| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain due to osteoarthritis of the knee or hip |
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| E.1.1.1 | Medical condition in easily understood language |
| Pain of the knee or hip due to a joint disease that results from breakdown of joint cartilage and underlying bone |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023476 |
| E.1.2 | Term | Knee osteoarthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020108 |
| E.1.2 | Term | Hips osteoarthritis |
| 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 |
| The primary objective of the study is to evaluate the efficacy of fasinumab compared with placebo, when administered for up to 16 weeks in patients with pain due to osteoarthritis (OA) of the knee or hip. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
2. To evaluate the efficacy of fasinumab compared with placebo, when administered for up to 44 weeks in patients with pain due to OA of the knee or hip
3. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 16 weeks in patients with pain due to OA of the knee or hip
4. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 52 weeks in patients with pain due to OA of the knee or hip
5. To assess the safety and tolerability of fasinumab compared with naproxen, when administered for up to 104 weeks in patients with pain due to OA of the knee or hip
6. To evaluate the pharmacokinetic (PK) profile of fasinumab administered to patients with pain due to OA of the knee or hip for up to 52 weeks and up to 104 weeks
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Optional Pharmacogenomic sub-study |
|
| E.3 | Principal inclusion criteria |
Key Inclusion Criteria for Year 1
1. Male and female patients, at least 18 years of age, at screening
2. A clinical diagnosis of OA of the knee or hip based on the American College of Rheumatology criteria with radiologic evidence of OA (K-L score ≥2 for the index joint) at the screening visit
3. Moderate to severe pain in the index joint defined at both the screening and randomization visits
4.Willing to discontinue current pain medications and to adhere to study requirements for rescue treatments (acetaminophen/paracetamol to be taken as needed with a maximum daily dose of 2500 mg [countries where 500 mg strength tablets/capsules are available] or 2600 mg [countries where 325 mg strength tablets/capsules are available])
5. A history of at least 12 weeks of analgesics use for pain due to OA of the knee or hip, as defined by
a. Inadequate pain relief from acetaminophen/paracetamol AND
b. Intolerance to or inadequate pain relief from opioid or tramadol therapy, unwillingness to take opioid or tramadol therapy for a medically acceptable reason, or lack of access to an opioid or to tramadol
6. Currently using a stable dose of NSAID, defined as using oral NSAIDs at regularly prescribed doses for approximately 4 days per week over the last 4 weeks (patients who are screen failures prior to the randomization visit but who met the NSAID use criterion at screening would still meet this criterion if they are eligible for rescreening)
7. Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments during the initial 16 weeks of treatment
8. Stable treatment with glucosamine sulfate and chondroitin sulfate treatments must be stopped during the pre-randomization period
9. Consent to allow all radiographs and medical/surgical/hospitalization records of care received elsewhere prior to and during the study period to be shared with the investigator
10. Willing to maintain current activity and exercise levels throughout the study
11. Willing and able to comply with clinic visits and study-related procedures and willing to provide follow-up information related to any JR surgery that occurs within the period of time covered by their intended participation in the study
12. Able to understand and complete study-related questionnaires
Key Inclusion Criteria for Year 2
Note: Any Year 1 patient attending their week 52 visit on or after 26 March 2020 will no longer have the option to enroll into Year 2.
1. Completed the treatment period of Year 1
2. Did not permanently discontinue study drug during Year 1
3. Received no less than 10 of the 13 planned doses of SC study drug during the treatment period of Year 1
4. Provide informed consent for Year 2
5. Willing to continue to maintain current activity and exercise levels throughout Year 2
6. Willing and able to comply with clinic visits and study-related procedures and willing to provide follow-up information related to any JR surgery that occurs within the period of
time covered by their intended participation in the study
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|
| E.4 | Principal exclusion criteria |
Key Exclusion Criteria for Year 1:
1. Non-compliance with the NRS recording during the pre-randomization period (4 or more
consecutive missed diary entries)
2. History or presence at the screening visit of non-OA inflammatory joint disease (eg,
rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-gout, gout,
spondyloarthropathy, polymyalgia rheumatica, joint infections within the past 5 years),
Paget's disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis,
fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy
3. History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency fracture, rapidly progressive OA type 1 or type 2), stress fracture, recent stress fracture, neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is eligible), knee dislocation (patella dislocation is eligible), congenital hip dysplasia with degenerative joint disease, extensive subchondral cysts, evidence of bone fragmentation or collapse, or primary metastatic tumor with the exception of chondromas or pathologic fractures during the screening period
4. Trauma to the index joint within 3 months prior to the screening visit
5. Signs or symptoms of carpal tunnel syndrome within 6 months of screening visit
6. Patient is not a candidate for MRI
7. Is scheduled for a JR surgery to be performed during the study period or who would be
unwilling or unable to undergo JR surgery if one eventually became necessary
8. History or presence at the screening visit of autonomic neuropathy, diabetic neuropathy, or other peripheral neuropathy, including reflex sympathetic dystrophy
9. History or diagnosis of chronic autonomic failure syndrome including pure autonomic failure, multiple system atrophy (Shy-Drager syndrome)
10.History of naproxen intolerance, or existence of a medical condition that is high risk for naproxen-associated complications (eg, high risk of gastrointestinal bleed, previous ulcer, condition requiring use of anti-coagulants or anti-platelet therapy, or acute coronary syndrome)
11. Known allergy or sensitivity to doxycycline or related compounds, or monoclonal antibodies
12. Poorly controlled diabetes (defined as any single value of hemoglobin A1c [HbA1c] >9.0%) at the screening visit
13. Known history of human immunodeficiency virus infection
14. Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes
simplex virus encephalitis
15. History of sickle cell disease, including sickle cell anemia and β-thalassemia
16. Confirmed elevated screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 times the upper limit of normal (ULN)
17. Resting heart rate of <50 beats per minute (bpm) or >100 bpm (by vital sign assessment
or as captured during electrocardiogram [ECG] assessment) at the screening or randomization visits
18. History or presence of 2nd or 3rd degree heart block, 1st degree heart block with abnormal QRS complex, or bifascicular block by ECG assessment at the screening visit
19. History or presence of orthostatic hypotension, as defined in Section 8.2.3.4, at the screening, pre-randomization, or randomization visits
20.History of poorly controlled hypertension
21.Congestive heart failure with NY Heart Classification of stage III or IV
22.History of peripheral vascular disease, transient ischemic attack, cerebrovascular accident, myocardial infarction, unstable angina, or documented atherosclerotic cardiovascular disease
37.Pregnant or breastfeeding women
38. Women of childbearing potential who have a positive pregnancy test result or do not have their pregnancy test result at baseline
39.Women of childbearing potential who are unwilling to practice highly effective contraception prior to start of the first treatment, during the study, and for at least 20 weeks after the last dose.
