Efficacy and Safety of Intravenous Neridronic Acid in CRPS-I

Complex Regional Pain Syndrome, Type I Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02402530
• Other study ID #: KF7013-01
• Secondary ID: U1111-1151-21812
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 2015
• Est. completion date: November 2016

Study information

• Verified date: May 2018
• Source: Grünenthal GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 459
• Est. completion date: November 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Complex Regional Pain Syndrome, Type I
• Complex Regional Pain Syndromes
• Reflex Sympathetic Dystrophy
• Syndrome

Intervention

Drug:
• Placebo
Matching placebo administered as intravenous infusion.
• Neridronic acid 62.5 mg
Neridronic acid administered as intravenous infusion.

Locations

Country	Name	City	State
Germany	Site DE107 - Studienzentrum A. Schwittay	Böhlen
Germany	Site DE104 - Schmerzzentrum Dr. med. C. Wachter & T. Tusker	Fellbach
Germany	Site DE101 - Klinische Forschung Hannover Mitte GmbH	Hannover
Germany	Site DE103 - Algesiologikum Studienzentrum und Algesiologikum MVZ	Munich
Germany	Site DE102 - Universitätsklinikum Würzburg Neurologische Klinik	Würzburg
United Kingdom	Site GB104 - The Royal Victoria Infirmary	Cambridge
United Kingdom	Site GB108 - Darlington Memorial Hospital, Centre for Research and clinical Intervention	Darlington
United Kingdom	Site GB109 - Royal Devon Exeter Hospital	Exeter
United Kingdom	Site GB101 - Guys and St. Thomas NHS Foundation Trust - St Thomas Hospital	London
United Kingdom	Site GB111 - Chelsea and Westminster Hospital - NHS Foundation Trust	London
United States	Site US166 - Albany Medical College	Albany	New York
United States	Site US110 - Orange County Research Institute	Anaheim	California
United States	Site US107 - Austin Center for Clinical Research	Austin	Texas
United States	Site US134 - Lovelace Scientific Resources, Inc	Austin	Texas
United States	Site US123 - Northwest Clinical Research Center	Bellevue	Washington
United States	Site US144 - Bellevue Surgery Center	Bellevue	Washington
United States	Site US173 - Bellevue Surgery Center	Bellevue	Washington
United States	Site US169 - Massachusetts General Hospital	Boston	Massachusetts
United States	Site US137 - Montefiore Medical Center	Bronx	New York
United States	Site US172 - Core Healthcare Group	Cerritos	California
United States	Site US112 - Clinical Trials of South Carolina	Charleston	South Carolina
United States	Site US103 - Great Lakes Clinical Trials	Chicago	Illinois
United States	Site US108 - Catalina Research Institute	Chino	California
United States	Site US153 - Clinical Research of West Florida Inc - Clearwater	Clearwater	Florida
United States	Site US162 - South Lake Pain Institute	Clermont	Florida
United States	Site US175 - Inland Pain Medicine	Colton	California
United States	Site US106 - Mountain View Clinical Research	Denver	Colorado
United States	Site US119 - G & L Research	Foley	Alabama
United States	Site US113 - Pioneer Research Solutions, Inc	Houston	Texas
United States	Site US152 - UC San Diego Healthcare Systems, Center for Pain Medicine	La Jolla	California
United States	Site US105 - Advanced Biomedical Research of America	Las Vegas	Nevada
United States	Site US154 - Woodland International Research Group	Little Rock	Arkansas
United States	Site US102 - Samaritan Center for Medical Research	Los Gatos	California
United States	Site US143 - Florida Pain Institute	Merritt Island	Florida
United States	Site US111 - Sunrise Research Institute	Miami	Florida
United States	Site US122 - Precision Research Organization, LLC	Miami Lakes	Florida
United States	Site US157 - North Star Medical Research	Middleburg Heights	Ohio
United States	Site US131 - Better Health Clinical Research, Inc	Newnan	Georgia
United States	Site US104 - Discovery Clinical Trials	Orlando	Florida
United States	Site US129 - International Clinical Research Institute	Overland Park	Kansas
United States	Site US149 - Founders Research Corporation	Philadelphia	Pennsylvania
United States	Site US133 - Gold Coast Research LLC	Plantation	Florida
United States	Site US101 - Princeton Medical Institute	Princeton	New Jersey
United States	Site US145 - University of Rochester	Rochester	New York
United States	Site US126 - Northern California Research	Sacramento	California
United States	Site US127 - Advance Clinical Research, Inc	Saint Louis	Missouri
United States	Site US171 - Florida Medical Pain Management	Saint Petersburg	Florida
United States	Site US118 - Omega International Pain Clinic	Salt Lake City	Utah
United States	Site US116 - Arizona Pain Specialists	Scottsdale	Arizona
United States	Site US117 - Valley Pain Consultants	Scottsdale	Arizona
United States	Site US161 - Swedish Pain and Headache Center	Seattle	Washington
United States	Site US151 - Premier Pain Centers	Shrewsbury	New Jersey
United States	Site US156 - University Clinical Research Center	Somerset	New Jersey
United States	Site US121 - Clinical Research of West Florida	Tampa	Florida
United States	Site US124 - Quality of Life Medical and Research Centers LLC	Tucson	Arizona
United States	Site US164 - Advanced Clinical Research	West Jordan	Utah
United States	Site US165 - Palm Beach Research	West Palm Beach	Florida
United States	Site US114 - Abington Neurological Associates	Willow Grove	Pennsylvania
United States	Site US135 - The Center for Clinical Research	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Grünenthal GmbH

