E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 evaluate the change in pain intensity, in terms of the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) pain score of the target knee
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E.2.2 | Secondary objectives of the trial |
- To evaluate changes in symptoms of OA - To evaluate the changes in physical functioning - To evaluate administration regimens of AMZ001 - To evaluate the safety and tolerability of AMZ001 - To evaluate changes in quality of life
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 the American College of Rheumatology (ACR) clinical and radiographic criteria. 3. Radiological OA grade 1, 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 specifications for central 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. The subject should have undergone a washout-period of at least 5 half-lives of any analgesic medication before completing the screening questionnaire. 6. Women of child-bearing potential must use at least an acceptably effective method of contraception (progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action, male or female condom with or without spermicide, cap, diaphragm or sponge with spermicide). 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 agree to use condom from enrolment up to 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. On stable pain therapy (i.e., at least 3 days per week for the previous month) with an oral NSAID or acetaminophen/paracetamol prior to the Screening Visit. 9. Except for osteoarthritis, the subject is in reasonably good health as determined by the Investigator. |
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E.4 | Principal exclusion criteria |
1. Known or suspected hypersensitivity to or previous hypersensitivity reactions to diclofenac, other non-steroidal anti-inflammatory drugs or related substances including aspirin, any of the excipients in either of the investigational products, or any physical impediment to gel application on the target knee. 2. Intra-articular delivery of corticosteroids or hyaluronic acid in the target knee within 6 months of screening or into any other joint within 30 days of screening. 3. High dose (equivalent to > 5 mg of prednisone/day) systemic corticosteroid treatment of more than 14 days during the past 6 months prior to screening. 4. Major surgery or arthroscopy of the target knee within the previous year prior to screening. 5. Planned surgery of the target knee within the next 3 months. 6. Use of a currently unapproved investigational drug, device or biologic within 6 months prior to screening. 7. Presence of concomitant non-osteoarthritic disease affecting either knee, such as rheumatoid arthritis, psoriasis, gout or pseudogout, if there is reason to believe that the disease(s) may significantly interfere with the interpretation of the clinical response to the study drug. 8. Medical history of coronary artery bypass graft surgery. 9. Current malignancy or treatment for malignancy within the past five years, with the exception of non-melanoma skin cancer, unless affecting the target knee area, or carcinoma in situ events. 10. Any other abnormal laboratory results or significant medical conditions that the Investigator believes should preclude the subject's participation in the trial. 11. Secondary osteoarthritis of the target knee, previous procedures or trauma affecting joint homeostasis including total meniscectomy or septic arthritis, or any other serious condition leading to secondary OA of the target knee. 12. Reported incidence of any of the following diseases: 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 subscore, presence of significant radicular back pain, or at least one migraine attack within the past 12 months before screening, as reported by the subject. 13. 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, regardless of the eligibility of the contralateral knee. 14. Body Mass Index > 45.0 kg/m2. 15. Estimated glomerular filtration rate < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) method. 16. Generalized skin irritation, previous skin reactions upon use of topical NSAIDs, current skin irritation or redness at the planned site of gel application, or significant skin disease including psoriasis, as judged by the investigator. 17. Known presence of gastroduodenal ulcer or any gastrointestinal bleeding (except hemorrhoidal) within 6 months prior to screening. 18. Use of any topical medication on the planned application site within 15 days of the time of randomization. 19. Use of moderate or higher doses of opioid medication for the treatment of pain within 6 weeks before the screening visit. 20. Use of duloxetine, pregabalin, or gabapentin within 4 weeks before the screening visit. 21. History of alcohol or drug abuse within the past year prior to randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this trial is the change from baseline in WOMAC pain sub-score (questions 1 to 5) in the target knee as evaluated at week 4. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 4. Subjects will fill in the WOMAC questionnaire in all the visits (from the screening visit to visit 6). |
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E.5.2 | Secondary 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 and intermittent OA 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 physical function assessed by the chair-stand test 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 - Change from baseline in WOMAC pain sub-score (questions 1 to 5) between groups receiving AMZ001 QD and BID in the target knee as evaluated at week 4 - Changes from baseline in constant and intermittent OA pain assessed by ICOAP scores between groups receiving AMZ001 QD and BID 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) between groups receiving AMZ001 QD and BID at week 4 - Changes from baseline in physical function assessed by the chair-stand test between AMZ001 QD and BID at week 4 - Changes from baseline in WOMAC total score and the WOMAC function and stiffness scores between AMZ001 QD and BID at week 4. - Changes from baseline in the impact of OA on daily living as assessed by the Patient Global Assessment (PGA) score at week 4 - Changes from baseline in work productivity and activity assessed by the WPAI at week 4 - Changes from baseline in quality of life assessed by the EQ5D at week 4 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At week four. All the questionnaires and assessments will be filled in/performed at every visit (From Visit 2 to Visit 6). |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Double blind for AMZ001/Placebo groups and single blind for comparator group |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Voltaren (commercial diclofenac 1%) |
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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 |
Czech Republic |
Denmark |
United States |
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E.8.7 | Trial 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
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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 | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |