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    Summary
    EudraCT Number:2020-000249-14
    Sponsor's Protocol Code Number:APPA-P2-1
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-06-12
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2020-000249-14
    A.3Full title of the trial
    A placebo-controlled, double-blinded, randomized, trial using a combination of apocynin and paeonol (APPA) for the treatment of knee osteoarthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A placebo-controlled, double-blinded, randomized, trial using a combination of apocynin and paeonol (APPA) for the treatment of knee osteoarthritis
    A.4.1Sponsor's protocol code numberAPPA-P2-1
    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 SponsorAKL Research and Development Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportAKL Research and Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNordic Bioscience Clinical Development
    B.5.2Functional name of contact pointRegulatory Affairs Department
    B.5.3 Address:
    B.5.3.1Street AddressHerlev Hovedgade 82
    B.5.3.2Town/ cityHerlev
    B.5.3.3Post code2730
    B.5.3.4CountryDenmark
    B.5.5Fax number+4573707900
    B.5.6E-mailregulatory@nordicbioscience.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code APPA
    D.3.4Pharmaceutical form Capsule
    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 INNPaeonol
    D.3.9.1CAS number 552-41-0
    D.3.9.3Other descriptive namePAEONOL
    D.3.9.4EV Substance CodeSUB195783
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number311.1
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApocynin
    D.3.9.1CAS number 498-02-2
    D.3.9.3Other descriptive nameApocynin
    D.3.9.4EV Substance CodeSUB214911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number88.9
    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 placeboCapsule
    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
    Radiographic and symptomatic knee osteoarthritis in either one or both knees
    E.1.1.1Medical condition in easily understood language
    Radiographic and symptomatic knee osteoarthritis in either one or both knees
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10023476
    E.1.2Term Knee osteoarthritis
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the change in pain, in terms of the WOMAC pain score of the target knee.
    E.2.2Secondary objectives of the trial
    • To evaluate changes in symptoms of OA
    • To evaluate the changes in physical functioning
    • To evaluate the safety and tolerability of APPA
    • To evaluate changes in quality of life
    Exploratory Objectives
    • To explore biomarkers of joint tissue turnover
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is able to read and understand the language and content of the study material, understand the requirements for study visits, and is willing to provide information at the scheduled evaluations and appropriate written informed consent has been obtained.
    2. Femorotibial osteoarthritis of the knee, according to the American College of Rheumatology (ACR) clinical and radiographic criteria (Altman et al. 1986) (Appendix A).
    3. Radiological OA grade 2 or 3 of the target knee, using the Kellgren-Lawrence method (Kellgren & Lawrence 1957) as graded by central, independent reading of X-ray obtained during screening, or on a recent (within 6 months) X-ray image which fulfills the protocol specifications for reading.
    4. Age between 40 years and 85 years at the time of screening, both included; of either sex.
    5. Pain score rated on an 11-point numerical rating scale of the target knee of ≥ 20 and ≤ 45 out of 50 in response to the WOMAC pain sub-score (5 questions), at the time of screening and baseline. The subject should have undergone a washout-period of at least 5 half-lives of any analgesic medication before completing the questionnaires.
    6. Women of child-bearing potential must use a highly effective method of contraception (Please see Appendix B). Postmenopausal status is defined as being amenorrheic for at least 1 year prior to screening. Sexually active men with a female partner of childbearing potential must ensure that their female partner uses a highly effective method of contraception and agree to use condom from enrolment up to at least 3 months after the study end. Furthermore, male participants must agree not to donate sperm throughout the study and at least 3 months after the study end.
    7. Knee pain in the target knee for 14 days of the preceding month (periarticular knee pain due to OA and not due to non-OA conditions such as bursitis, tendonitis, etc.) based on subject report.
    8. Inadequate response or intolerance to analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs) as reported by the subject
    E.4Principal exclusion criteria
    1. Known or suspected hypersensitivity to or previous hypersensitivity reactions to APPA, or any of the excipients in the investigational product.
