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    EudraCT Number:2022-003633-19
    Sponsor's Protocol Code Number:SYN321-01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2023-01-27
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2022-003633-19
    A.3Full title of the trial
    A prospective, double-blinded, randomized, placebo-controlled phase 1/2a study to assess safety, tolerability, systemic exposure, and preliminary efficacy of single intraarticular injections of 3 dose levels of SYN321 and placebo in patients with symptomatic knee osteoarthritis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective, double-blinded, randomized, placebo-controlled phase 1/2a study to assess safety, tolerability, systemic exposure, and preliminary efficacy of single intraarticular injections of 3 dose levels of SYN321 and placebo in patients with symptomatic knee osteoarthritis.
    A.4.1Sponsor's protocol code numberSYN321-01
    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 SponsorSynartro AB
    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 supportSynartro AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSynartro AB
    B.5.2Functional name of contact pointHead of Clinical Development
    B.5.3 Address:
    B.5.3.1Street AddressVasagatan 28, 6th level
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code11120
    B.5.4Telephone number+4670-687 35 26
    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.3.1Product nameSYN321
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraarticular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDiclofenac ethoxyethylamino succinyl hyaluronan (DEASHA)
    D.3.9.3Other descriptive nameSYN321
    D.3.9.4EV Substance CodeSUB301582
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number33 to 98
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboSolution for injection
    D.8.4Route of administration of the placeboIntraarticular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Knee osteoarthritis
    E.1.1.1Medical condition in easily understood language
    Knee osteoarthritis
    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 safety and tolerability of SYN321 after single IA injection in patients with symptomatic KOA. Three (3) dose levels of SYN321 will be evaluated: 33, 65 mg and 98 mg in volumes of 1.5, 3 and 4.5 mL.
    E.2.2Secondary objectives of the trial
    - To determine the systemic exposure of diclofenac, linker (and linker associated metabolites), and diclofenac lactam (break down products from SYN321).
    - To assess the preliminary efficacy following single IA injections of SYN321 at 3 dose levels in patients with symptomatic KOA.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Willing and able to give written informed consent for participation in the study and willing and able to participate in all procedures and follow-up evaluations necessary to complete the study.
    2. Male or female patient clinically diagnosed with KOA, no later than 3 months prior to Visit 1. The KOA diagnosis should be confirmed in the patient’s medical record.
    3. Dominant pain in one knee due to KOA with weight bearing pain between 4 and 8 inclusive on the NRS scale (0-10) at the time of inclusion (checked at screening [Visit 1] and confirmed at Visit 2, pain during the last 7 days).
    4. Age 40 to 79 years, inclusive at the time of Visit 1.
    5. BMI ≥ 18.5 and < 35.0 kg/m2.
    6. Patients without abnormal clinically significant medical history, physical findings, vital signs, hypotension, cardiovascular disease, ECG, and laboratory values at the time of the screening visit, as judged by the Investigator. (Discussion is encouraged between the Investigator and the Medical monitor regarding the clinical relevance of any abnormal laboratory value during the pre-dose period.)
    7. Patient is willing to discontinue all pain medication (COX-2 inhibitors, NSAIDs, and opioid analgesics) at least 10 days before study drug administration (prior to Day 1) and for the study duration. Paracetamol will be allowed as rescue medication up to max 4000 mg/day (except for 24 hours prior to visit to the study site).
    8. Patient agrees not to take additional knee symptom-modifying drugs (e.g., glucosamine, collagen, HA) at least 10 days before study drug administration (prior to Day 1) and for the study duration.
    9. WOCBP must practice abstinence heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the patient) or agree to use a highly effective method of contraception with a failure rate of < 1 % to prevent pregnancy from that least 2 weeks prior to the administration of IMP to 4 weeks after the last administration of IMP. In addition, any male partner of a female patient must, unless he has undergone vasectomy, agree to use a condom from the first administration of IMP until 4 weeks after the last administration of IMP.
    The following are considered highly effective methods of contraception:
    - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal),
    - progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable),
    - intrauterine device [IUD]or intrauterine hormone-releasing system [IUS]).
    WOCBP must refrain from donating eggs from the first IMP administration until 3 months after the last IMP administration.
    WOCBP are pre-menopausal females who have undergone any of the following surgical procedures; hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, or who are post-menopausal defined as 12 months of amenorrhea (in questionable cases a blood sample with detection of follicle stimulating hormone [FSH] >25 IU/L is confirmatory).
    Male patients must be willing to use condom or be vasectomized or practice sexual abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the patient) to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the first administration of IMP until 3 months after the last administration of IMP. Any female partner of a non-vasectomized male patient who is of child-bearing potential must use contraceptive methods with a failure rate of < 1% to prevent pregnancy (see above) from at least 2 weeks prior to the first administration of IMP to 4 weeks after the last administration of IMP.
