Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)
Condition: Complex Regional Pain Syndrome (CRPS)
MeSH terms: Complex Regional Pain Syndromes; Reflex Sympathetic Dystrophy; Syndrome; Somatoform Disorders
Intervention: Neridronic acid 100 mg; Placebo
Intervention description: 100 mg neridronic acid supplied in glass vials in 8 mL of excipients.; Glass vials with matching placebo.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Blinded treatment in Treatment Period A, open-label infusion in Treatment Period B.
Enrollment: 267.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Neridronic Acid; Neridronate; CRPS; Reflex sympathetic dystrophy (RSD)

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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).

        Exclusion Criteria:

          -  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.

          -  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 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 throughout the trial.

          -  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.

          -  Participation in another investigational drug trial within 3 months prior to Visit 1,
             or any previous trial involving neridronic acid, with the exception of participants
             participating in study 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 giving informed consent.

        Criteria to continue into Treatment Period B

          -  A value of at least 4 on the pain intensity question (question number 29, GLOBAL07) of
             the Patient-Reported Outcomes Measurement Information System (PROMIS®) (PROMIS-29
             profile) at Visit 11.

          -  The following exclusion criteria are not met:

               -  Evidence of renal impairment (eGFR less than 30 mL/min/1.73 m2 using the 2009
                  CKD-EPI creatinine equation [Levey et al. 2009] or a urinary ACR greater than 150
                  mg/g), based on central safety laboratory data obtained prior to Visit 11. A
                  single repeat laboratory test is allowed.

               -  Corrected QT interval (QTcF) greater than 470 ms (average of 3 ECGs obtained at
                  Visit 10) according to the central ECG reading facility evaluation or QTcF
                  greater than 470 ms at pre-dose ECG at Visit 11 according to the investigator's
                  judgment; serum potassium outside the central laboratory's reference range at
                  Visit 10 (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; 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 re-allocation.

               -  Participants taking forbidden concomitant medications/therapies or not being able
                  to follow the rules of use of concomitant treatment.

               -  Recent tooth extraction or other invasive dental procedure (within 3 months prior
                  to Visit 11), 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 further course of the trial.

               -  Serum calcium outside of the central laboratory's reference range, despite
                  appropriate supplementation between Visit 10 and Visit 11, based on the last
                  central safety laboratory data obtained prior to Visit 11. Two repeat laboratory
                  tests are allowed.

               -  Vitamin D deficiency prior to IMP re-allocation, defined as a 25(OH)D level less
                  than 30 ng/mL (75 nmol/L), based on the last central safety laboratory data
                  obtained prior to Visit 11, i.e., inability to normalize 25(OH)D levels to at
                  least 30 ng/mL (75 nmol/L) despite appropriate supplementation between Visit 10
                  and Visit 11. Two repeat laboratory tests are allowed.

               -  Elevated aspartate aminotransferase or alanine aminotransferase greater than
                  2-fold upper limit of normal, based on central safety laboratory data obtained at
                  Visit 10, or current evidence of chronic liver disease. A single repeat
                  laboratory test is allowed.

          -  No other criterion for trial and/or IMP discontinuation is met.