Countries where clinical trial is conducted

United States,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in the Worst Pain Intensity	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.	Baseline; Week 12
Other	Change in the Average Pain Intensity	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.	Baseline; Week 12
Other	Change from Baseline in the Pain Intensity Scores at Each Week	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.	Baseline to Week 12
Other	Response to Treatment: Proportion of Participants with 0 to 100% Decrease in the Pain Intensity Score	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).	Baseline; Week 12
Other	Response to Treatment: Proportion of Participants With at Least a 2 Point Decrease in the Pain Intensity Score	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.	Baseline; Week 12
Other	Change in the Pain Anxiety Symptom Scale (PASS) Total Score	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.	Baseline; Week 12
Other	Change in the Center for Epidemiological Studies Depression (CES-D) Scale Total Score	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.	Baseline; Week 12
Other	Change in Pain Disability Index (PDI)	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.	Baseline; Week 6; Week 12
Other	Change in the Medical Outcomes Study (MOS) Sleep Scale: Sleep Problems Index	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.	Baseline; Week 6; Week 12
Other	Change in Pain Medication Score	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.	Baseline; Week 6; Week 12; Month 6; Month 9; Month 12
Other	Change in the Current Pain Intensity in the Extended Follow-up Period	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".	Baseline; Month 6; Month 9; Month 12
Other	Change in the Average Pain Intensity in the Extended Follow-up Period	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".	Baseline; Month 6; Month 9; Month 12
Other	Change in the Worst Pain Intensity in the Extended Follow-up Period	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".	Baseline; Month 6; Month 9; Month 12
Other	Change in the BPI Interference Score in the Extended Follow-up Period	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.	Baseline; Month 6; Month 9; Month 12
Other	PGIC in the Extended Follow-up Period	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.	Baseline; Month 6; Month 9; Month 12
Other	Change in the EQ-5D-5L Index Score in the Extended Follow-up Period	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.	Baseline; Month 6; Month 9; Month 12
Other	Change in the EQ VAS in the Extended Follow-up Period	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.	Baseline; Month 6; Month 9; Month 12
Other	Change in the Complex Regional Pain Syndrome (CRPS) Severity Score	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.	Baseline; Week 6; Week 12; Month 6; Month 9; Month 12
Other	Presence or Absence of Complex Regional Pain Syndrome (CRPS)	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".	Month 6; Month 9; Month 12
Other	Change from Baseline in Bone Turnover Markers	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.	Baseline to Month 12
Primary	Change in the Pain Intensity Score to 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.	Baseline; Week 12
Secondary	Response to treatment: Proportion of Participants With at Least 30 Percent Reduction in the Pain Intensity Score	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.	Baseline; Week 12
Secondary	Response to treatment: Proportion of Participants With at Least 50 Percent Reduction in the Pain Intensity Score	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.	Baseline; Week 12
Secondary	Change in the Brief Pain Inventory (BPI) Interference Score	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.	Baseline; Week 12
Secondary	Patient Global Impression of Change (PGIC)	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.	Baseline; Week 12
Secondary	Change in the EuroQol-5 Dimension 5 Level (EQ-5D-5L) Index Score	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.	Baseline; Week 12
Secondary	Change in the EuroQol Visual Analog Scale (EQ VAS)	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.	Baseline; Week 12