|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Osteoarthritis of the knee
|E.1.1.1||Medical condition in easily understood language ||
|Osteoarthritis of the knee
|E.1.1.2||Therapeutic area ||Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|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 ||
|Evaluate the analgesic efficacy of ASP7962 relative to placebo
|E.2.2||Secondary objectives of the trial ||
● Evaluate the efficacy of ASP7962 relative to placebo on pain on walking, function and stiffness
● Evaluate the time course of efficacy of ASP7962 relative to placebo
● Evaluate the improvement in overall patient status of ASP7962 relative to placebo
● Evaluate the safety and tolerability of ASP7962 relative to placebo
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations.
2. Patient is a male or female patient and aged 18 to 80 years, at screening.
3. Patient has a primary diagnosis of OA of the index knee with symptoms for at least 6 months prior to screening and patient meets American College of Rheumatology clinical classification criteria for OA of the knee, defined by the following.
Knee pain and at least 3 of the following 6 (a-f):
a) Age > 50 years
b) Morning stiffness < 30 minutes
c) Crepitus on active motion
d) Bony tenderness
e) Bony enlargement
f) No palpable warmth of synovium
4. Patient has a radiographic image of the index knee (according to the minimum quality criteria for radiographic image as set by the central radiology reader) showing evidence of OA with a Kellgren-Lawrence grade ≥ 2 at screening (based on central reading).
5. Patient has moderate to severe index knee pain (pain due to OA of the knee at least 5 days per week for the last 3 months prior to screening, as determined by patient’s medical history).
6. Patient is ambulatory and the index knee must not contain any orthopedic and/or prosthetic device.
7. WOMAC pain subscale score (with a 48-hour recall period) in the index knee ≥ 4 at baseline (visit 2 predose, mean of all questions on pain subscale).
8. This criterion has been removed.
9. WOMAC physical function subscale score ≥ 4 at baseline (visit 2 predose, mean of all questions on the physical function subscale with a 48-hour recall period).
10. Patient is willing to discontinue all current pain medications during the baseline and treatment periods (until day 57) (except for allowed rescue medications). Low dose aspirin for cardioprophylaxis is allowed.
11. Patient is compliant with daily pain recording.
12. Male patient and their female spouse/partners who are of
childbearing potential must be using a barrier method* and 1 form of
highly effective birth control** starting at screening and continuing
throughout the study period and for 90 days after the final study drug
13. Male patient must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
14. Female patient must either:
● Be of non childbearing potential:
■ post-menopausal (defined as at least 1 year without any menses) prior to screening, or
■ documented surgically sterile
● Or, if of childbearing potential:
■ agree not to try to become pregnant during the study and for 28 days after the final study drug administration,
■ and have a negative pregnancy test at screening and at baseline (visit 2 predose),
■and, if heterosexually active, agree to consistently use a barrier
method* and 1 form of highly effective birth control** starting at
screening and continuing throughout the study period and for 28 days
after the final study drug administration.
15. Female patient must agree not to breastfeed starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
16. Female patient must not donate ova starting at screening and continuing throughout the study period and for 28 days after the final study drug administration.
17. Patient agrees not to participate in another investigational study from screening through the follow-up period (until day 57).
* Barrier methods of birth control include:
•Condom or occlusive cap (diaphragm or cervical/ vault caps) with
** Highly effective forms of birth control include:
•Consistent and correct usage of established oral contraception
(including progestogen-only oral contraception associated with
inhibition of ovulation).
•Established intrauterine device (IUD) or intrauterine system (IUS).
|E.4||Principal exclusion criteria||
|3.Current or prior clinically significant neurologic disease, including but
not limited to peripheral neuropathy, stroke, cognitive impairment and
4.Any clinically significant uncontrolled musculoskeletal disorder (with
the exception of OA), cardiovascular, gastrointestinal, endocrinologic
(diabetes mellitus is allowed if controlled [glycated hemoglobin (HbA1c)
≤ 8.0%] and no peripheral neuropathy), hematologic, hepatic,
immunologic, metabolic, urologic, pulmonary, dermatologic, renal
and/or other major disease.
5.Active malignancy or a history of malignancy (except for treated
nonmelanoma skin cancer) within the past 5 years.
6.History of inflammatory arthritis (including rheumatoid arthritis), or a
history of RPOA (including osteonecrosis or avascular necrosis of bone
and/or joints), or has other diagnoses that may increase the risk of
RPOA, or severe knee malalignment or any other joint-related condition
that makes the patient unsuitable for study participation.
7.Findings suggestive of RPOA or increased risk for RPOA on screening
radiographs of either index or non-index joints.
8.History of shoulder surgery, clinically significant trauma or current
symptoms, including pain or impaired range of motion at shoulder joint.
9.Patient has a coagulopathy, is receiving anticoagulants or has been
diagnosed with thrombocytopenia or a functional platelet disorder.
