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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT03530345
Ethics application status
Date submitted
7/05/2018
Date registered
8/05/2018
Date last updated
28/05/2019

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
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above
Neurological 0 0 0 0
Other neurological disorders

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

Experimental: Neridronic acid - Neridronic acid administered by 4 intravenous infusions within 10 Days

Placebo Comparator: Placebo - Matching placebo administered by 4 intravenous infusions within 10 Days


Treatment: Drugs: Neridronic acid
Neridronic acid administered by 4 intravenous infusions within 10 Days

Treatment: Drugs: Placebo
Matching placebo administered by 4 intravenous infusions within 10 Days

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). - 11-point numerical rating scale (NRS) - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported once daily (in the evening, 24-hour recall) in an electronic diary.
Timepoint [1] 0 0
Change 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. - 11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall).
Timepoint [1] 0 0
Change 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. - 11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall).
Timepoint [2] 0 0
Change 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. - 11-point NRS - from 0 = "no pain" to 10 = "pain as bad as you can imagine" - reported at the visits on a tablet computer (24-hour recall).
Timepoint [3] 0 0
Change 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). - Dynamic mechanical allodynia: a tactile stimulus is applied in a single sweeping motion (1 cm to 2 cm length) on the skin on the affected limb.
The participants are asked to judge the stimulus intensity by means of an NRS (0 to 10). "0" in this case means "no pain". Each "pricking", "stinging" or "burning" sensation is defined as a painful sensation, which should always be evaluated by giving a value greater than "0". "10" corresponds to the individual maximum pain imaginable.
Timepoint [4] 0 0
Change 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. - Pressure pain threshold: using a pressure algometer (contact area 1 cm2), the threshold for pressure-induced pain is measured on the thenar muscle/abductor hallucis muscle in 3 series of slowly increasing stimulus intensities (at a rate of about 50 kPa/s). The threshold is then determined as the arithmetic mean of the 3 series (in kPa).
The ratio of the thresholds of the affected limb versus the unaffected limb will be calculated.
Timepoint [5] 0 0
Change 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. - In participants with the CRPS sign of edema on the CRPS severity score at baseline, circumference of the hand or foot will be measured by the investigator with measurement tape using the figure-of-eight method at both the affected limb and the contralateral unaffected limb. Each measurement will be performed 3 times. The average of the 3 measurements will be used for further analysis.
The ratio of the averages of the affected limb versus the unaffected limb will be calculated.
Timepoint [6] 0 0
Change 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 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).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 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.

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
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
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
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United States of America
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Alabama
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Arizona
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Arkansas
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Colorado
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Florida
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United States of America
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Georgia
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Illinois
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Kentucky
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Louisiana
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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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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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Virginia
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France
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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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Berlin
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Germany
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Cottbus
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Germany
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Hamburg
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Germany
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Hannover
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Germany
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Mainz
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Germany
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Schwerin
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Germany
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Wiesbaden
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Germany
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Wuerzburg
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Korea, Republic of
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Daejeon
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Korea, Republic of
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Seongnam-si
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Korea, Republic of
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Seoul
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Korea, Republic of
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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
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Spain
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Torrevieja
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Spain
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Valencia
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Spain
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Xativa
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Ukraine
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Dnipro
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Ukraine
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Ivano-Frankivsk
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Ukraine
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Kharkiv
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Ukraine
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Kherson
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Ukraine
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Kyiv
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Ukraine
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Lviv
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Ukraine
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Vinnytsia

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

Ethics approval
Ethics application status

Summary
Brief summary
The aim of this trial is to investigate the efficacy and safety of intravenous neridronic
acid in subjects with Complex Regional Pain Syndrome (CRPS).

The trial consists 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 will continue in Follow-up Period 2 until Week 52. Participants meeting the
pre-specified criteria will enter the open-label Treatment Period B with 4 additional
infusions (neridronic acid) over 10 days and follow-up visits until Week 52.
Trial website
https://clinicaltrials.gov/show/NCT03530345
Trial related presentations / publications
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. Erratum in: Ann Intern Med. 2011 Sep 20;155(6):408.
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
Grünenthal Clinical Trial Helpdesk
Address 0 0
Country 0 0
Phone 0 0
+49 241 569 3223
Fax 0 0
Email 0 0
Clinical-Trials@grunenthal.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03530345