E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10031165 |
E.1.2 | Term | Osteoarthritis knee |
E.1.2 | System Organ Class | 100000004859 |
|
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 efficacy and safety of a single IA injection of 400 U or 200 U BOTOX compared with placebo as treatment for knee OA symptoms |
|
E.2.2 | Secondary objectives of the trial |
To explore the efficacy of a single IA injection of BOTOX (400 U or 200 U) compared with placebo on knee synovial effusion neurotransmitter/biomarker concentration profiles. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female, 40 to 75 years of age on the day of randomization (day 1).
2. Written informed consent has been obtained.
3. Written documentation has been obtained prior to initiating any study specific procedures in accordance with the relevant country and local privacy requirements, where applicable (e.g. Written Authorization for Use and Release of Health and Research Study Information (US sites) and written Data Protection consent (EU sites).
4. Diagnosis of primary idiopathic OA in the study knee in accordance with the American College of Rheumatology (ACR) modified clinical classification criteria for ≥ 52 weeks prior to visit 1.
5. Kellgren-Lawrence grade II or III as confirmed by x-ray obtained at visit 1 or ≤ 12 weeks prior to visit 1.
6. Washout of all prohibited acute and chronic pain medications (eg, anti-inflammatory drugs and analgesics) other than protocol permitted rescue treatment or other medications/treatments allowed per protocol is
completed at least 2 days prior to visit 2.
7. The average daily pain score over the first 7 days after initiation of the baseline period must be 4.0 to 9.0. This score is specific for the study knee as derived from daily pain scores recorded by the subject in the e-diary.
8. No evidence of abnormal mechanical symptoms such as locking or catching of the study knee per medical history or physical examination.
9. If a subject has bilateral knee OA, the subject must be able to distinguish which knee is the predominant source of pain. This knee must be designated as the study knee.
10. Body weight ≥ 60 kg and ≤ 150 kg inclusive.
11. For females of childbearing potential, a negative urine pregnancy test at visits 1, 2, and 3 (prior to the administration of the study medication) is required.
12. Must be ambulatory without assistive walking devices, able to perform usual daily activities, and agree to maintain the similar activity level throughout the course of the study.
13. Subject’s global assessment of knee OA is ‘fair’, ‘poor’, or ‘very poor’ at visit 2.
14. Ability to follow study instructions, likely to comply with the daily e-diary recording, and likely to complete all required visits. |
|
E.4 | Principal exclusion criteria |
1. Concurrent chronic pain conditions, or peripheral or central neuropathy that may affect sensation of the study knee area, including but not limited to back pain, hip pain, disc herniation, peripheral nerve entrapment, diabetic neuropathy, post-stroke pain, or fibromyalgia.
2. painDETECT Questionnaire score ≥ 13 at visit 2.
3. Subject diagnosed with any condition suggestive of a secondary cause of knee OA including but not limited to knee trauma, articular fracture, major dysplasias or congenital abnormality, acromegaly, ochronosis, hemochromatosis, Wilson’s disease, or primary osteochondromatosis.
4. History of or current evidence of rheumatoid arthritis as diagnosed by American College of Rheumatology (ACR) criteria.
5. Presence of bursitis, or tear of meniscus or ligament of the study knee, or history of significant injury or surgery to the study knee ≤ 52 weeks prior to visit 1.
6. Surgery of the study knee, such as, arthroplasty, arthroscopy inspection, or repair of knee ligaments that is planned to occur during the study period.
7. Treatment with IA hyaluronic acid in the study knee ≤ 24 weeks prior to visit 1.
8. Treatment with IA corticosteroid in the study knee ≤ 12 weeks prior to visit 1.
9. History or current diagnosis of gout or pseudogout with any joint involvement.
10. History or current diagnosis of Reiter’s, Sjögren’s syndrome, psoriasis or systemic lupus erythematosus or other autoimmune diseases with any joint involvement.
11. Evidence of skin infection or joint infection of the study knee.
12. Evidence of abnormal coagulation status (eg, excessive tooth bleeding with brushing) or subjects with hemophilia or other blood diseases affecting coagulation (eg, aplastic anemia, leukemia), or under chemo-/radio-therapy.
13. Use of prohibited medications or treatments for at least 2 days prior to initiating the baseline period or during the baseline period (which starts at visit 2 and ends at day -1)
14. Subject has initiated or changed their established physiotherapy or occupational therapy program that is specific to the lower extremities ≤ 14 days prior to visit 3.
15. Subjects using concomitant transcutaneous electrical nerve stimulation (TENS) or acupuncture to either lower extremity ≤ 14 days prior to visit 3.
16. Subject does not record a minimum of 5 days’ worth of e-diary data for the first 7 days after initiation of the baseline period at visit 2.
17. History of severe, progressive, or current unstable medical conditions other than OA.
18. Subjects with an active malignancy of any type or a history of malignancy ≤ 5 years prior to visit 1, except for basal cell carcinoma of the skin that has been excised ≥ 12 weeks prior to visit 1.
19. History of substance abuse or dependence ≤ 52 weeks prior to visit 1, excluding nicotine and caffeine.
20. Subjects with moderately severe or severe depression as indicated by Patient Health Questionnaire-9 total score of ≥ 15 or a score of > 0 on item # 9 at visit 1.
21. Subjects with severe anxiety as indicated by Generalized Anxiety Disorder score of ≥ 15 at visit 1.
22. Subjects with clinically relevant level of catastrophizing defined as Pain Catastrophizing Scale score of ≥ 30 at visit 1.
23. Known allergy or sensitivity to the study medication or its components.
24. Females who are pregnant, nursing, or planning a pregnancy during the study period.
25. Females of childbearing potential, not using a reliable means of contraception
26. Current enrollment in an investigational drug or device study or participation in such a study ≤ 30 days prior to entry into this study (ie, visit 1) or prior enrollment in any study evaluating botulinum toxin of any serotype for any condition.
27. Any medical or neurological condition that may put the subject at increased risk with exposure to BOTOX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, concomitant use of aminoglycosides, or any other significant diseases that might interfere with neuromuscular function.
28. Previous treatment with botulinum toxin of any serotype for any reason or immunization to any botulinum toxin serotype.
29. Investigator site personnel directly affiliated with this study and/or their immediate families (defined as spouse, parent, child, or sibling, whether adopted or biologic).
30. Subject has a condition or is in a situation which in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline of the 7-day average of the daily pain score |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• WOMAC pain score
• WOMAC physical function score
• GIC
• Daily worst pain score for the study knee |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary efficacy WOMAC and GIC variables will be summarized for each visit week at which the variable is to be recorded. |
|
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) | 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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
|
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |