A Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee

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:

• Age > 50 years
• Morning stiffness < 30 minutes
• Crepitus on active motion
• Bony tenderness
• Bony enlargement
• 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.