Complex Regional Pain Syndrome (CRPS)
Conditions
Keywords
Neridronic Acid, Neridronate, CRPS, reflex sympathetic dystrophy (RSD)
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.
Interventions
100 mg neridronic acid supplied in glass vials in 8 mL of excipients.
DRUGPlacebo
Glass vials with matching placebo.
Sponsors
Grünenthal GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Blinded treatment in Treatment Period A, open-label infusion in Treatment Period B.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary) | From the Baseline Phase (Day -7 to Day -1) to Week 12 | In the Baseline Phase and in Treatment Period A/Follow-up Period 1, participants were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = no pain to 10 = pain as bad as you can imagine and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 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). The number of participants with response at Week 12 was planned to be determined. |
| 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. | From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) | 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). The number of participants with response at Week 26 was planned to be determined. |
| Change From Baseline to Week 26 in the Average Pain Intensity Recorded on the Tablet Computer. | From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26) | 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). Changes from baseline to Week 26 were planned to be analyzed. |
| Change From Baseline to Week 12 in the Pressure Pain Threshold (PPT) Ratio for the Thenar Muscle/Abductor Hallucis Muscle. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 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 was planned to be calculated. |
| Change From Baseline to Week 12 in the Ratio of the Figure of Eight Measurements of the Affected Limb Versus the Unaffected Limb. | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 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 was planned to be calculated and used for the determination of the change from baseline. |
| Change From Baseline to Week 12 in the Pain Intensity Level of Dynamic Mechanical Allodynia (DMA). | From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12) | 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. Change from baseline was planned to analyzed. |
Countries
Australia, France, Germany, New Zealand, South Korea, Spain, United States
Participant flow
Recruitment details
First participant enrollment on 30 May 2018. After a pooled interim analysis of primary endpoint data of studies KF7013-02 and KF7013-04 (NCT03560986), recruitment was stopped as interim results indicated futility. Last participant's last assessment was on 31 July 2019.
Pre-assignment details
182 participants were enrolled (signed consent), 57 were allocated to treatment and received study medication. Of 125 participants not allocated, 95 did not meet inclusion/met exclusion criteria, 1 was lost to follow-up, 9 withdrew consent, 1 experienced technical problems, and 19 were not allocated for other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Neridronic Acid - Treatment Period A Neridronic acid 400 mg administered by 4 intravenous infusions within 10 Days in Treatment Period A. | 28 |
| Placebo - Treatment Period A Matching placebo administered by 4 intravenous infusions within 10 Days in Treatment Period A. | 29 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period A/Follow-up Period 1 | Lost to Follow-up | 1 | 0 |
| Treatment Period A/Follow-up Period 1 | Other reasons for discontinuation | 17 | 21 |
| Treatment Period A/Follow-up Period 1 | Withdrawal by Subject | 3 | 1 |
| Treatment Period B/Follow-up Period 2 | Other reasons for discontinuation | 5 | 7 |
Baseline characteristics
| Characteristic | Neridronic Acid - Treatment Period A | Total | Placebo - Treatment Period A |
|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 11 | 47.8 years STANDARD_DEVIATION 11.6 | 49.4 years STANDARD_DEVIATION 12.1 |
| Age, Customized < 18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 85 years and above | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 18 to <65 years | 28 Participants | 53 Participants | 25 Participants |
| Age, Customized From 65 to <85 years | 0 Participants | 4 Participants | 4 Participants |
| Complex regional pain syndrome (CRPS) type CRPS Type I | 25 Participants | 46 Participants | 21 Participants |
| Complex regional pain syndrome (CRPS) type CRPS Type II | 3 Participants | 11 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 52 Participants | 28 Participants |
| Region of Enrollment Australia | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Germany | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment New Zealand | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment South Korea | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Spain | 3 Participants | 8 Participants | 5 Participants |
| Region of Enrollment United States | 22 Participants | 44 Participants | 22 Participants |
| Sex: Female, Male Female | 22 Participants | 44 Participants | 22 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 7 Participants |
| Time since diagnosis of CRPS | 9.15 months | 10.37 months | 11.37 months |
| Time since onset of CRPS symptoms | 17.72 months | 14.23 months | 13.47 months |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 28 | 0 / 22 | 0 / 7 | 0 / 23 | 0 / 5 |
| other Total, other adverse events | 15 / 29 | 16 / 28 | 0 / 22 | 3 / 7 | 1 / 23 | 0 / 5 |
| serious Total, serious adverse events | 0 / 29 | 2 / 28 | 0 / 22 | 0 / 7 | 0 / 23 | 0 / 5 |
Outcome results
Primary
Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary)
In the Baseline Phase and in Treatment Period A/Follow-up Period 1, participants were asked to assessed their average CRPS-related pain on an 11-point numerical rating scale (NRS) - from 0 = no pain to 10 = pain as bad as you can imagine and report it once daily (in the evening, 24-hour recall) in an electronic diary. Changes from baseline (average for the Baseline Phase) to the weekly average for Week 12 were calculated.
Time frame: From the Baseline Phase (Day -7 to Day -1) to Week 12
Population: Full Analysis Set; all participants treated in Treatment Period A with all data available at the time of last participant out following premature study termination.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Neridronic Acid - Treatment Period A | Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary) | -1.23 units on a scale | Standard Error 0.31 |
| Placebo - Treatment Period A | Change From Baseline to Week 12 in the Average Pain Intensity Score (Weekly Average of Pain Values Recorded Daily in the Electronic Diary) | -0.16 units on a scale | Standard Error 0.305 |
Comparison: Mixed-effects model for repeated measures (MMRM) defined with baseline pain intensity as covariate, the factors geographic region, week, treatment and treatment-by-week as fixed effects, and an unstructured covariance matrix to model the covariance structure of the repeated measurements.p-value: 0.011195% CI: [-1.89, -0.26]Mixed Models Analysis
Secondary
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. Change from baseline was planned to analyzed.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.
Secondary
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 was planned to be calculated.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.
Secondary
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 was planned to be calculated and used for the determination of the change from baseline.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.
Secondary
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). Changes from baseline to Week 26 were planned to be analyzed.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.
Secondary
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). The number of participants with response at Week 12 was planned to be determined.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 8 (Week 12)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.
Secondary
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). The number of participants with response at Week 26 was planned to be determined.
Time frame: From baseline (Visit 2 [Day 1]) to Visit 11 (Week 26)
Population: Data were not collected or analyzed because a confirmatory testing strategy was not performed as pre-specified in the protocol that secondary endpoints would only be tested if neridronic acid was superior to placebo on the primary outcome measure. A confirmatory or descriptive analysis was not performed due to early study termination.