E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Knee Joint Osteoarthritis |
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E.1.1.1 | Medical condition in easily understood language |
Knee Joint Osteoarthritis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023476 |
E.1.2 | Term | Knee osteoarthritis |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effect of MIV-711 on target knee average pain over 26 weeks as measured by an 11-point numerical rating scale (1 week recall) in patients with symptomatic and radiographic knee osteoarthritis |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of MIV-711 on MRI target knee bone area in patients with symptomatic and radiographic knee OA over 26 weeks
The effect of MIV-11 on:
- worst target knee pain (1 week recall)
- average contralateral knee pain (1 week recall)
- constant and intermittent OA pain
- global improvements in knee problem, knee pain and knee function
- knee joint OA symptoms (function, pain, stiffness)
- global disease activity
- quality of life (QOL)
- MRI bone marrow lesion volume
- MRI cartilage thickness loss
- in the semi quantitative MRI Osteoarthritis Knee Score (MOAKS) parameters
- patient reported e-diary daily recall knee joint pain
- patient reported e-diary daily recall analgesics use
- The safety and tolerability of MIV-711
- biomarkers for bone resorption (serum CTX-I) and for cartilage degradation (urine CTX-II) assessment
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Current average knee pain, defined as pain in either knee, within 1 week before Visit 1, for which the patient gives a severity score of ≥4, <10 on a 0-10 NRS.
2. Inclusive of 40-80 years old.
3. Diagnosis of primary knee osteoarthritis, based upon the following:
- Fulfilling the American College of Rheumatology Clinical and Radiographic (ACR) criteria for OA defined as knee pain for most days of the prior month and at least one of the following three factors: age >50 years, morning stiffness of less than 30 minutes and knee crepitus on motion.
- X-ray evidence within the last 12 months for Kellgren and Lawrence (K-L) classification grade 2 or 3.
4. Female patients must be non-pregnant, non-lactating and of non-childbearing potential either as naturally (spontaneously) post-menopausal or due to hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy (as determined by patient medical history). Naturally (spontaneously) post-menopausal is defined as being amenorrhoic for 12 months without an alternative medical cause and with a screening follicle stimulating hormone indicating post-menopausal state.
5. 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 sterilisation (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).
6. The patient’s usual analgesic regimen (in case of use) should remain the same for 4 weeks prior to the signature of the informed consent form.
7. Needs to be able to communicate well with the investigators and staff.
8. Able to comply with the requirements of the study procedures and provide written informed consent prior to any study related procedures. |
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E.4 | Principal exclusion 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. A history of cancer within the previous 5 years (except for cutaneous basal-cell or squamous-cell cancer resolved by excision and cancer in situ which are allowed).
4. Ongoing or a history of atrial fibrillation.
5. Currently receiving medication that affects cartilage or bone metabolism (hormone replacement therapy taken for more than 6 months is allowed).
6. Current or recurrent disease that could affect the action, absorption or disposition of MIV-711, or could affect clinical assessments or clinical laboratory assessments.
7. 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.
8. Known or suspected intolerance or hypersensitivity to the investigational product, closely related compounds, or any of the stated ingredients.
9. A positive human immunodeficiency virus (HIV) antibody screen, a positive Hepatitis B surface antigen (HBsAg) screen, and/ or a positive Hepatitis C virus (HCV) antibody screen. A positive anti-HBc test in conjunction with a negative anti-HBs test.
10. History of alcohol or other substance abuse within the last year.
11. Use of an investigational product within 30 days prior to receiving the first dose of investigational product or active enrolment in another drug or vaccine clinical study.
12. Significant target knee injury or surgery within the 6 months preceding enrolment in the study.
13. 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.
14. 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 venipuncture or lack of adequate venous access for required blood sampling during the study period).
15. Use of intra-articular hyaluronic acid in the target knee within the 3 months preceding enrolment in the study.
16. Use of intra-articular, intra-muscular or oral corticosteroids in the 2 months preceding enrolment.
17. Commencement of non-pharmacological OA interventions within two months preceding enrolment.
18. 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.
19. Patients with contra-indication to MRI of the knee. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from visit 2 (baseline) to visit 8 in NRS average target knee pain score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy endpoint:
- Change from visit 2 (baseline) to visit 8 in knee joint MRI bone area
- Change from visit 2 (baseline) to visit 8 in NRS worst target knee pain score
- Change from visit 2 (baseline) to visit 8 in NRS average contralateral knee pain score
- Change from visit 2 (baseline) to visit 8 in constant and intermittent OA pain
- Change from visit 2 (baseline) to visit 8 in knee joint OA symptoms; WOMAC (function, pain, stiffness)
- Change from visit 2 (baseline) to visit 8 in global disease activity
- Change from visit 2 (baseline) to visit 8 in global improvements in knee problem, knee pain and knee function
- Change from visit 2 (baseline) to visit 8 in quality of life (QOL)
- Change from visit 2 (baseline) to visit 8 in MRI bone marrow lesion volume
- Change from visit 2 (baseline) to visit 8 in MRI cartilage thickness loss
- Change from visit 2 (baseline) to visit 8 in the semi quantitative MRI Osteoarthritis Knee Score (MOAKS) parameters
- Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall knee joint pain
- Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall analgesics use
- Changes from visit 2 (baseline) to visit 8 in serum biomarkers C-terminal telopeptide of collagen type I (sCTX-I for bone resorption assessment) and urinary C-terminal telopeptide of collagen type II (uCTX-II for cartilage degradation assessment)
Safety endpoints:
- Incidence and severity of adverse events
- Incidence and severity of clinical laboratory abnormalities
- Summary of changes in physical examination compared to baseline by patient
- Mean change from visit 2 (baseline) in vital signs (blood pressure, heart rate and temperature)
- Categorical summary of absolute vital signs and vital sign changes compared to visit 2 (baseline) by patient |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If 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 |
United Kingdom |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |