A Phase 3 Randomized, Double-Blind, Active-Controlled, Multicenter Study of the Long-Term Safety and Efficacy of Subcutaneous Administration of Tanezumab in Subjects with Osteoarthritis of the Hip or Knee

PHRR160322-001197

A4091058

2015-CT0303

A Phase 3 Randomized, Double-Blind, Active-Controlled, Multicenter Study of the Long-Term Safety and Efficacy of Subcutaneous Administration of Tanezumab in Subjects with Osteoarthritis of the Hip or Knee

Completed

Ostearthritis

Secondary Outcome:

- Characterize the long-term joint safety risk using a composite endpoint (includes adjudication outcomes of rapidly progressive osteoarthritis (type-1 or type-2 combined), subchrondral insufficiency fracture (or SPONK) primary osteonectrosis, or pathological fracture).

- Characterize the long-term risk of the following individual adjudication outcomes occurring: rapidly progressive osteoarthritis (type-1 only), rapidly progressive osteoarthritis (type-2 only), rapidly progressive osteoarthritis (type-1 or type-2 combined), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, and pathological fracture.

- Characterize the long-term risk of all-cause total joint replacements (subjects who undergo total joint replacement plus subjects who have an adjudicated outcome of rapidly progressive osteoarthritis type-1 or type-2, subchondral insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture whether they undergo total joint replacement or not) occurring.

- Characterize joint space width changes in subjects with Kellgren-Lawrence Grade 2 or 3 Osteoarthritis of the index knee or index hip.

- Demonstrate superior efficacy of tanezumab 5 mg and tanezumab 2.5 mg versus each separate NSAID treatment group (naproxen 500 mg BID, celecoxib 100mg BID and diclofenac ER 75 mg BID) at week 16.

- Demonstrate the efficacy of tanezumab 2.5mg and tanezumab 5mg versus NSAID (combined) treatment at all time points to Week 56.

- Evaluate the long-term safety of tabezumab 2.5mg and tanezumab 5mg SC.

- Explore relationships between adjudicated outcomes of rapdily progressive osteoarthritis (type-1 or type-2), subchondral insufficiency fracture (or SPONK), primary osteonecrosis, or pathological fracture and variables that may be associated with these orthopedic risks.

- Characterize changes in physical activity level.

Completed

• Philippines

Clinical Trial

20150624161601

2015-10-23

0000-00-00

Unspecified

10

Unspecified

01 Jul 2015

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

Inclusion criteria

1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.

2. Male or female of any race, ≥ 18 years of age.

3. A diagnosis of osteoarthritis of the index hip or knee based on American College of Rheumatology criteria with X-ray confirmation (a Kellgren-Lawrence X-ray Grade of ≥2 as diagnosed by the Central Reader)

4. Subjects must meet the following criteria pertaining to their osteoarthritis treatment regimen:

- Documented history indicating that acetaminophen therapy has not provided sufficient pain relief;

- Currently receiving a stable dose regimen of oral NSAID therapy consisting of either naproxen 500 mg/day to 1000 mg/day, celecoxib 200 mg/day (either 100mg BID or 200mg QD), or diclofenac 100 mg/day to 150 mg/day, be tolerating their NSAID regimen, be taking this medication regularly (defined as an average of at least 5 days per week) during the 30day period prior to the Screening visit.

- Maintain a stabilized dose regimen of either naproxen 500 mg BID, celecoxib 100 mg BID or diclofenac ER 75 mg BID (depending on subject’s pre-study NSAID) with a minimum compliance of 70% (ie, 5 to 7 days per week) for at least the final 2 weeks of Screening period directly prior to the Baseline (Day 1) visit.

And at least 1 of the following criteria:

- Documented history indicating that tramadol treatment has not provided adequate pain relief or subject is unable to take tramadol due to contraindication or inability to tolerate;

- Documented history indicating that opioid treatment has not provided adequate pain relief or subject is unwilling to take opioids, or unable to take opioids due to contraindication or inability to tolerate.

5.  WOMAC Pain subscale NRS ≥5 in the index knee or index hip at Screening.

6.  Be willing to discontinue all non-study pain medications for osteoarthritis and not use prohibited pain medications throughout the duration of the study except as permitted per protocol.

7.  Female subjects of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for 112 days (16 weeks) after the last dose of assigned subcutaneous investigational product.

8.  Female subjects who are not of childbearing potential (ie, must meet at least one of the following criteria):

- Have undergone a documented hysterectomy and/or bilateral oophorectomy;

- Have medically confirmed ovarian failure; or

- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle stimulating hormone (FSH) level confirming the post-menopausal state.

9. Subjects who are willing and able to comply with lifestyle guidelines, scheduled visits, treatment plan, laboratory tests, and other study procedures through the End of Study visit.

Exclusion criteria

Subjects with any of the following characteristics/conditions will not be included in the study:

1.  Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.

2.  Body mass index (BMI) of > 39 kg/m2. For subjects requiring DXA scan body weight ≥300 lbs is exclusionary.

3.  History of other disease that may involve the index joint including inflammatory joint disease such as rheumatoid arthritis, seronegative spondyloarthropathy (eg, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease related arthropathy), crystalline disease (eg, gout or pseudogout), endocrinopathies, metabolic joint diseases, lupus erythematosus, joint infections, Paget’s disease, or tumors.