40.Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors/angiotensin
receptor blockers (ARBs) and diuretics, or presence of an estimated glomerular filtration
rate (GFR) <30 mL/minute/1.73m2
Key Exclusion Criteria for Year 2
1.Women of childbearing potential who are unwilling to continue to practice highly effective contraception during the study, and for at least 20 weeks after the last dose. Highly effective contraceptive measures include stable use of combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; vasectomized partner; and or sexual abstinence.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Change in the WOMAC pain subscale scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo.
2. Change in the WOMAC physical function subscale scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo.
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints of the study are:
1. Change in the Patient Global Assessment (PGA) scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with placebo
2. Percentage of patients treated with fasinumab, compared with that of patients treated with placebo, who had a response at week 16, with response defined as an improvement by ≥30% in the WOMAC pain subscale scores
3. Change in WOMAC pain subscale scores from baseline to week 16 in patients treated with fasinumab, compared with that of patients treated with naproxen
4. Change in WOMAC physical function subscale scores from baseline to week 16 in patients treated with fasinumab, compared with that of patients treated with naproxen
5. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated with fasinumab, compared with that of patients treated with placebo
6. Change in WOMAC physical function subscale scores from baseline to week 44 in patients treated with fasinumab, compared with that of patients treated with placebo
7. Change in the PGA scores from baseline to week 44 in patients treated with fasinumab compared with that of patients treated with placebo
8. Change in the PGA scores from baseline to week 16 in patients treated with fasinumab compared with that of patients treated with naproxen
9. Change in WOMAC pain subscale scores from baseline to week 44 in patients treated with fasinumab, compared with that of patients treated with naproxen
10. Change in WOMAC physical function subscale scores from baseline to week 44 in patients treated with fasinumab, compared with that of patients treated with naproxen
11. Percentage of patients treated with fasinumab, compared with that of patients treated with naproxen, who had a response at week 16, with response defined as an improvement by ≥30% in the WOMAC pain subscale scores
12. Change in WOMAC pain subscale scores from baseline to the average score across weeks 4, 8, 12 and 16, in patients treated with fasinumab compared with that of patients treated with placebo
13. Change in WOMAC physical function subscale scores from baseline to the average score across weeks 4, 8, 12 and 16, in patients treated with fasinumab compared with that of patients treated with placebo
14. Change in WOMAC pain subscale scores from baseline to the average score across weeks 36, 40 and 44 in patients treated with fasinumab compared with that of patients treated with placebo
15. Change in WOMAC physical function subscale scores from baseline to the average score across weeks 36, 40 and 44 in patients treated with fasinumab compared with that of patients treated with placebo
Safety Endpoints for Year 1 (All Randomized and Treated Patients)
Safety endpoints for Year 1 (through week 52) will include:
-Incidence of AA (as confirmed by independent adjudication)
-Incidence of DA (as confirmed by independent adjudication)
-Incidence of TEAEs
-Incidence of sympathetic nervous system dysfunction (as diagnosed after consultation with an appropriate specialist, such as a neurologist and/or cardiologist)
-Incidence of peripheral sensory AEs that require a neurology or other specialty consultation
-Incidence of all-cause JRs
The incidence of JRs at the telephone survey 52 weeks after the last dose of study drug (week 100) will also be evaluated.
Safety Endpoints for Year 2 (All Randomized and Treated Patients Proceeding
into Year 2):
The safety endpoints listed above will be evaluated for Year 2 from the first dose of study drug given in Year 2 through week 104E (end of treatment), as well as for the periods of Year 1 and 2 from day 1 through week 104E. The incidence of JRs at the telephone survey 52 weeks after the last dose of study drug (week 152E) will also be evaluated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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) | No |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Denmark |
| Germany |
| Hungary |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The end of study is defined as the last phone contact of the last patient in this study. The end of study phone contact will be at week 100 for patients participating in Year 1 only or week 152 E or patients participating in Year 1 and Year 2. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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