timeFrame: at Week 12
measure: Patient Global Impression of Change (PGIC) at Week 26
timeFrame: at Week 26
measure: Change in the Pain Interference Score of the Brief Pain Inventory (BPI)
timeFrame: Baseline to Week 12 and Week 26
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: US017: Cactus Clinical Research, Inc.
state: Arizona
city: Tucson
country: United States
facility: US028: Quality of Life Medical and Research Centers LLC
state: Arizona
city: Little Rock
country: United States
facility: US045: Woodland International Research Group
state: Arkansas
city: Rogers
country: United States
facility: US044: Woodland Research Northwest
state: Arkansas
city: Anaheim
country: United States
facility: US012: Orange County Research Institute
state: California
city: Cerritos
country: United States
facility: US022: Core Healthcare Group
state: California
city: Laguna Hills
country: United States
facility: US033: Alliance Research Centers
state: California
city: Laguna Woods
country: United States
facility: US027: The Helm Center for Pain Management
state: California
city: Los Gatos
country: United States
facility: US003: Samaritan Center for Medical Research
state: California
city: Montclair
country: United States
facility: US010: Catalina Research Institute, LLC
state: California
city: Sacramento
country: United States
facility: US014: Northern California Research
state: California
city: Denver
country: United States
facility: US034: Mountain View Clinical Research, Inc.
state: Colorado
city: Clermont
country: United States
facility: US032: South Lake Pain Institute
state: Florida
city: Miami
country: United States
facility: US001: Sunrise Research Institute, Inc
state: Florida
city: Miami
country: United States
facility: US046: AMPM Research Clinic
state: Florida
city: Orlando
country: United States
facility: US035: Compass Research
state: Florida
city: Plantation
country: United States
facility: US031: Gold Coast Research, LLC
state: Florida
city: Tampa
country: United States
facility: US011: Clinical Research of West Florida, Inc.
state: Florida
city: West Palm Beach
country: United States
facility: US040: Palm Beach Research Center
state: Florida
city: Newnan
country: United States
facility: US026: Better Health Clinical Research Inc.
state: Georgia
city: Chicago
country: United States
facility: US004: Northwestern University - Feinberg School of Medicine - Rehabilitation Institute of Chicago (RIC)
state: Illinois
city: Chicago
country: United States
facility: US036: University Anesthesiologists, S.C.
state: Illinois
city: Chicago
country: United States
facility: US029: Great Lakes Clinical Trials LLC
state: Illinois
city: Overland Park
country: United States
facility: US005: International Clinical Research Institute
state: Kansas
city: Saint Louis
country: United States
facility: US037: St. Louis Clinical Trials, LC
state: Missouri
city: Omaha
country: United States
facility: US051: Creighton University, Osteoporosis Research Center
state: Nebraska
city: Princeton
country: United States
facility: US002: Princeton Medical Institute
state: New Jersey
city: Shrewsbury
country: United States
facility: US049: Premier Pain Centers, LLC
state: New Jersey
city: Albany
country: United States
facility: US048: Albany Medical College
state: New York
city: Rochester
country: United States
facility: US043: Translational Pain Research, University of Rochester
state: New York
city: Winston-Salem
country: United States
facility: US009: The Center for Clinical Research, LLC
state: North Carolina
city: Middleburg Heights
country: United States
facility: US016: North Star Medical Research, LLC
state: Ohio
city: Oklahoma City
country: United States
facility: US007: Medical Research International
state: Oklahoma
city: Willow Grove
country: United States
facility: US006: Abington Neurological Associates, LTD.
state: Pennsylvania
city: Charleston
country: United States
facility: US020: Clinical Trials of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: US038: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: US019: Austin Center for Clinical Research
state: Texas
city: Houston
country: United States
facility: US008: Pioneer Research Solutions
state: Texas
city: Salt Lake City
country: United States
facility: US023: Axios Research, LLC
state: Utah
city: Bellevue
country: United States
facility: US018: Washington Center for Pain Management
state: Washington
city: Bellevue
country: United States
facility: US015: Northwest Clinical Research Center
state: Washington
city: Seattle
country: United States
facility: US013: Swedish Pain Services/ Research Institute
state: Washington
city: Hannover
country: Germany
facility: DE001: Klinische Forschung Hannover-Mitte GmbH
city: Hannover
country: Germany
facility: DE004: Schmerzambulanz Medizinishe Hochschule Hannover
city: Leipzig
country: Germany
facility: DE006: AmBeNet GmbH
city: Würzburg
country: Germany
facility: DE002: Schmerztagesklinik der Anästhesiologie Universitätsklinikum Würzburg
Study officials:
affiliation: Grünenthal GmbH
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.