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    Summary
    EudraCT Number:2016-001096-73
    Sponsor's Protocol Code Number:MIV-711-202
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-08
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2016-001096-73
    A.3Full title of the trial
    An Open-Label, One-Arm Phase II Extension Study to Evaluate Safety and Tolerability of MIV-711 in Patients with Knee Joint Osteoarthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Safety and Tolerability of MIV-711 in Patients with Knee Joint Osteoarthritis
    A.4.1Sponsor's protocol code numberMIV-711-202
    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 SponsorMedivir AB
    B.1.3.4CountrySweden
    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 supportMedivir AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedivir AB
    B.5.2Functional name of contact pointMIV-711 Clinical Study Information
    B.5.3 Address:
    B.5.3.1Street AddressBlasieholmsgatan 2
    B.5.3.2Town/ cityStockholm
    B.5.3.3Post code111 48
    B.5.3.4CountrySweden
    B.5.6E-mailclinicaloperations@medivir.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.3.1Product nameMIV-711 (HCl)
    D.3.2Product code MIV-711
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNone
    D.3.9.1CAS number 1657002-22-6
    D.3.9.2Current sponsor codeMIV-711
    D.3.9.3Other descriptive nameMIV-711 (HCl), MV076159 (HCl), CK1509
    D.3.9.4EV Substance CodeSUB34470
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Knee Join Osteoarthritis
    E.1.1.1Medical condition in easily understood language
    Knee Join 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 19.0
    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
    Primary Objective Study Population A -
    To assess the safety and tolerability of 200 mg MIV-711 q.d. over 52 (26+26) weeks in patients with symptomatic and radiographic knee osteoarthritis.
    E.2.2Secondary objectives of the trial
    Secondary Objectives Study Population A
    To assess, in patients with symptomatic and radiographic knee OA, over 52 (26+26) weeks:
    • The effect of MIV-711 on MRI cartilage thickness loss
    • The effect of MIV-711 on MRI bone marrow lesion volume
    • The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score (MOAKS) parameters
    • To assess the effect of MIV-711 on MRI knee joint bone area.

    Secondary Objective Study Population B
    To assess the effect of 200 mg MIV-711 q.d. on safety and tolerability over 26 weeks in patients with symptomatic and radiographic knee osteoarthritis.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following criteria to be eligible for enrolment in this study:
    1. Previously enrolled in Study MIV-711-201 including completion of Visit 8 either by
    • Receiving MIV-711 200 mg and had non-significant clinical worsening on the primary endpoint as defined by NRS increase of ≤2
    OR by
    • Receiving placebo and had a clinically significant worsening on the primary endpoint as defined by NRS increase of ≥2
    The NRS result will be derived using the primary endpoint from Study MIV-711-201: NRS average knee pain in the target knee with 7 days recall: increase from Baseline (Visit 2 of Study MIV-711-201) to Visit 8 of Study MIV-711-201.
    2. Female patients must be non-pregnant, non-lactating and of nonchildbearing potential either as naturally(spontaneously) postmenopausal or due to hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy (as determined by patient medical history). Naturally (spontaneously) post-menopausal is defined as being amenorrhoeic for 12 months without an alternative medical cause and with a Screening follicle stimulating hormone test indicating
    post-menopausal state.
    3. Male patients should avoid fathering a child by either of the following methods:
    • True sexual abstinence: meaning that heterosexual abstinence is in line with the preferred and usual lifestyle of the patient (periodic abstinence such as that based on calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of a trial, or withdrawal/coitus interruptus are not acceptable methods of
    contraception).
    • Willingness to use two effective means of contraception with their partner from the time of first IMP administration until 3 months after the last dose of IMP. Two or more of the following methods are acceptable and must include at least one barrier method: i) Surgical sterilization (i.e., bilateral tubal ligation for female partners; vasectomy for male), ii) placement of an intrauterine device or intrauterine system, iii) hormonal contraception (implantable, patch, oral), iv) barrier methods including condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Male patients who have been sterilised are required to use one barrier method of contraception (condom).
    4. The patient's usual analgesic regimen (in case of use) should remain the same as for Visit 8 in Study MIV-711-201 (i.e., Visit 1 in Study MIV- 711-202).
    NOTE: If a patient is experiencing increased or decreased pain and requires an increase or a decrease in the dose of analgesics, or an occasional change of analgesics medication during his/her participation in the study, then this will be allowed and should be properly documented in the patient file and the CRF.
    5. Needs to be able to communicate well with the investigators and staff.
    6. Able to comply with the requirements of the study procedures and provide written informed consent prior to any study related procedures.
    E.4Principal exclusion criteria
    Patients will be excluded from enrolment in this study if they meet any of the following criteria:
    1. The presence of any inflammatory arthritis (e.g., gout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, seronegative spondylarthropathy) or any underlying condition, other than OA, that may result in abnormal cartilage and bone metabolism.
    2. Any generalised pain condition that may interfere with the evaluation of the target knee pain (e.g., fibromyalgia) as judged by the investigator.
