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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03530345




Registration number
NCT03530345
Ethics application status
Date submitted
7/05/2018
Date registered
21/05/2018

Titles & IDs
Public title
Efficacy and Safety of Intravenous Neridronic Acid in CRPS
Scientific title
Randomized, Double-blind, Placebo-controlled Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome (CRPS)
Secondary ID [1] 0 0
2016-003833-91
Secondary ID [2] 0 0
KF7013-02
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Complex Regional Pain Syndrome (CRPS) 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Neridronic acid 100 mg
Treatment: Drugs - Placebo

Experimental: Neridronic acid - Neridronic acid 100 mg - 4 intravenous (i.v.) infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The investigational medicinal product (IMP) was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.

The maximum neridronic acid dose was 800 mg: 400 mg in Treatment Period A and 400 mg in Treatment Period B.

Placebo comparator: Placebo - Matching placebo - 4 intravenous infusions within 10 days (i.e., on Days 1, 4, 7, and 10). The IMP was diluted in sterile normal saline to a volume of approximately 500 mL before slow administration.


Treatment: Drugs: Neridronic acid 100 mg
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.

Treatment: Drugs: Placebo
Glass vials with matching placebo.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
Timepoint [1] 0 0
From the Baseline Phase (Day -7 to Day -1) to Week 12
Secondary outcome [1] 0 0
Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer.
Timepoint [1] 0 0
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Secondary outcome [2] 0 0
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.
Timepoint [2] 0 0
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Secondary outcome [4] 0 0
Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA).
Timepoint [4] 0 0
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Secondary outcome [5] 0 0
Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle.
Timepoint [5] 0 0
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Secondary outcome [6] 0 0
Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb.
Timepoint [6] 0 0
From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/05/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
31/07/2019
Sample size
Target
Accrual to date
Final
182
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
AU002 - Royal North Shore Hospital Michael J Cousins Pain Management and Research Centre - St Leonards
Recruitment hospital [2] 0 0
AU005 - Port Kembla Public Hospital - Wollongong
Recruitment hospital [3] 0 0
AU003 - Neuro Trials Victoria Pty Ltd - Noble Park
Recruitment hospital [4] 0 0
AU001 - The Avenue Cardiovascular Centre Level 1 Masada Private Hospital - St Kilda East
Recruitment postcode(s) [1] 0 0
2065 - St Leonards
Recruitment postcode(s) [2] 0 0
2502 - Wollongong
Recruitment postcode(s) [3] 0 0
3174 - Noble Park
Recruitment postcode(s) [4] 0 0
3183 - St Kilda East
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
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Arizona
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United States of America
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Arkansas
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United States of America
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California
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Colorado
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Florida
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Georgia
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Illinois
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Kentucky
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Massachusetts
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Michigan
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Mississippi
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Missouri
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New Jersey
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New York
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North Carolina
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Ohio
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Oklahoma
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Pennsylvania
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South Carolina
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Texas
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Utah
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United States of America
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Virginia
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France
State/province [24] 0 0
Amiens Cedex 1
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France
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Grenoble
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France
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Nantes Cedex 2
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Germany
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Bad Homburg
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Germany
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Berlin
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Germany
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Cottbus
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Germany
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Hamburg
Country [31] 0 0
Germany
State/province [31] 0 0
Hannover
Country [32] 0 0
Germany
State/province [32] 0 0
Mainz
Country [33] 0 0
Germany
State/province [33] 0 0
Schwerin
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Daejeon
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Korea, Republic of
State/province [35] 0 0
Seongnam-si
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Korea, Republic of
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Seoul
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Korea, Republic of
State/province [37] 0 0
Suwon
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New Zealand
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Auckland
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New Zealand
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BAY OF Plenty
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New Zealand
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Canterbury
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Spain
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Alicante
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Puerto Real
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Spain
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Sevilla
Country [46] 0 0
Spain
State/province [46] 0 0
Valencia
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Spain
State/province [47] 0 0
Xativa

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Grünenthal GmbH
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Grünenthal Study Director
Address 0 0
Grünenthal GmbH
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Information available on the Grünenthal Group Web Site (see URL below for details); according to the European Federation of Pharmaceutical Industries and Associations (EFPIA) Data Sharing Principles.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP)
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://www.grunenthal.com/r-d-vision-mission/clinical-trials/data-sharing-clinical-trials


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT03530345