Clinical trial NCT03560986: Efficacy and Safety of Intravenous Neridronic Acid in Complex Regional Pain Syndrome (CRPS)
Official title: Placebo-controlled Efficacy and Safety Trial of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Complex Regional Pain Syndrome (CRPS)
Keywords: Neridronic Acid
Neridronate
CRPS
Reflex sympathetic dystrophy (RSD)
Lead sponsor: Grünenthal GmbH
Sponsor class: INDUSTRY
First posted: 2018-06-19
Enrollment: 267
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
timeFrame: From the Baseline Phase (Day -7 to Day -1) to Week 12
Secondary outcomes:
measure: Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
measure: 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
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
measure: 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
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
measure: Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA)
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
measure: Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
measure: Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb
timeFrame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Other outcomes:
Locations:
city: Cottonwood
country: United States
facility: US446 - Clinical Trial Connection
state: Arizona
city: Tempe
country: United States
facility: US453 - Physicians Research Group II, LLC
state: Arizona
city: Tucson
country: United States
facility: US428 - Quality of Life Medical and Research Center LLC
state: Arizona
city: Little Rock
country: United States
facility: US422 - Woodland International Research Group
state: Arkansas
city: Canoga Park
country: United States
facility: US454 - Alliance Research Institute
state: California
city: Canyon Country
country: United States
facility: US415 - Clearview Medical Research LLC
state: California
city: Laguna Hills
country: United States
facility: US410 - Alliance Research Centers
state: California
city: Lomita
country: United States
facility: US432 - Torrance Clinical Research Institute Inc.
state: California
city: Los Angeles
country: United States
facility: Us414 - Alexander Ford Md
state: California
city: Los Gatos
country: United States
facility: US441 - Samaritan Center for Medical Research
state: California
city: Santa Ana
country: United States
facility: US406 - CI Trials
state: California
city: Santa Ana
country: United States
facility: US411 - Syrentis Clinical Research
state: California
city: Denver
country: United States
facility: US420 - Mountain View Clinical Research, INC
state: Colorado
city: Brooksville
country: United States
facility: US447 - ASCLEPES Research Centers
state: Florida
city: Clearwater
country: United States
facility: US457 - Florida Spine Institute
state: Florida
city: Clermont
country: United States
facility: US430 - South Lake Pain Institute
state: Florida
city: Miami
country: United States
facility: US434 - Finlay Medical Research
state: Florida
city: Miami
country: United States
facility: US407 - Oceane 7 Medical and Research Center, Inc.
state: Florida
city: Miami
country: United States
facility: US436 - Cordova Research Institute
state: Florida
city: Tampa
country: United States
facility: US417 - Tampa Pain Relief Center
state: Florida
city: West Palm Beach
country: United States
facility: US403 - Palm Beach Research Center
state: Florida
city: Riverdale
country: United States
facility: US404 - Infinite Clinical Trials
state: Georgia
city: Suwanee
country: United States
facility: US424 - Georgia Neurology and Sleep Medicine Assoc.
state: Georgia
city: Boise
country: United States
facility: US431 - Injury Care Research, LLC
state: Idaho
city: Chicago
country: United States
facility: US437 - Great Lakes Clinical Trials LLC
state: Illinois
city: Lake Charles
country: United States
facility: US435 - Centex Studies Inc
state: Louisiana
city: Wheaton
country: United States
facility: US448 - The Center for Rheumatology and Bone Research
state: Maryland
city: Plymouth
country: United States
facility: US450 - SRI International
state: Michigan
city: Wyoming
country: United States
facility: US449 - Michigan Pain Consultants
state: Michigan
city: Omaha
country: United States
facility: US433 - Creighton University - Osteoporosis Research Center
state: Nebraska
city: New York
country: United States
facility: US419 - Manhattan Behavioral Medicine
state: New York
city: Charlotte
country: United States
facility: US440 - OnSite Clinical Solutions LLC
state: North Carolina
city: Hickory
country: United States
facility: US405 - OnSite Clinical Solutions LLC
state: North Carolina
city: Oklahoma City
country: United States
facility: US416 - Medical Research International
state: Oklahoma
city: Allentown
country: United States
facility: US429 - Lehigh Valley Health
state: Pennsylvania
city: Willow Grove
country: United States
facility: US438 - Abington Neurological Associates, LTD.
