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Efficacy and Safety of Intravenous Neridronic Acid in CRPS-I

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Grünenthal GmbH
ClinicalTrials.gov Identifier:
NCT02402530
First received: March 25, 2015
Last updated: November 11, 2016
Last verified: November 2016
  Purpose

This clinical trial is being conducted to demonstrate the efficacy of neridronic acid in the treatment of pain associated with complex regional pain syndrome type I (CRPS-I).

The trial is divided into 3 periods: a 60-day enrollment period, a 12-week trial period, and an extended follow-up period with visits at Month 6, Month 9, and Month 12. The extended follow-up period will be terminated for all participants after the last participant enrolled completes their Month 6 visit (Visit 9). The double-blind will be maintained throughout the 12-week trial period and extended follow-up period.


Condition Intervention Phase
Complex Regional Pain Syndrome, Type I Drug: Placebo Drug: Neridronic acid 62.5 mg Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind Trial Investigating the Efficacy and Safety of Intravenous Neridronic Acid in Subjects With Complex Regional Pain Syndrome Type I (CRPS-I)

Resource links provided by NLM:


Further study details as provided by Grünenthal GmbH:

Primary Outcome Measures:
  • Change in the Pain Intensity Score to Week 12. [ Time Frame: Baseline; Week 12 ]
    The Pain Intensity Score is the mean value of current pain intensity ratings, obtained twice-daily for 1 week, using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine". All pain intensity ratings for the primary endpoint will be in reference to the CRPS-affected limb.


Secondary Outcome Measures:
  • Response to treatment: Proportion of Participants With at Least 30 Percent Reduction in the Pain Intensity Score [ Time Frame: Baseline; Week 12 ]
    Participants with at least a 30 percent decrease in the Pain Intensity Score will be considered to have responded to treatment. The Pain Intensity Score is determined as for the primary endpoint.

  • Response to treatment: Proportion of Participants With at Least 50 Percent Reduction in the Pain Intensity Score [ Time Frame: Baseline; Week 12 ]
    Participants with at least a 50 percent decrease in the Pain Intensity Score will be considered to have responded to treatment. The Pain Intensity Score is determined as for the primary endpoint.

  • Change in the Brief Pain Inventory (BPI) Interference Score [ Time Frame: Baseline; Week 12 ]
    The BPI Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants will rate 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) [ Time Frame: Baseline; Week 12 ]
    The PGIC is a self-reported measure of perceived change in overall condition since the start of the study. Participants will select 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 outcome.

  • Change in the EuroQol-5 Dimension 5 Level (EQ-5D-5L) Index Score [ Time Frame: Baseline; Week 12 ]
    The EQ-5D-5L Index Score describes the participant's overall health status and is derived from self-reported scores in 5 health dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Participants will rate each dimension at one of 5 levels, with level 1 indicating the best health state (no problems) and level 5 indicating worst health state (e.g., unable to walk about). The EQ-5D-5L Index Score ranges from 0 to 1, with 0 representing death and 1.0 representing perfect health.

  • Change in the EuroQol Visual Analog Scale (EQ VAS) [ Time Frame: Baseline; Week 12 ]
    The EQ VAS is a self-reported measure of the participant's overall health "today". Participants will place a mark on a 20 cm vertical scale numbered from 0 to 100, with 0 labeled as "the worst health you can imagine" and 100 labeled as "the best health you can imagine". The EQ VAS ranges from 0 to 100, with higher scores representing better overall health.


Other Outcome Measures:
  • Change in the Worst Pain Intensity [ Time Frame: Baseline; Week 12 ]
    This will be determined as for the primary endpoint, using worst pain intensity ratings. Participants will rate their worst pain intensity during the previous 12 hours twice each day using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine". Worst pain intensity ratings are in reference to the CRPS-affected limb.

  • Change in the Average Pain Intensity [ Time Frame: Baseline; Week 12 ]
    This will be determined as for the primary endpoint, using average pain intensity ratings. Participants will rate their average pain intensity during the previous 12 hours twice each day using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine". Average pain intensity ratings are in reference to the CRPS-affected limb.

