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    Summary
    EudraCT Number:2015-001527-22
    Sponsor's Protocol Code Number:AXS02-301
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-30
    Trial 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 ConcernedUK - MHRA
    A.2EudraCT number2015-001527-22
    A.3Full title of the trial
    CREATE-1 Study: CRPS Treatment Evaluation 1 Study. A Randomized, Double-blind, Placebo-controlled Study to
    Assess the Efficacy and Safety of AXS-02 (Disodium Zoledronate Tetrahydrate) Administered Orally to 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
    CREATE-1 Study: CRPS Treatment Evaluation 1 Study. A Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of AXS-02 (Disodium Zoledronate Tetrahydrate) Administered Orally to Subjects with Complex Regional Pain Syndrome Type I (CRPS-I)
    A.3.2Name or abbreviated title of the trial where available
    CREATE­1 Study: CRPS Treatment Evaluation 1 Study
    A.4.1Sponsor's protocol code numberAXS02-301
    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 SponsorAxsome Therapeutics, Inc.
    B.1.3.4CountryUnited States
    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 supportAxsome Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAxsome Therapeutics, Inc.
    B.5.2Functional name of contact pointJeffrey Nelson
    B.5.3 Address:
    B.5.3.1Street Address25 Broadway, 9th Floor
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10004
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12123323241
    B.5.6E-mailjnelson@axsome.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU 3/13/1192
    D.3 Description of the IMP
    D.3.1Product nameDisodium Zoledronate Tetrahydrate
    D.3.2Product code AXS-02
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDisodium Zoledronate Tetrahydrate
    D.3.9.1CAS number 165800-07-7
    D.3.9.2Current sponsor codeAXS-02
    D.3.9.3Other descriptive nameDisodium (1-Hydroxy-2-(1H-Imidazol-1-yl)-1- Phosphonoethyl)Phosphonic Acid Tetrahydrate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 placeboTablet
    D.8.4Route of administration of the placeboOral 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 (CRPS-I).
    E.1.1.1Medical condition in easily understood language
    Severe pain in a limb accompanied by autonomic, sensory, motor and trophic changes
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    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 assess the effect of AXS-02 versus placebo on the mean of the Pain Intensity Difference (PID) from Baseline to Week 12, where pain intensity is measured by the weekly average daily pain intensity using the NRS.
    E.2.2Secondary objectives of the trial
    Effect of AXS-02 vs placebo on
    -PGI-C at Week 12 (key secondary).
    -CGI-C at Week 12.
    -mPID(week 6-12), (mean of the PIDs measured over the interval from Week 6 to Week 12. Proportion of responders with ≥50% reduction from Baseline in NRS score at Week 12)
    -PID over time.
    -Proportion of responders with ≥50% reduction from Baseline in NRS score over time.
    -Proportion of responders with ≥30% reduction from Baseline in NRS score over time.
    -Change from Baseline in the BPI Pain Intensity score and BPI Pain Interference score over time.
    -Change from Baseline in the EQ-5D™ over time.
    -PGI-C and CGI-C scores at Week 12.
    -Change from Baseline in SF-MPQ-2 and pain on motion over time.
    -Proportion of subjects with resolution of baseline disease symptoms of allodynia wk 12,hyperalgesia, skin color changes, and local edema.
    -Use of rescue medication
    -Bone turnover markers (s-CTX, s-P1NP).
    -Safety as assessed by AEs, vital signs, and laboratory assessments.
    -Disease recurrence.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The sub-study is entitled CREATE-1 – Bone Turnover Markers (BTM) Sub-Study: A Longitudinal Study Evaluating the Effect of AXS-02 on Bone Turnover Over 52-weeks and the Protocol number will be AXS02-301-BTM.

    The objective of this study is to assess the long-term effect of AXS-02 on bone resorption, as measured by sCTX, and bone formation, as measured by sP1NP.

