Clinical trial NCT03530345: Efficacy and Safety of Intravenous Neridronic Acid in CRPS
Official title: Randomized, Double-blind, Placebo-controlled Trial Investigating the Efficacy and Safety 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: 2018-05-21
Enrollment: 182
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 or placebo) over 10 days, and a Follow-up Period 1 until Week 26.

At Week 26, participants not meeting the pre-specified criteria to continue into Treatment Period B continued in Follow-up Period 2 until Week 52. 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.


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.
* 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 severe 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 (2 repeat laboratory tests are 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 (e.g., citalopram, escitalopram) are eligible if the QT interval values do not meet the exclusion criteria, the medication was started at least 1 month prior to Visit 1, 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.
* 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 severe 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 or magnesium 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. One repeat laboratory test is 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 (with a minimum interval of 3 days).
* 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: Huntsville
country: United States
facility: US015 - Tennessee Valley Pain Consultants
state: Alabama
city: Mobile
country: United States
facility: US043 - Horizon Research Partners
state: Alabama
city: Peoria
country: United States
facility: US045 - Holland Center for Family Health
state: Arizona
city: Hot Springs
country: United States
facility: US003 - HealthStar Research
state: Arkansas
city: Anaheim
country: United States
facility: US049 - Orange County Research Institute
state: California
city: Cerritos
country: United States
facility: US053 - Core Healthcare Group
state: California
city: Colton
country: United States
facility: US013 - Inland Pain Medicine
state: California
city: Laguna Woods
country: United States
facility: US044 - The Helm Center for Pain Management
state: California
city: West Covina
country: United States
facility: US052 - Providere' Research Inc.
state: California
city: Greenwood Village
country: United States
facility: US036 - Denver Back Pain Specialists
state: Colorado
city: Boca Raton
country: United States
facility: US007 - Neurology Offices of South Florida
state: Florida
city: Fort Myers
country: United States
facility: US030 - Gulfcoast Clinical Research Center
state: Florida
city: Kissimmee
country: United States
facility: US004 - The Chappel Group Research
state: Florida
city: Lake Worth
country: United States
facility: US023 - AGR Research
state: Florida
city: Ocala
country: United States
facility: US020 - SIMEDHealth
state: Florida
city: Panama City
country: United States
facility: US012 - NeuroMedical Research Center
state: Florida
city: Tampa
country: United States
facility: US046 - Clinical Research of West Florida, Inc.
state: Florida
city: Marietta
country: United States
facility: US027 - Drug Studies America
state: Georgia
city: Newnan
country: United States
facility: US041 - Better Health Clinical Research, Inc.
state: Georgia
city: Bloomington
country: United States
facility: US032 - Millennium Pain Center
state: Illinois
city: Edgewood
country: United States
facility: US011 - Otrimed Corporation
state: Kentucky
city: North Attleboro
country: United States
facility: US040 - Regeneris Medical
state: Massachusetts
city: Flint
country: United States
facility: Us054 - Aa Mrc
state: Michigan
city: Troy
country: United States
facility: US025 - Oakland Medical Research
state: Michigan
city: Jackson
country: United States
facility: US009 - Elite Clinical Research
state: Mississippi
city: Jackson
country: United States
facility: US017 - Jackson Anesthesia Pain Center
state: Mississippi
city: Chesterfield
country: United States
facility: US033 - Galen Research
state: Missouri
city: Shrewsbury
country: United States
facility: US050 - Premier Pain Centers
state: New Jersey
city: Amherst
country: United States
facility: US029 - Dent Neurologic Institute
state: New York
city: North Massapequa
country: United States
facility: US038 - DiGiovanna Institute For Medical Education
state: New York
city: Charlotte
country: United States
facility: US022 - The Neurological Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: US047 - The Center for Clinical Research
state: North Carolina
city: Dayton
country: United States
facility: US005 - Hometown Urgent Care and Research
state: Ohio
city: Oklahoma City
country: United States
facility: US021 - SP Research PLLC
state: Oklahoma
city: Philadelphia
country: United States
facility: US028 - Founders Research Corporation
state: Pennsylvania
city: Spartanburg
country: United States
facility: US018 - Carolinas Center for Advanced Management of Pain
state: South Carolina
city: Houston
country: United States
facility: US055 - Diversified Medical Practices
state: Texas
city: Salt Lake City
country: United States
facility: US048 - Axios Research
state: Utah
city: Richmond
country: United States
facility: US037 - Clinical Research Partners
state: Virginia
city: St Leonards
country: Australia
facility: AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre
state: New South Wales
city: Wollongong
country: Australia
facility: AU005 - Port Kembla Public Hospital
state: New South Wales
city: Noble Park
country: Australia
facility: AU003 - Neuro Trials Victoria Pty Ltd
state: Victoria
city: St Kilda East
country: Australia
facility: AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital
state: Victoria
city: Amiens Cedex 1
country: France
facility: FR004 - Centre Hospitalier Universitaire Amiens Picardie
city: Grenoble
country: France
facility: FR001 - Centre Hospitalier Universitaire Grenoble Alpes Centre de la douleur
city: Nantes Cedex 2
country: France
facility: FR002 - L'Hôpital Privé du Confluent Département d'évaluation et traitement de la douleur
city: Bad Homburg
country: Germany
facility: DE006 - Center for Clinical Research Dr. med. I. Schoel
city: Berlin
country: Germany
facility: DE011 - Klinische Forschung Berlin Mitte GmbH
city: Cottbus
country: Germany
facility: DE009 - BAG Anästhesie, Schmerztherapie, Palliativmedizin
city: Hamburg
country: Germany
facility: DE002 - Klinische Forschung Hamburg GmbH
city: Hannover
country: Germany
facility: DE010 - Klinische Forschung Hannover Mitte
city: Mainz
country: Germany
facility: DE013 - Klinik und Poliklinik für Neurologie Universitätsmedizin Mainz
city: Schwerin
country: Germany
facility: DE005 - Klinische Forschung Schwerin GmbH
city: Daejeon
country: Korea, Republic of
facility: KR008 - Chungnam National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: KR003 - Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: KR002 - Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: KR005 - Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: KR007 - Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: KR004 - Seoul St Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: KR006 - Korea University Guro Hospital
city: Suwon
country: Korea, Republic of
facility: KR001 - Ajou University Medical Center
city: Grafton
country: New Zealand
facility: NZ004 - Optimal Clinical Trials
state: Auckland
city: Tauranga
country: New Zealand
facility: Nz001 - Bay of Plenty Clinical Trials Unit, Bay of Plenty District Health Board
state: BAY OF Plenty
city: Christchurch
country: New Zealand
facility: NZ002 - Southern Clinical Trials Group Ltd
state: Canterbury
city: Alicante
country: Spain
facility: ES009 - General Hospital of Alicante
city: Barcelona
country: Spain
facility: ES002 - Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: ES005 - Hospital Sanitas La Moraleja Pain Unit
city: Puerto Real
country: Spain
facility: ES004 - Hospital Universitario Puerto Real Unidad de Anestesiologia
city: Sevilla
country: Spain
facility: ES006 - Hospital Infanta Luisa Rheumatology
city: Valencia
country: Spain
facility: ES007 - Hospital Clínico Universitario de Valencia
city: Xativa
country: Spain
facility: ES008 - Hospital Lluis Alcanyis Anesthesiology and Pain Unit
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.