Complex Regional Pain Syndrome
Conditions
Keywords
Neridronic Acid, Neridronate, CRPS, RSD (reflex sympathetic dystrophy)
Brief summary
The aim of this trial was to investigate the safety of intravenous neridronic acid in patients with complex regional pain syndrome (CRPS). The trial was divided into 3 periods: a 60-day enrollment period, a treatment period consisting of 4 infusions over 10 days, and a follow-up period of approximately 50 weeks (with visits at Week 2, Week 6, Week 12, Week 26, Week 39, and Week 52).
Detailed description
At the Enrollment Visit the trial objectives, procedures, and risks were explained to the participants and the informed consent form was signed. Medical history was obtained, a physical examination was conducted, and other safety assessments were performed. Signs and symptoms of CRPS were assessed to confirm the diagnosis of CRPS according to the Budapest clinical criteria. Participants were trained to report their pain. Calcium and vitamin D supplementation were initiated to ensure sufficient vitamin D levels prior to treatment. Participants meeting all eligibility criteria received infusions of investigational medicinal product (IMP) during visits on Day 1, Day 4, Day 7, and Day 10. Flexibility of ±1 day was allowed for Day 4, Day 7, and Day 10 whilst ensuring a minimum period of 48 hours between infusions. During the treatment period and follow-up period, pain intensity ratings were captured at the site visits in a patient reported-outcome system.
Interventions
DRUGNeridronic acid
Neridronic acid administered as intravenous infusion.
Sponsors
Grünenthal GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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 complex regional pain syndrome 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. * Ongoing moderate to severe chronic pain, including a baseline current pain intensity score of greater than or equal to 4 using an 11-point Numerical Rating Scale, referring to the CRPS-affected limb, at Visit 2 (prior to dosing). * 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 trials of at least 2 treatments for CRPS, one of which must be a pharmacologic treatment. * Women of child-bearing potential must have a negative urine beta-human chorionic gonadotropin (β-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 (e.g., oral contraceptives or intrauterine device), 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 impairment).
Exclusion criteria
* Evidence of renal impairment (estimated glomerular filtration rate \[eGFR\] less than 60 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 creatinine ratio greater than 150 mg/g), based on central safety laboratory data obtained prior to Visit 2, or a history of chronic kidney disease. 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); concomitant use of drug(s) with known potential to cause hypocalcemia (e.g., aminoglycosides). * Vitamin D deficiency, defined as a 25(OH)D level less than 30 ng/mL, 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 must be documented prior to allocation to investigational medicinal product (IMP). * Corrected QT interval (according to Fridericia's formula; QTcF) greater than 470 ms (average of 3 electrocardiograms \[ECGs\] obtained at Visit 1); serum potassium outside the central laboratory's reference range at Visit 1; 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 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) or tricyclic antidepressants are eligible if the QT-interval values do not meet the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Day 1 to Week 52 | The primary endpoint of this trial was a binary endpoint assessing whether or not a participant experienced any TEAE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Current Pain Intensity Score | Baseline to Week 12 and Week 26 | The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = no pain and 10 = pain as bad as you can imagine, a higher score indicates more pain. |
| Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score | Baseline, at Week 12 and Week 26 | Participants with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment. |
| Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score | Baseline, at Week 12 and Week 26 | Participants with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment. |
| Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event | Day 1 to Day 10 | The investigator could choose to permanently discontinue a participant from treatment if continued exposure of the participant to neridronic acid could have posed an undue risk to the participant. |
| Patient Global Impression of Change (PGIC) at Week 26 | at Week 26 | The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from very much improved to very much worse. A response of very much improved or much improved is generally regarded as a clinically important improvement. |
| Change in the Pain Interference Score of the Brief Pain Inventory (BPI) | Baseline to Week 12 and Week 26 | The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities. |
| Patient Global Impression of Change (PGIC) at Week 12 | at Week 12 | The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from very much improved to very much worse. A response of very much improved or much improved is generally regarded as a clinically important improvement. |
Countries
Germany, United States
Participant flow
Recruitment details
The first participant was enrolled on 20 December 2016.
Pre-assignment details
A total of 580 participants signed an informed consent form, 318 participants hereof were allocated to treatment. Two of the allocated participants did not meet inclusion criteria/met exclusion criteria, thus 316 participants received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Neridronic Acid Neridronic acid 100 mg administered on Day 1, Day 4, Day 7, and Day 10, resulting in a total dose of neridronic acid 400 mg.
Neridronic acid: Neridronic acid administered as intravenous infusion. | 316 |
| Total | 316 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 1 |
| Overall Study | Incl. criteria not met/Exclusion met | 2 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 26 |
| Overall Study | Missing | 1 |
| Overall Study | Other reasons | 5 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 30 |
Baseline characteristics
| Characteristic | Neridronic Acid |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 26 Participants |
| Age, Categorical Between 18 and 65 years | 290 Participants |
| Age, Continuous | 47.4 years |
| Baseline current pain intensity 11-point NRS | 6.59 units on a scale STANDARD_DEVIATION 1.58 |
| Baseline Pain Interference score of the Brief Pain Inventory (BPI) | 7.3 units on a scale STANDARD_DEVIATION 1.75 |
| Body mass index (BMI) | 28.3 kg/m^2 STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 300 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 297 Participants |
| Region of Enrollment Germany | 8 participants |
| Region of Enrollment United States | 308 participants |
| Sex: Female, Male Female | 237 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 316 |
| other Total, other adverse events | 275 / 316 |
| serious Total, serious adverse events | 27 / 316 |
Outcome results
Primary
Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE)
The primary endpoint of this trial was a binary endpoint assessing whether or not a participant experienced any TEAE.