10.History of paracetamol intolerance, or existence of medical condition
or use of concomitant medication for which paracetamol is
11.Any contraindication to naproxen.
12.Any contraindication to tramadol.
15.a.Lifetime history of ischemic or hemorrhagic stroke, cardiac arrest,
torsade de pointes, clinically significant structural heart disease or a
personal or family history of long QT syndrome. b.Within 12 months
prior to visit 2: acute coronary syndrome (e.g.,myocardial infarction,
unstable angina [ischemic heart disease is allowed, if in the
investigator's opinion, it is clinically stable]); transient ischemic attack;
coronary or peripheral revascularization procedure; clinically significant
cardiac arrhythmias (including atrial fibrillation or flutter), heart block
(first degree heart block is allowed provided PR interval is not greater
than 240 msec) or other clinically significant cardiovascular disorder.
c.Current heart failure (NYHA class III and IV).
16.Resting pulse rate < 50 or > 100 beats per minute (bpm); systolic
blood pressure (SBP) > 160 mm Hg; diastolic blood pressure (DBP) > 90
mm Hg at screening or baseline.
17.History of unexplained syncopal events or has symptomatic
orthostatic hypotension at screening or baseline, defined as postural
related symptoms and at least one of the following: standing SBP ≥ 20
mm Hg lower than supine SBP, standing DBP ≥ 10 mm Hg lower than
19.Any liver tests (aspartate aminotransferase [AST], alanine
aminotransferase [ALT], total bilirubin [TBL]) > 1.5 times the upper limit
of normal [ULN] at screening.
20.Estimated glomerular filtration rate of ≤ 60 mL/min/1.73m2 (MDRD
calculation) at screening.
23.Previously received antibodies to NGF within 3 months prior to
26.Received intra-articular corticosteroid or intra-articular local
anesthetics within 3 months prior to screening, intra articular hyaluronic
acid within 6 months prior to screening or any of these therapies during
the screening or baseline periods.
27.Received systemic corticosteroids within the past 30 days before
screening or during the screening or baseline periods (topical, nasal and inhaled corticosteroids are permitted).
28.Received any medications or nonmedication therapy with efficacy in
reducing pain of OA of the knee, including over-the-counter (OTC)
products (with the exception of ice packs, rest, and paracetamol) during
the baseline period.
29.Started or stopped physiotherapy, acupuncture or transcutaneous
electrical nerve stimulation related to treatment of the index knee within
4 weeks prior to screening or during the screening or baseline periods.
Stable regimens of these therapies introduced more than 4 weeks prior
to screening will be allowed if the regimen is to continue unchanged
during the study.
30.Used opioids for more than 4 days during the week preceding
screening or during the screening period; or has received any opioids
during the baseline period.
31.Used dipeptidyl peptidase 4 (DPP-4) inhibitors within 12 months prior
to visit 2.
32.Regularly used any strong systemic inducer of cytochrome P450
(CYP) 3A metabolism (e.g.,rifampin, St John's wort) in the 3 months
before visit 2.
36.Any painful condition syndrome (e.g.,neuropathy, fibromyalgia) or
other concurrent medical or arthritic condition that has the potential to
confound the assessment of pain in the index knee.
|E.5 End points
|E.5.1||Primary end point(s)||
|Change from baseline to week 4 in WOMAC pain subscale score
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|E.5.2||Secondary end point(s)||
|Secondary Efficacy Endpoints:
• Change from baseline to EOT in WOMAC pain, physical function, and stiffness subscale scores, WOMAC total score, and WOMAC walking pain
• Change from baseline to weeks 1 and 2 in WOMAC pain subscale score
• Change from baseline to weeks 1, 2 and 4 in WOMAC physical function and stiffness subscale scores, WOMAC total score, and WOMAC walking pain
• Change from baseline to EOT and to weeks 1, 2, 3 and 4 in mean daily average pain score assessed by the NRS in the patient’s daily diary
• Change from baseline in overall patient improvement assessed by Patient Global Assessment (PGA) at EOT and weeks 1, 2 and 4
• Proportion of patients that achieves ≥ 30% decrease from baseline to EOT in WOMAC pain subscale score
• Proportion of patients that achieves ≥ 50% decrease from baseline to EOT in WOMAC pain subscale score
Secondary Safety Endpoints
● Incidence and severity of TEAEs
● Vital signs, orthostatic challenge test
● Safety laboratory tests, including liver tests
● 12-lead ECG parameters
● Physical examination
● C-SSRS (evaluation of suicidal ideation and behavior).
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|Week 1, week 2, week 3, week 4
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| 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.184.108.40.206||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.8.1.3||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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| Yes
|E.8.2.2||Placebo || Yes
|E.8.2.4||Number of treatment arms in the trial||3
The trial involves single site in the Member State concerned
|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||5
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||33
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| No
|E.8.6.2||Trial being conducted completely outside of the EEA|| No
|E.8.7||Trial has a data monitoring committee|| Yes
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||
|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||6