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    Summary
    EudraCT Number:2014-001915-37
    Sponsor's Protocol Code Number:KF7013-01
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-04-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2014-001915-37
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of intravenous neridronic acid in CRPS-I
    A.4.1Sponsor's protocol code numberKF7013-01
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1151-2181
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGrünenthal GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGrünenthal GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGrünenthal GmbH
    B.5.2Functional name of contact pointGrünenthal Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressZieglerstr. 6
    B.5.3.2Town/ cityAachen
    B.5.3.3Post code52078
    B.5.3.4CountryGermany
    B.5.4Telephone number492415693223
    B.5.6E-mailClinical-Trials@grunenthal.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nerixia 100 mg/8 mL concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAbiogen Pharma S.p.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNeridronic acid 100 mg/8 mL concentrate for solution for infusion
    D.3.2Product code GRT7013
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNERIDRONATE SODIUM
    D.3.9.1CAS number 80729-79-9
    D.3.9.2Current sponsor codeGRT7013
    D.3.9.3Other descriptive nameSodium neridronate hemihydrate
    D.3.9.4EV Substance CodeSUB27150
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complex regional pain syndrome type I (CRPS-I)
    E.1.1.1Medical condition in easily understood language
    Complex regional pain syndrome type I
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10064334
    E.1.2Term Complex regional pain syndrome Type I
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the efficacy of neridronic acid, versus placebo, in treatment of pain associated with CRPS-I.
    E.2.2Secondary objectives of the trial
    To assess the effect of neridronic acid on pain interference with daily function.
    To assess the effect of neridronic acid on Patient Global Impression of Change (PGIC) in response to treatment.
    To assess the effect of neridronic acid on quality of life.
    To assess the effect of neridronic acid on signs and symptoms of CRPS.
    To assess the safety and tolerability of neridronic acid in subjects with CRPS-I.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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-acting and short-acting 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the change in the Pain Intensity Score from baseline to Week 12.
    The Pain Intensity Score, related to the CRPS-affected limb, will be determined from current pain intensity ratings, captured in an electronic diary, using an 11-point numerical rating scale (NRS). Subjects will be asked to rate their current CRPS-related pain intensity twice daily, once in the morning and once in the evening. Subjects rate their pain on this scale from 0 = “no pain” to 10 = “pain as bad as you can imagine”.
    The Baseline Pain Intensity Score will be calculated as the average of 14 current pain intensity ratings obtained over the 7-day baseline pain assessment phase prior to allocation to IMP, starting from the evening of Day -7 and concluding on the morning of Day 1 prior to IMP administration. At least 10 pain intensity ratings must be available for determination of the Baseline Pain Intensity Score. The Week 12 Pain Intensity Score will be determined in a similar manner (i.e., calculated from ratings obtained during the week prior to Visit 8, culminating with the morning rating on the day of Visit 8). All available ratings (of the 14 possible ratings in this time period) will be used in the calculation.
    All pain intensity ratings for the primary endpoint will be in reference to the CRPS-affected limb (or most painful limb at the time of screening if more than 1 limb is affected by CRPS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Pain Intensity Score from baseline to Week 12.
    E.5.2Secondary end point(s)
    Response to treatment, defined as a 30% reduction in the Pain Intensity Score from baseline to Week 12.
    Response to treatment, defined as a 50% reduction in the Pain Intensity Score from baseline to Week 12.
    Change in the Brief Pain Inventory (BPI) interference scale score from baseline to Week 12.
    The Patient Global Impression of Change (PGIC) questionnaire score at Week 12.
    Change in the EuroQol-5 dimension 5 level (EQ-5D-5L) index score and visual analog scale (VAS) from baseline to Week 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response to treatment, change in the BPI, change in the EQ-5D-5L: Baseline to Week 12.
    Patient Global Impression of Change (PGIC) questionnaire score: Week 12.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Subjects will be followed for up to 12 months after the first infusion of IMP.
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Germany
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The extended follow-up period will be terminated for all subjects after the last subject enrolled completes their Month 6 visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 225
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who complete or discontinue from the trial should continue treatment with their regular physicians in accordance with standard practices.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-08-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-02
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