  • Change from Baseline in the Pain Intensity Scores at Each Week [ Time Frame: Baseline to Week 12 ]
    Pain Intensity Scores will be determined as for the primary endpoint using current pain intensity ratings obtained twice-daily. Mean values will be assessed during each of the first 12 weeks of the study.

  • Response to Treatment: Proportion of Participants with 0 to 100% Decrease in the Pain Intensity Score [ Time Frame: Baseline; Week 12 ]
    Pain Intensity Scores will be determined as for the primary endpoint using current pain intensity ratings obtained twice-daily. Participants will be considered to have responded to treatment using increments of 10% decrease in the Pain Intensity Score, starting from 0% (no decrease in the Pain Intensity Score), 10%, 20%, etc., to 100% (Pain Intensity Score at Week 12 = 0).

  • Response to Treatment: Proportion of Participants With at Least a 2 Point Decrease in the Pain Intensity Score [ Time Frame: Baseline; Week 12 ]
    Pain Intensity Scores will be determined as for the primary endpoint using current pain intensity ratings obtained twice-daily. Participants will be considered to have responded to treatment if they have at least a 2 point decrease in the Pain Intensity Score.

  • Change in the Pain Anxiety Symptom Scale (PASS) Total Score [ Time Frame: Baseline; Week 12 ]
    The PASS Total Score is the sum of 20 self-reported items in the PASS Questionnaire. Participants will rate each item in terms of its frequency, ranging from 0 (never) to 5 (always). The PASS Total Score ranges from 0 to 100, with higher scores indicating greater levels of pain-related anxiety.

  • Change in the Center for Epidemiological Studies Depression (CES-D) Scale Total Score [ Time Frame: Baseline; Week 12 ]
    The CES-D Total Score is the sum of 20 self-reported items comprising symptoms associated with depression. Participants will rate each item in terms of its frequency from "rarely or none of the time (less than 1 day)" to "most or all of the time (5 to 7 days)" during the last week. The CES-D Total Score ranges from 0 to 60, with a score over 21 indicating the possibility of major depression.

  • Change in Pain Disability Index (PDI) [ Time Frame: Baseline; Week 6; Week 12 ]
    The PDI is the sum of self-reported ratings of disability in 7 categories of activities, including family/home responsibilities, recreation, social activity, self-care, etc. Participants will rate the level of disability that they typically experience due to pain in each of the 7 categories. Ratings are made using a numeric rating scale, with 0 indicating "no disability" and 10 indicating "worst disability". The PDI ranges from 0 to 70, with higher values indicating greater disability due to pain.

  • Change in the Medical Outcomes Study (MOS) Sleep Scale: Sleep Problems Index [ Time Frame: Baseline; Week 6; Week 12 ]
    The MOS Sleep Scale Sleep Problems Index is derived from participant's responses to questions related to sleep adequacy, sleep disturbance, daytime somnolence, and other aspects of sleep. Participants will respond to 12 questions in the MOS Sleep Scale Questionnaire. Responses are scored, summed and converted to a 0 to 100 scale, with higher scores indicating worse sleep problems.

  • Change in Pain Medication Score [ Time Frame: Baseline; Week 6; Week 12; Month 6; Month 9; Month 12 ]
    The Pain Medication Score will be derived using the Medication Quantification Scale (MQS III) and is based entirely on information available from the participant's prior and concomitant medications. The MQS III algorithm derives a single numerical value representing the amount of pain medications taken by each participant, taking into account the medication class and dosage.

  • Change in the Current Pain Intensity in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    Participants will rate their current CRPS-related pain intensity at each visit in the extended follow-up period using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine".

  • Change in the Average Pain Intensity in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    Participants will rate their average CRPS-related pain intensity, recalled over the last 24 hours, at each visit in the extended follow-up period using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine".

