A Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee
A Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee
The purpose of the study is to evaluate the analgesic efficacy of ASP7962 relative to
 placebo.

 This study will also evaluate the efficacy of ASP7962 relative to placebo on pain on walking,
 function and stiffness; the time course of efficacy of ASP7962 relative to placebo; the
 improvement in overall patient status of ASP7962 relative to placebo as well as the safety
 and tolerability of ASP7962 relative to placebo.
Inclusion Criteria:

 -  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:

 1. Age > 50 years

 2. Morning stiffness < 30 minutes

 3. Crepitus on active motion

 4. Bony tenderness

 5. Bony enlargement

 6. No palpable warmth of synovium

 -  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).

 -  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).

 -  Patient is ambulatory and the index knee must not contain any orthopedic and/or
 prosthetic device.

 -  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).

 -  WOMAC physical function subscale score ≥ 4 at baseline (visit 2 predose, mean of all
 questions on physical function subscale with a 48-hour recall period).

 -  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.

 -  Patient is compliant with daily pain recording. Compliance with diary completion will
 be defined as daily average pain ratings on at least 5 days of the baseline period, of
 which at least 3 days are in the last 4 days prior to visit 2.

 -  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 administration.

 -  Male patient must not donate sperm starting at screening and throughout the study
 period and for 90 days after the final study drug administration.

 -  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.

 -  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.

 -  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.

 -  Patient agrees not to participate in another investigational study from screening
 through the follow-up period (until day 57).

 Exclusion Criteria:

 Medical History / Clinical Status:

 -  Patient has a history of suicide attempt or suicidal behavior. Suicidal ideation
 within the last 12 months (a response of "yes" to questions 4 or 5 on the suicidal
 ideation portion of the Columbia-Suicide Severity Rating Scale [C-SSRS]), or who are
 at significant risk to commit suicide, as judged by the investigator at screening and
 at the time of randomization.

 -  Patient has current or prior psychosis, major depressive disorder or other clinically
 significant psychiatric disorder.

 -  Patient has a current or prior clinically significant neurologic disease, including
 but not limited to peripheral neuropathy, stroke, cognitive impairment and seizure.
 Childhood febrile seizures are not exclusionary.

 -  Patient has 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.

 -  Patient has an active malignancy or a history of malignancy (except for treated
 nonmelanoma skin cancer) within the past 5 years.

 -  Patient has a history of inflammatory arthritis, (including rheumatoid arthritis or a
 history of RPOA, osteonecrosis or avascular necrosis of bone and/or joints), or has
 other diagnoses that may increase the risk of RPOA (e.g., pre-existing atrophic OA,
 subchondral insufficiency fracture), or severe knee malalignment or any other
 joint-related condition that makes the patient unsuitable for study participation
 (e.g., joint pain that is disproportionately severe, or which has atypical features
 for OA pain, should trigger further medical evaluation to rule out subchondral
 insufficiency fracture).

 -  Patient has findings suggestive of RPOA or increased risk for RPOA on screening
 radiographs of either index or non-index joints (based on central reading).

 -  Patient has a history of shoulder surgery, clinically significant trauma or current
 symptoms, including pain or impaired range of motion at shoulder joint.

 -  Patient has a coagulopathy, is receiving anticoagulants or has been diagnosed with
 thrombocytopenia or a functional platelet disorder.

 -  Patient has a history of paracetamol intolerance, or existence of medical condition or
 use of concomitant medication for which paracetamol is contraindicated.

 -  Patient has any contraindication to naproxen including but not limited to:

 -  Known hypersensitivity to tramadol (a patient with intolerance or
 hypersensitivity is allowed, if the patient accepts to limit rescue medication
 toparacetamol).

 -  Asthma, rhinitis, nasal polyps, urticarial or allergic-type reactions after
 taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

 -  Anticipated coronary artery bypass graft surgery during the study.

 -  Active or history of peptic ulceration.

 -  Active or history of gastrointestinal bleeding (with the exception of
 hemorrhoids) or perforation.

 -  Patient has any contraindication to tramadol including but not limited to

 -  Known hypersensitivity to tramadol.