    A subject will be eligible for entry into the study if the following criteria is met:
    1. Participated in the CREATE-1 study and received at least 1 dose of AXS-02.
    2. Has not received a bisphosphonate since their participation in the CREATE-1 study and does not plan to receive one during their participation in this study.
    3. Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements.

    The primary endpoint will be the amount of bone resorption, as measured by sCTX. The secondary endpoint will be the amount of bone formation, as measured by sP1NP.

    Up to 30 subjects may be included in this study.
    E.3Principal inclusion criteria
    A subject will be eligible for study participation if the subject meets all of the following criteria:
    1. Is male or female at least 18 years of age.
    2. Has a confirmed diagnosis of CRPS-I according to the new criteria from the IASP
    (Budapest clinical diagnostic criteria [Appendix C]).
    3. Has CRPS-I in one upper or lower limb.
    4. Has a baseline weekly average (the average of the daily pain intensity scores from the 7 days
    before Day 1 dosing) pain intensity score ≥5 based on an 11-point (0-10) NRS in the affected limb.
    5. Has been diagnosed with CRPS-I within 6 months at the time of screening.
    6. Has a history of a traumatic event inciting CRPS symptoms (eg, fracture, crushing injury, orthopedic surgery) within 12 months of Screening.
    7. Has failed trials of at least 2 available treatment modalities for CRPS. If receiving treatments or follow-up for CRPS-I, has been on a stable regime, except for chronic opioid therapy, for at least 3 weeks. See Section 8.13 for details.
    8. If female and of childbearing potential, is nonlactating and nonpregnant (has negative pregnancy test results at Screening and Baseline).
    9. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 year or
    surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or hysterectomy]) or practicing 1 or
    more of the following medically acceptable methods of birth control:
    -Hormonal methods such as oral, implantable, injectable, vaginal ring, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject’s usual menstrual cycle period) before study drug administration.
    -Total abstinence from sexual intercourse since the last menses before study drug administration, abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle.
    -Intrauterine device.
    -Vasectomized partner.
    -Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies or cream).
    10. Is willing and able to complete the pain evaluations and quality of life questionnaires.
    11. Is willing to take supplemental calcium and Vitamin D during the study.
    12. Is able to provide written informed consent to participate in the study and able to understand the procedures and study requirements.
    13. Is willing to voluntarily sign and date an informed consent form that is approved by an institutional review board before the conduct of any study procedure.
    E.4Principal exclusion criteria
    A subject will be excluded from the study if the subject meets any of the following criteria:
    1. Has a documented history or diagnosis of peripheral neuropathy, including diabetic neuropathy
    or other metabolic or toxic neuropathy.
    2. Has type I diabetes mellitus, or poorly controlled type II diabetes mellitus.
    3. Has severe renal impairment (creatinine clearance of < 35 mL/min).
    4. Has bilirubin, alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase levels >2 times the upper limit of normal.
    5. Has hypocalcemia.
    6. Has an abnormality of the esophagus that delays esophageal emptying, such as stricture or achalasia.
    7. Is unable to stand or sit upright for at least 30 minutes.
    8. Has significant difficulty swallowing tablets or is unable to tolerate oral medication.
    9. Has current sign or symptom of severe and/or progressive or uncontrolled hepatic, renal, gastrointestinal (including untreated gastroesophageal reflux disease [GERD]), endocrine, hematological, cardiac, pulmonary, or neurological disease.
    10. Has a clinically significant psychiatric disorder (eg, treatment-refractory major depression, schizophrenia, bipolar disorder, panic disorder, or generalized anxiety disorder).
    11. Has any other clinically significant medical or pain condition (eg, Parkinson’s disease, cognitive impairment, or fibromyalgia) or clinical laboratory abnormality that would in the investigator's judgment interfere with the subject's ability to participate in the study.
    12. Is on chronic opioid therapy within 4 weeks of randomization. NOTE: NOTE: Chronic is defined as “daily or near daily use of opioids for at least 90 days”. For all other opioid use, the subject must not have received a dose of opioids within 10 days prior to randomization (Day 1).
    13. Has had a previous allergic reaction or hypersensitivity to bisphosphonates.
    14. Received prior treatment with zoledronic acid.
    15. Received treatment with a bisphosphonate within 6 months before study entry.
    16. Received treatment with calcitonin within 3 months before study entry.
    17. Received a sympathetic nerve block within 3 weeks prior to Baseline (Day -7).
    18. Received treatment with high-dose oral or parenteral steroids (eg, 0.5 to 1 mg/kg per day orally) within the last 3 months, or anticipates a need for concomitant high-dose steroid treatment during the study (use of steroids in treatment of mild asthma or allergic rhinitis or topically for skin conditions will be permitted).
    19. Has a known or suspected history of alcoholism or drug abuse or misuse within 2 years of Screening.
    20. Has active litigation or a pending workers' compensation decision.
    21. Previously participated in another clinical study of AXS-02 or received any investigational drug or device or investigational therapy within 30 days before Screening.
    22. Has elevated risk for osteonecrosis of the jaw with bisphosphonate treatment, including patients with recent tooth extraction, significant dental or periodontal disease, prior radiation to the head or neck (within 1 year of screening), or a history of malignancy within 2 years (except basal cell carcinoma).
    23. Has serum 25-hydroxy vitamin D levels of less than 20 ng/ml and has not received an oral bolus dose of supplemental vitamin D in addition to daily supplemental vitamin D (800-1000 international units [IU]). An oral bolus dose should be given as 50,000 IU of vitamin D. Vitamin D levels after the initial bolus dose will be managed by the investigator.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the mean of the Pain Intensity Difference (PID) from Baseline to Week 12, where pain intensity is measured by the weekly average daily pain intensity using the NRS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The NRS scores will be collected from Screening (Visit 1) and daily through Week 12 via a PRO diary.
    E.5.2Secondary end point(s)
    The key secondary endpoint is:
    -Patients’ Global Impressions of Change (PGI-C) at Week 12


