Safety of Intravenous Neridronic Acid in CRPS
Condition: Complex Regional Pain Syndrome
MeSH terms: Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Syndrome
Intervention: Neridronic acid
Intervention description: Neridronic acid administered as intravenous infusion.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 580.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neridronic Acid; Neridronate; CRPS; RSD (reflex sympathetic dystrophy)

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).
    

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.