    10. Patients without contraindications for treatment with diclofenac.
    E.4Principal exclusion criteria
    1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient’s ability to participate in the study.
    2. Previous IA fracture of the knee.
    3. Patient has rheumatoid arthritis, psoriatic arthritis, or has been diagnosed with any other disorders that is the primary source of their knee pain, including but not limited to: osteonecrosis, radiculopathy, bursitis, tendinitis, tumor, cancer.
    4. IA injections of steroids or HA or other invasive procedure (e.g., arthroscopy, arthrography, surgery) in the knee within 3 months prior to screening.
    5. Conditions or medications that could confound the assessment of pain, as judged by the Investigator.
    6. Conditions that could be adversely affected by an IA injection (e.g., eczema, skin infection, high bleeding risk etc.), as judged by the Investigator.
    7. Any clinically significant illness (except KOA), medical/surgical procedure, or trauma within 4 weeks of the administration of IMP.
    8. Malignancy within the past 5 years, with the exception of in situ removal of basal cell carcinoma.
    9. Any planned major surgery within the duration of the study.
    10. Patients who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the study.
    11. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibodies and/or human immunodeficiency virus (HIV).
    12. After 10 minutes supine rest at the time of screening, any vital signs outside the following ranges:
    - Systolic blood pressure (BP): <90 or >160 mmHg, or
    - Diastolic blood pressure <50 or >95 mmHg, or
    - Pulse <40 or >90 bpm
    13. Prolonged QTcF (> 450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator.
    14. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to SYN321, including disinfectants and adhesives or hypersensitivity to acetylsalicylic acid.
    15. History of asthma, angioedema, urticaria or acute rhinitis induced by NSAID, including acetylsalicylic acid.
    16. Regular use of any prescribed or non-prescribed medications, including but not limited to antacids, analgesics, herbal remedies, vitamins and minerals, within 10 days prior to the first administration of IMP, as well as nasal decongestants without cortisone, antihistamine, or anticholinergics for a maximum of 10 days, at the discretion of the Investigator. For intake of allowed medications and rescue medication and others, refer to Section and in the clinical study protocol.
    17. Patient has taken pain medication or has received pain medicine other than paracetamol for conditions unrelated to KOA of the index knee within 10 days prior to the injection.
    18. Planned treatment or treatment with another investigational drug within 3 months prior to Day 1. Patients consented and screened but not dosed in previous phase 1 studies will not be excluded.
    19. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, snuffing, chewing tobacco) less than 3 times/week before the screening visit will be allowed.
    20. Positive screen for drugs of abuse or alcohol at screening. Positive results that are expected given the patient’s medical history and prescribed medications can be disregarded as judged by the Investigator.
    21. History of or current alcohol abuse or excessive intake of alcohol, as judged by the Investigator.
    22. History of or current drug abuse, as judged by the Investigator.
    23. History of or current use of anabolic steroids, as judged by the Investigator.
    24. Plasma donation within 1 month of screening or blood donation (or corresponding blood loss) during the last 3 months prior to screening.
    25. The Investigator considers the patient unlikely to comply with study procedures, restrictions, and requirements.
    E.5 End points
    E.5.1Primary end point(s)
    - Frequency, seriousness, and intensity of AEs.
    - Clinically significant changes in electrocardiogram (ECG), vital signs, safety laboratory measurements (hematology, clinical chemistry, coagulation), physical examination findings and local tolerability.
    E.5.1.1Timepoint(s) of evaluation of this end point
    According to study flowchart.
    E.5.2Secondary end point(s)
    - Concentration of diclofenac, linker (and linker associated metabolites) and diclofenac lactam in plasma and urine. The following pharmacokinetic (PK) parameters will be explored: maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve (AUC) Additional PK parameters may be explored if deemed appropriate.
    - Self-registered pain using the NRS (0-10) once daily every day until Day 56. NRS sum of pain intensity difference (SPID) for current pain in the index knee will be analyzed for all time points measured.
    - Self-registered function and quality of life using Knee Injury and Osteoarthritis Outcome Score (KOOS). Change from baseline in average sum of KOOS scores, KOOS subscale scores.
    - Use of rescue medication.
    E.5.2.1Timepoint(s) of evaluation of this end point
    According to study flowchart.
    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 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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    Single ascending dose study
    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 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 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
    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 months6
    E.8.9.1In the Member State concerned days
    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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 18
    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 state36
    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)
    This is a phase 1/2a study and thus there will be no treatment with SYN321 after the end of study participation.
    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 Decision2023-03-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-04-05
    P. End of Trial
    P.End of Trial StatusOngoing
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