    Other secondary endpoints are:
    -Clinicians’ Global Impressions of Change (CGI-C) scores at Week 12.
    -Proportion of subjects with resolution of allodynia at Week 12.
    -mPID(week 6-12), defined as the mean of the PIDs measured over the interval from Week 6 to Week 12
    Proportion of responders with ≥50% reduction from Baseline in NRS score at Week 12.
    -Proportion of responders with a ≥30% reduction from baseline in NRS score at week 4.
    Other Exploratory Endpoints:
    -PID over time.
    -Proportion of responders with a ≥30% reduction from baseline in NRS score over time.
    -Proportion of responders with a ≥50% reduction from baseline in NRS score over time.
    -Change from Baseline in the BPI Pain Intensity score (average of Questions 3, 4, 5, and 6) and BPI Pain Interference score (average of Questions 9A-9G) over time.
    -Change from Baseline in the EQ-5D™ over time.
    -Change from Baseline in the SF-MPQ-2 over time.
    -Change from Baseline in pain on motion over time.
    -Proportion of subjects with resolution of baseline disease symptoms of hyperalgesia, skin color changes, and local edema.
    -Use of rescue medication.
    -Bone turnover markers (s-CTX and s-P1NP).
    -Disease recurrence.

    Safety endpoints include the following:
    -Incidence of TEAEs.
    -Clinical laboratory test results.
    -Vital sign measurements.
    -Physical examination findings.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At screening, baseline, throughout treatment and follow-up.
    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 No
    E.6.7Pharmacodynamic No
    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) No
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    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 trial2
    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 concerned8
    E.8.5The trial involves multiple Member States No
    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
    Australia
    Canada
    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
    An independent Data Safety Monitoring Board (DSMB) will be convened once during the study to conduct an interim analysis of the safety and efficacy of AXS-02. Full details of the composition and conduct of the board will be outlined in a prospective DSMB charter to be finalized prior to the planned interim analysis.
    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 months3
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days26
    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: 140
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 Information not present in EudraCT
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 190
    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)
    After the end of the study, each subject will be treated according to standard clinical practice.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-02
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