    2. For women of childbearing potential:
    a) Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding
    b) Failure to agree to practice a highly effective method of contraception (see Appendix B), from enrollment up to at least 3 months after the study end.
    3. For sexually active men with a female partner of childbearing potential: Failure to agree to ensure that their female partner uses a highly effective method of contraception, to agree to use condom (see Appendix B) from enrollment up to at least 3 months after the study end, and to agree not to donate sperm throughout the study and at least 3 months after the study end.
    4. Intra-articular delivery of corticosteroids within 3 months or hyaluronic acid within 6 months of screening in the target knee or into any other joint within 30 days prior to screening.
    5. Systemic corticosteroid treatment of more than 14 days during the past 6 months prior to screening.
    6. Major surgery or arthroscopy of the target knee within the previous year prior to screening.
    7. Planned surgery on either knee within the next 3 months.
    8. Use of a currently unapproved investigational drug, device or biologic within 3 months prior to randomization.
    9. Presence of inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, gout or pseudogout with history of clinical attacks.
    10. Current malignancy or treatment for malignancy within the past five years, with the exception of treated non-melanoma skin cancer, unless affecting the target knee area, or carcinoma in situ events.
    11. Any other abnormal laboratory results or significant medical conditions that the Investigator believes should preclude the subject's participation in the trial.
    12. Prior septic arthritis of the target knee.
    13. Known osteoarthritis of the hip(s) if pain in either or both hip(s) exceeds that of the target knee using the WOMAC Hip Pain sub-score for that hip at the time of screening
    14. Presence of significant radicular back pain, as reported by the subject.
    15. Presence of severe pain in either knee, defined as > 45 out of 50 in response to the WOMAC pain sub-score (5 questions), at the time of screening or baseline, regardless of the eligibility of the contralateral knee.
    16. Body Mass Index ≥ 40 kg/m2
    17. Estimated glomerular filtration rate < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) method.
    18. Substantial use of moderate or higher strength opioid medication for the treatment of pain within 4 weeks before the baseline visit, as evaluated by the investigator.
    19. Use of duloxetine, pregabalin, or gabapentin within 4 weeks before the baseline visit.
    20. History of alcohol or drug abuse within the 5 years prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of this trial is the change from baseline in WOMAC pain sub-score (sum of questions 1 to 5) of the target knee as evaluated at week 4.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 4
    E.5.2Secondary end point(s)
    • Changes from baseline in WOMAC total score and the WOMAC function and stiffness scores at week 4
    • Changes from baseline in constant, intermittent OA and total pain assessed by ICOAP scores at week 4
    • Changes from baseline in WOMAC pain weight-bearing score (questions 1, 2, and 5) and non-weight bearing score (questions 3 and 4) at week 4
    • Changes from baseline in gait speed as assessed by the 20 Meter Walk test at week 4
    • Change from baseline in the weekly mean of the average daily pain intensity at Week 4
    • Area-under-effect curves of the weekly mean of the average daily pain intensity at Week 4
    • OMERACT-OARSI responder rate at week 4
    • Total dose of rescue medication calculated as the sum of tablets used, based on pill counts
    • Time between baseline and first use of rescue medication
    • Changes from baseline in the Patient Global Assessment (PGA) score at week 4
    • Changes from baseline in quality of life assessed by the EQ5D at week 4
    SAFETY ENDPOINTS
    • Nature, incidence and severity of AEs
    • Changes in laboratory safety parameters, vital signs, 12-lead ECG parameters, and weight
    EXPLORATORY ENDPOINTS
    • Time to achieve a clinically relevant pain reduction defined as a decrease from baseline of at least 1 points out of 10 in the 11-point average of daily pain score
    • Time to achieve “moderate improvement” and time to achieve “high improvement” in OMERACT-OARSI response
    • Changes in serum and urine biomarkers of joint tissue turnover
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 4
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 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 concerned3
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months12
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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)
    Standard Care
    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 Decision2020-07-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-08-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-16
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