state: Pennsylvania
city: Greenville
country: United States
facility: US425 - PCPMG Clinical Research Unit LLC
state: South Carolina
city: Houston
country: United States
facility: US423 - Biopharma Informatic Inc. Research Center
state: Texas
city: Houston
country: United States
facility: US443 - Centex Studies Inc
state: Texas
city: Bellevue
country: United States
facility: US421 - Northwest Clinical Research Center
state: Washington
city: Morgantown
country: United States
facility: US445 - Exemplar Research Inc
state: West Virginia
city: Markham
country: Canada
facility: CA404 - Jeffrey Weinberg Medicine Professional Corporation c/o Jacobs Pain Center
state: Ontario
city: Mississauga
country: Canada
facility: CA406 - Malton Medical Centre (attn: Vrijender Singh)
state: Ontario
city: Newmarket
country: Canada
facility: CA402 - SKDS Research Inc
state: Ontario
city: Oshawa
country: Canada
facility: CA407 - King Street Medical Clinic
state: Ontario
city: Sarnia
country: Canada
facility: CA403 - Bluewater Clinical Research Group
state: Ontario
city: Thornhill
country: Canada
facility: CA405 - Canadian Centre for Clinical TrialsCCCT
state: Ontario
city: Ostrava
country: Czechia
facility: CZ403 - CCBR Ostrava
city: Pardubice
country: Czechia
facility: CZ402 - CCR Czech a,s.
city: Prague 6
country: Czechia
facility: CZ401 - FORBELI s.r.o.
city: Elblag
country: Poland
facility: PL405 - Medical Solutions
city: Lublin
country: Poland
facility: PL404 - Zagiel Med Sp Zoo
city: Tarnów
country: Poland
facility: PL403 - Alergo-Med Specjalistyczna Przychodnia Lekarska Sp.z o.o
city: Belgrade
country: Serbia
facility: RS401 - Clinical Center of Serbia, Clinic for physical medicine and rehabilitation
city: Kragujevac
country: Serbia
facility: RS403 - Clinical Center Kragujevac, Department of Physical Medicine and rehabilitation
city: Nis
country: Serbia
facility: RS404 - Clinical Center Nis, Clinic for Physical Medicine and Rehabilitation
city: Novi Sad
country: Serbia
facility: RS405 - Clinical Center of Vojvodina, Medical Rehabilitation Clinic
city: Banska Bystrica
country: Slovakia
facility: SK402 - MUDr. Beata Dupejova, neurologicka ambulancia sro
city: Dubnica nad Vahom
country: Slovakia
facility: SK404 - Medical Center Konzilium
city: Krompachy
country: Slovakia
facility: SK403 - NEURES, s.r.o.
city: Pruske
country: Slovakia
facility: SK401 - MUDr. Viliam Cíbik, PhD, Algeziologická ambulancia
city: Barnsley
country: United Kingdom
facility: GB413 - MAC Clinical Research
city: Blackpool
country: United Kingdom
facility: GB412 - MAC Clinical Research
city: Cannock
country: United Kingdom
facility: GB415 - MAC Clinical Research
city: Exeter
country: United Kingdom
facility: GB416 - Royal Devon and Exeter Hospital
city: Leeds
country: United Kingdom
facility: GB410 - MAC Clinical Research
city: Liverpool
country: United Kingdom
facility: GB409 - MAC Clinical Research
city: London
country: United Kingdom
facility: GB407 - Pain and Neuromodulation Centre Ground Floor, Gassiot House, St Thomas Hospital
city: London
country: United Kingdom
facility: GB402 - St Pancras Clinical Research
city: Manchester
country: United Kingdom
facility: GB408 - MAC Clinical Research
city: Stockton-on-Tees
country: United Kingdom
facility: GB414 - MAC Clinical Research
Study officials:
affiliation: Grünenthal GmbH
name: Grünenthal 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.