    3. Ongoing or a history of atrial fibrillation.
    4. Currently receiving medication that affects cartilage or bone metabolism (other than study drug; hormone replacement therapy taken for more than 6 months is allowed).
    5. Current or recurrent disease that could affect the action, absorption or disposition of MIV-711, or could affect clinical assessments or clinical laboratory assessments.
    6. Any clinically severe or significant uncontrolled concurrent illness, which, in the opinion of the Investigator, would impair ability to give informed consent or take part in or complete this clinical study.
    7. Any medical condition, AE, clinical or laboratory finding from Study MIV-711-201 that, in the opinion of the Investigator, would preclude inclusion in the present clinical study.
    8. Known or suspected intolerance or hypersensitivity to the investigational medicinal product, closely related compounds, or any of the stated ingredients.
    9. History of alcohol or other substance abuse within the last year.
    10. Use of an investigational product other than MIV-711 during participation in Study MIV-711-201 and /or active enrolment in another drug or vaccine clinical study.
    11. Significant target knee injury or surgery during participation in Study MIV-711-201.
    12. A history of partial or complete joint replacement surgery in the target knee at any time, listed for knee surgery, or anticipating knee surgery during the study period.
    13. Any factor which, in the opinion of the investigator, would jeopardise the evaluation or safety of the patient or be associated with poor adherence to the clinical study protocol (e.g., inability to complete study diary, poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period).
    14. Use of intra-articular hyaluronic acid in the target knee during participation in Study MIV-711-201.
    15. Use of intra-articular, intra-muscular or oral corticosteroids during participation in Study MIV-711-201.
    16. Commencement of non-pharmacological OA interventions during participation in Study MIV-711-201.
    17. Vulnerable patients, e.g., patients kept in detention, soldiers, and employees of the sponsor or the Contract Research Organisation (CRO) with direct involvement in the proposed study or other studies under the direction of the investigator or the CRO, as well as family members of the employees or the investigator.
    18. Lack of MRI of the knee from Visit 8 in Study MIV-711-201 due to special circumstances, such as claustrophobia or difficulties to fit the knee coil.
    19. Patients with contra-indication to MRI of the knee.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint (Study Population A)
    The primary objective is to study the safety and tolerability of MIV-711 in OA patients who have received treatment for up to 52 (26+26) weeks.
    Safety endpoints:
    • Incidence and severity of AEs
    • Incidence and severity of clinical laboratory abnormalities
    • Physical examination findings by patient
    • Incidence and severity of ECG abnormalities
    • Mean change from Baseline (Visit 2 of Study MIV-711-201) in vital signs (blood pressure, heart rate, temperature) and oxygen saturation
    • Categorical summary of observed vital signs and vital sign changes compared to Baseline (Visit 2 of Study MIV-711-201), by patient
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study
    E.5.2Secondary end point(s)
    Secondary Endpoints (Study Population A)
    Bone parameters will be measured from MRIs of the bone area taken at Visit 2 (Enrolment) and Visit 8 of Study MIV-711-201 as well as the MRI of the bone area taken at Visit 5 in Study MIV-711-202.
    MRIs will be analysed semi-quantitatively by a central experienced musculoskeletal radiologist using the MOAKS and quantitatively using statistical shape modelling (SSM, Imorphics Ltd) for the features below.
    MOAKS scoring will be used to assess the following features:
    - Bone marrow lesions (BMLs) and cysts: 15 sub-regions graded for BML (including ill-defined lesions and cysts) size in regard to the total volume of the sub-region occupied by BML(s). Grade 0=none, grade 1<33% of sub-regional volume, grade 2=33–66% of sub-regional volume and grade 3>66% of sub-regional volume.
    - Articular cartilage: 14 articular cartilage regions graded for size of any cartilage loss (including partial and full thickness loss) as a % of surface area as related to the size of each individual region surface and % of loss in this sub-region that is full-thickness loss.
    - Osteophytes: 12 sites scored for presence and size of osteophytes. Grade 0=none; Grade 1=small; Grade 2= medium; Grade 3= large.
    Bone shape modelling of MRI will be used to assess:
    - Mean cartilage thickness (mm) for each of the anterior, posterior and central regions, with areas denuded of cartilage included as having zero thickness
    - Bone marrow lesion volume (mm3) by anatomical region: medial and lateral femorotibial region of femur, medial and lateral patellofemoral region of femur, medial and lateral tibia, and patella
    - Bone area (mm2) for anatomical regions: lateral and medial femur (patellofemoral); lateral and medial femur (femorotibial); lateral and medial patella, lateral and medial tibial condyle
    - Bone shape by distance along an OA shape vector for femur, tibia and patella
    - Index bone area/cartilage thickness.

    Secondary Endpoints (Study Population B)
    These are the same as the primary endpoints for Study Population A
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study
    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 Yes
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA3
    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
    Bulgaria
    Georgia
    Germany
    Moldova, Republic of
    Romania
    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
    LVLS
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 80
    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 of 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 Decision2016-09-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-28
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