Time frame: Day 1 to Week 52
Population: Safety Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with TEAE | 277 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with serious TEAE | 27 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with non-serious TEAE | 275 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with unexpected TEAE | 267 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with related TEAE | 190 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with related serious TEAE | 3 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with TEAE leading to IMP discont. | 12 Participants |
| Neridronic Acid | Number of Participants With Occurrence of Any Treatment Emergent Adverse Event (TEAE) | Participants with TEAE leading to trial discont. | 6 Participants |
Secondary
Change From Baseline in the Current Pain Intensity Score
The current Complex Regional Pain Syndrome (CRPS)-related pain intensity score was captured at each visit using an 11-point numerical rating scale where 0 = no pain and 10 = pain as bad as you can imagine, a higher score indicates more pain.
Time frame: Baseline to Week 12 and Week 26
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Neridronic Acid | Change From Baseline in the Current Pain Intensity Score | Baseline to Week 26 | -1.57 units on a scale | Standard Deviation 2.45 |
| Neridronic Acid | Change From Baseline in the Current Pain Intensity Score | Baseline to Week 12 | -1.54 units on a scale | Standard Deviation 2.27 |
Secondary
Change in the Pain Interference Score of the Brief Pain Inventory (BPI)
The Brief Pain Inventory (BPI) Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants rated their interference of pain with general activity, walking, work, sleep and other activities in the past 24 hours, with possible ratings from 0 (does not interfere) to 10 (completely interferes). The BPI interference Score ranges from 0 to 10, with higher values indicating greater pain interference of daily activities.
Time frame: Baseline to Week 12 and Week 26
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Neridronic Acid | Change in the Pain Interference Score of the Brief Pain Inventory (BPI) | Baseline to Week 12 | -2.2 score on a scale | Standard Deviation 2.49 |
| Neridronic Acid | Change in the Pain Interference Score of the Brief Pain Inventory (BPI) | Baseline to Week 26 | -2.1 score on a scale | Standard Deviation 2.64 |
Secondary
Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event
The investigator could choose to permanently discontinue a participant from treatment if continued exposure of the participant to neridronic acid could have posed an undue risk to the participant.
Time frame: Day 1 to Day 10
Population: Safety Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neridronic Acid | Number of Participants With Occurrence of Permanent Discontinuation From Treatment Due to an Adverse Event | 12 Participants |
Secondary
Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score
Participants with at least a 30 percent decrease in the current pain intensity score were considered to have responded to treatment.
Time frame: Baseline, at Week 12 and Week 26
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neridronic Acid | Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score | At least 30% pain reduction - Week 12 | 105 Participants |
| Neridronic Acid | Number of Participants With Response to Treatment, Defined as at Least 30% Decrease From Baseline in the Current Pain Intensity Score | At least 30% pain reduction - Week 26 | 110 Participants |
Secondary
Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score
Participants with at least a 50 percent decrease in the current pain intensity score were considered to have responded to treatment.
Time frame: Baseline, at Week 12 and Week 26
Population: Full Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neridronic Acid | Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score | At least 50% pain reduction - Week 12 | 75 Participants |
| Neridronic Acid | Number of Participants With Response to Treatment, Defined as at Least 50% Decrease From Baseline in the Current Pain Intensity Score | At least 50% pain reduction - Week 26 | 74 Participants |
Secondary
Patient Global Impression of Change (PGIC) at Week 12
The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from very much improved to very much worse. A response of very much improved or much improved is generally regarded as a clinically important improvement.
Time frame: at Week 12
Population: Full Analysis Set; 286 out of 316 participants attended the visit at Week 12 and were asked to complete the PGIC questionnaire.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Very Much Improved | 31 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Much Improved | 71 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Minimally Improved | 98 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | No Change | 45 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Minimally Worse | 23 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Much Worse | 12 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Very Much Worse | 3 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 12 | Missing | 3 Participants |
Secondary
Patient Global Impression of Change (PGIC) at Week 26
The Patient Global Impression of Change (PGIC) is a self-reported measure of perceived change in overall condition since the start of the study. Participants selected one of seven responses ranging from very much improved to very much worse. A response of very much improved or much improved is generally regarded as a clinically important improvement.
Time frame: at Week 26
Population: Full Analysis Set; 273 out of 316 participants attended the visit at Week 26 and were asked to complete the PGIC questionnaire.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Very Much Improved | 38 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Much Improved | 58 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Minimally Improved | 84 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | No Change | 52 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Minimally Worse | 25 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Much Worse | 10 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Very Much Worse | 2 Participants |
| Neridronic Acid | Patient Global Impression of Change (PGIC) at Week 26 | Missing | 4 Participants |