 -  Patient has used a monoamine oxidase inhibitor within 2 weeks prior to screening
 or during the screening or baseline periods.

 -  Patient has a body mass index (BMI) > 39 kg/m2.

 Cardiovascular:

 -  Patient has a clinically significant abnormality on 12-lead electrocardiogram (ECG) at
 screening or baseline (visit 2 predose).

 -  Patient has any of the following:

 -  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.

 -  Within 12 months prior to visit 2: acute coronary syndrome (e.g., myocardial
 infarction, unstable angina [ischemic heart disease is allowed]); 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.

 -  Current heart failure (New York Heart Association [NYHA] class III and IV).

 -  Patient has a 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 (visit 2 predose). These assessments may be repeated once, after a reasonable
 time period at the investigator's discretion. If the repeat measurement is meeting the
 above criteria, the patient will be excluded.

 -  Patient has a history of unexplained syncopal events or has symptomatic orthostatic
 hypotension at screening or baseline (visit 2 predose), 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 supine DBP.

 Clinical Chemistry / Hematology:

 -  Patient has (according to the investigator) clinically significant abnormalities in
 clinical chemistry, hematology or urinalysis at screening. These assessments may be
 repeated once, after a reasonable time period at the investigator's discretion (but
 within the screening period).

 -  Patient has any liver tests (aspartate aminotransferase [AST], alanine
 aminotransferase [ALT], total bilirubin [TBL]) > 1.5 times the upper limit of normal
 [ULN] at screening. These assessments may be repeated once, after a reasonable time
 period at the investigator's discretion (but within the screening period).

 -  Patient has an estimated glomerular filtration rate of ≤ 60 mL/min/1.73m2
 (Modification of Diet in Renal Disease [MDRD] calculation) at screening.

 -  Patient has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis
 A virus antibodies (immunoglobulin M) (anti-HAV [IgM]), hepatitis C virus antibodies
 (anti-HCV), or antibodies to human immunodeficiency virus type 1(HIV-1) and/or type 2
 (HIV-2) at screening.

 Prior Medication / Medical Intervention:

 -  Patient has received any investigational drug within 28 days (or 5 half-lives of the
 investigational drug, whichever is longer) before screening or is scheduled to receive
 an investigational drug other than blinded study treatments during the course of this
 study.

 -  Patient has previously received antibodies to NGF within 3 months prior to screening.

 -  Patient has had any major surgery or orthopedic surgery within 3 months before
 screening or has plans for surgical intervention during the study.

 -  Patient who is not a suitable candidate for joint replacement surgery and who is
 unable to stop chronic NSAID use.

 -  Patient has 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.

 -  Patient has received systemic corticosteroids within the past 30 days before screening
 or during the screening or baseline periods (topical, nasal and inhaled
 corticosteroids are permitted.)

 -  Patient has 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.

 -  Patient has 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.

 -  Patient has 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.

 -  Patient has used dipeptidyl peptidase 4 (DPP-4) inhibitors within 12 months prior to
 visit 2.

 -  Patient has 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.

 -  Patient has not complied with the requirements for restricted and prohibited
 medications and nonmedication therapies during the baseline period.

 Recreational Drug Use:

 -  Patient has a positive drug screen for alcohol or recreational drugs (including
 cannabinoids) or nonprescribed controlled substances at screening (these assessments
 may be repeated once, after a reasonable time period at the investigator's discretion,
 but within the screening period) or at baseline.

 -  Patient has a history of alcohol or drug abuse/dependence/misuse within 1 year prior
 to screening.

 General:

 -  Patient has 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, in the investigator's opinion.

 -  Patient has a Hospital Anxiety and Depression Scale (HADS) score > 12 on either
 subscale at screening or baseline (visit 2 predose).

 -  Patient is involved in an ongoing or settled workers compensation claim, disability or
 litigation related to the index knee or any pain problem.

 -  Any condition that, in the investigator's opinion, makes the patient unsuitable for
 study participation.

 -  Patient is an employee of the Astellas Group, the Contract Research Organization (CRO)
 involved or the investigator site executing the study.