  • Change in the Worst Pain Intensity in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    Participants will rate their worst CRPS-related pain intensity, recalled over the last 24 hours, at each visit in the extended follow-up period using an 11-point numerical rating scale where 0 = "no pain" and 10 = "pain as bad as you can imagine".

  • Change in the BPI Interference Score in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    The BPI Interference Score is the mean value of 7 self-reported items in question 9 of the BPI Short Form Questionnaire. Participants will rate 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.

  • PGIC in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    The PGIC is a self-reported measure of perceived change in overall condition since the start of the study. Participants will select 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 outcome.

  • Change in the EQ-5D-5L Index Score in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    The EQ-5D-5L Index Score describes the participant's overall health status and is derived from self-reported scores in 5 health dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Participants will rate each dimension at one of 5 levels, with level 1 indicating the best health state (no problems) and level 5 indicating worst health state (e.g., unable to walk about). The EQ-5D-5L Index Score ranges from 0 to 1, with 0 representing death and 1.0 representing perfect health.

  • Change in the EQ VAS in the Extended Follow-up Period [ Time Frame: Baseline; Month 6; Month 9; Month 12 ]
    The EQ VAS is a self-reported measure of the participant's overall health "today". Participants will place a mark on a 20 cm vertical scale numbered from 0 to 100, with 0 labeled as "the worst health you can imagine" and 100 labeled as "the best health you can imagine". The EQ VAS ranges from 0 to 100, with higher scores representing better overall health.

  • Change in the Complex Regional Pain Syndrome (CRPS) Severity Score [ Time Frame: Baseline; Week 6; Week 12; Month 6; Month 9; Month 12 ]
    The CRPS Severity Score is the sum of the number of CRPS-related symptoms, reported by the participant over the past 48 hours, and signs, observed by the clinician during a brief examination. Participants are queried for 8 CRPS-related symptoms and assessed for 8 CRPS-related signs, for a score between 0 and 16, with higher scores indicating greater CRPS severity.

  • Presence or Absence of Complex Regional Pain Syndrome (CRPS) [ Time Frame: Month 6; Month 9; Month 12 ]
    The presence or absence of CRPS will be determined based on CRPS-related signs, assessed by the clinician in a brief examination. Participant reported symptoms for CRPS from the Enrollment Visit will be included with signs applying the CRPS diagnostic criteria ("Budapest clinical criteria"). Participants who meet criteria for CRPS using the diagnostic criteria will be considered as "CRPS present", and those who do not meet the criteria will be considered as "CRPS absent".

  • Change from Baseline in Bone Turnover Markers [ Time Frame: Baseline to Month 12 ]
    Serum levels of bone formation markers (procollagen type I amino-terminal propeptide and bone alkaline phosphatase) and a bone resorption marker (C-terminal telopeptide of type I collagen) will be determined from blood samples taken during the trial. This information will be used for an exploratory evaluation of bone turnover in response to neridronic acid.


Enrollment: 464
Study Start Date: April 2015
Study Completion Date: November 2016
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Matching placebo administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10
Drug: Placebo
Matching placebo administered as intravenous infusion.
Experimental: 125 mg Neridronic acid
Neridronic acid 62.5 mg administered as intravenous infusion on Day 1 and Day 4; matching placebo administered as intravenous infusion on Day 7 and Day 10
Drug: Neridronic acid 62.5 mg
Neridronic acid administered as intravenous infusion.
Experimental: 250 mg Neridronic acid
Neridronic acid 62.5 mg administered as intravenous infusion on Day 1, Day 4, Day 7 and Day 10
Drug: Neridronic acid 62.5 mg
Neridronic acid administered as intravenous infusion.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Informed consent signed.
  • Male or female participant between 18 years and 80 years of age.
  • A diagnosis of complex regional pain syndrome type I according to the clinical diagnostic criteria using the International Association for the Study of Pain clinical diagnostic criteria (Budapest criteria).
  • Baseline Pain Intensity Score of 4 or greater using an 11-point Numerical Rating Scale referring to the CRPS-affected limb.
  • In stable treatment and follow-up therapy for CRPS type I for at least 1 month.
  • Participant has undergone a recent regular dental examination.
  • Women of child-bearing potential must have a negative urine ß-HCG pregnancy test at enrollment.
  • Women of child-bearing potential must practice protocol defined acceptable methods of birth control during 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.
  • Compliance with the use of electronic diary assessed prior to allocation to treatment.

