Clinical trial NCT02611466 (phase 2, status: completed)
Conditions: osteoarthritis of the knee, chronic lower back pain
ICD codes: M15.4, M15.0, M16.9, M17.9, M19.011, M19.012, M19.019
Drugs: asp7962, naproxen, placebo
SMILES: COC1=C(O)C=CC(CNC(=O)CCCC\C=C\C(C)C)=C1, CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O
Eligibility criteria:

        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.