Exclusion Criteria:

  • A diagnosis of complex regional pain syndrome type II.
  • Documented history or diagnosis of peripheral neuropathy, including diabetic peripheral neuropathy or other metabolic or toxic neuropathy, or any other chronic pain condition that would significantly affect a participant's ability to report CRPS-related pain.
  • Body weight less than 40 kg.
  • Evidence of renal impairment or a history of chronic kidney disease.
  • Serum calcium or magnesium outside of the central laboratory's reference range; history of hypocalcemia; any metabolic disorder anticipated to increase risk for hypocalcemia.
  • Vitamin D deficiency. Participants with vitamin D deficiency prior to enrollment may be enrolled with appropriate supplementation during the enrollment period.
  • Corrected QT interval greater than 470 milliseconds; treatment with medications within the last 30 days prior to allocation to IMP that have potential to prolong the QT interval or anticipated need for such medications during the course of the trial.
  • Any prior use of a bisphosphonate for treatment of CRPS, any prior administration of intravenous bisphosphonate, administration of oral bisphosphonate within the previous year, anticipated requirement for treatment with oral or intravenous bisphosphonate for another condition such as osteoporosis during the trial, or administration of denosumab (Prolia) or other bone turnover suppressing drugs within the past 6 months.
  • History of any allergic or hypersensitivity reaction to neridronic acid or other bisphosphonate, or to vitamin D or calcium supplements.
  • Recent tooth extraction, 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.
  • Evidence of denture-related gum trauma or improperly fitting dentures causing injury.
  • Prior radiation therapy of the head or neck (within 1 year of enrollment).
  • Recent treatment with high doses of systemic steroids or anticipated need for concomitant high-dose steroid treatment during the trial.
  • History of malignancy within 2 years before enrollment with the exception of basal cell carcinoma.
  • Daily intake of long- and short-acting or controlled-release opioid analgesics of more than 200 mg morphine equivalents, regimens combining high-dose opioids and benzodiazepines, or any other treatment regimen considered unstable, unsafe, or have potential to affect the interpretation of the trial.
  • 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 allocation to investigational medicinal product.
  • Evidence of current alcohol or drug abuse, or history of alcohol or drug abuse within 2 years of enrollment, 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 participant's safety during trial participation.
  • 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.
  • Women who are pregnant or breastfeeding.
  • Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2-fold upper limit of normal (ULN), or evidence or history of liver disease.
  • Participation in an investigational drug trial within 3 months prior to enrollment, or prior participation in this trial with receipt of any infusion of IMP, even a partial infusion.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02402530

  Show 59 Study Locations
Sponsors and Collaborators
Grünenthal GmbH
Investigators
Study Director: Grünenthal Study Director Grünenthal GmbH
  More Information

Additional Information:
Responsible Party: Grünenthal GmbH
ClinicalTrials.gov Identifier: NCT02402530     History of Changes
Other Study ID Numbers: KF7013-01
U1111-1151-2181 ( Other Identifier: World Health Organization )
2014-001915-37 ( EudraCT Number )
Study First Received: March 25, 2015
Last Updated: November 11, 2016

Keywords provided by Grünenthal GmbH:
Neridronic Acid
Neridronate
CRPS
RSD

Additional relevant MeSH terms:
Syndrome
Complex Regional Pain Syndromes
Reflex Sympathetic Dystrophy
Disease
Pathologic Processes
Autonomic Nervous System Diseases
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Diphosphonates
Bone Density Conservation Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 23, 2017