4. Radiographic evidence of any of the following conditions in any screening radiograph as determined by the central radiology reviewer and as defined in the tanezumab program imaging atlas: excessive malalignment of the knee, severe chondrocalcinosis; other arthropathies (eg, rheumatoid arthritis), systemic metabolic bone disease (eg, pseudogout, Paget’s disease, metastatic calcifications), large cystic lesions, primary or metastatic tumor lesions, stress or traumatic fracture.

5.  Radiographic evidence of any following conditions as determined by the central radiology reviewer and as defined in the tanezumab program imaging atlas at Screening: 1.) rapidly progressive osteoarthritis, 2.) atrophic or hypotrophic osteoarthritis, 3.) subchondral insufficiency fractures, 4) spontaneous osteonecrosis of the knee (SPONK), 5) osteonecrosis, or 6) pathologic fracture

6.  A history of osteonecrosis or osteoporotic fracture (ie, subject with a history of osteoporosis and a minimally traumatic or atraumatic fracture).

7.  History of significant trauma or surgery to a knee, hip, or shoulder within the previous year.

8.  Planned surgical procedure during the duration of the study.

9.  Largely or wholly incapacitated, (eg, subject bedridden or confined to a wheelchair, permitting little or no selfcare).

10. Fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy or other moderate to severe pain that may confound the assessments or self-evaluation of the pain associated with osteoarthritis. Subjects with a present (current) history of sciatica are not eligible for participation. Subjects with a past history of sciatica who have been asymptomatic for at least one year and who have no evidence of radiculopathy or sciatic neuropathy on thorough neurologic examination are eligible for participation.

11. A past history of carpal tunnel syndrome (CTS) with signs ir symptoms of CTS in the one year prior to Screening.

12.  Considered unfit for surgery, defined as grade >3 on the American Society of Anesthesiologists (ASA) physical classification system for surgery, or subjects who would not be willing to undergo joint replacement surgery if required

13. Contraindications to magnetic resonance imaging

14. History of intolerance or hypersensitivity to the relevant oral NSAID (naproxen, celecoxib or diclofenac) the subject could be randomized to receive to any of its excipients or existence of a medical condition or use of concomitant medication for which the use of this NSAID is contraindicated.

15.  History of intolerance or hypersensitivity to acetaminophen (paracetamol) or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of acetaminophen is contraindicated.

16.  Use of prohibited medications without the appropriate washout period prior to Screening or Initial Joint Pain Assessment Period.

17.  Oral or intramuscular corticosteroids within 30 days prior to IPAP.

18.  Intra-articular corticosteroid injection in the index joint within 12 weeks, or to any other joint within 30 days prior to IPAP.

19.  Intra-articular hyaluronic acid injection in the index joint within 30 days (or within 18 weeks for long-acting formulations such as Synvisc) prior to IPAP.

20.  History of cancer within 5 years prior to Screening, except for cutaneous basal cell or squamous cell cancer resolved by excision.

21.  Signs and symptoms of clinically significant cardiac disease including but not limited to:

- Ischemic cardiac disease (eg, unstable angina, myocardial infarction) in the 6 months prior to Screening

- Surgery or stent placement for coronary artery disease in the 6 months prior to Screening;

- New York Heart Association (NYHA) Class III or IV congestive heart failure or known left ventricular dysfunction with ejection fraction ≤35%, cardiomyopathy, myocarditis in the 6 months prior to Screening

- Resting tachycardia (heart rate ≥120 ) or resting bradycardia (heart rate ≤45) on ECG at Screening

- QTcF interval >500 msec in the absence of confounding factors like bundle branch block or paced rhythm at Screening;

- Any other cardiovascular illness that in the opinion of the Investigator would render a subject unsuitable to participate in the study;

- Subjects with history of heart block

22. Diagnosis of a transient ischemic attack in the past 6 months prior to Screening, diagnosis of stroke with residual deficits (eg, aphasia, substantial motor or sensory deficits), that would preclude completion or required study activities.

23. History, diagnosis, or signs and symptoms of clinically significant neurological disease, including but not limited to:

- Alzheimer’s disease or other types of dementia;

- Clinically significant head trauma within the past year;

- Peripheral or autonomic neuropathy;

- Multiple sclerosis;

- Epilepsy or seizure disorder with history of seizure within the last 2 years;

- Myopathy

24. History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder, including but not limited to:

- Psychotic disorders;

- Somatoform disorders;

- Bipolar disorders;

- Hospital admission for depression or suicide attempt within 5 years of Screening, or active severe major depression at Screening (determined from medical history: if needed, severity of depression may be assessed using Patient Health Questionnaire (PHQ-9). A score of ≥15 on questions 1-9 of the PHQ-9 corresponds to severe depression.

- Any other psychiatric illness that in the opinion of the Investigator would render a subject unsuitable to participate in the study.

25. History of known alcohol, analgesic or drug abuse within 2 years of Screening.

26. Previous exposure to exogenous NGF or to an anti-NGF antibody.

27. History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG-fusion protein.

28. Resting, sitting blood pressure (BP) ≥160 mmHg in systolic pressure or ≥100 mmHg in diastolic pressure at Screening.  If a subject is found to have untreated significant hypertension at Screening and antihypertensive treatment is initiated, assessment for study eligibility should be deferred until BP and antihypertensive medication have been stable for at least one month.  For subjects with previously diagnosed hypertension, antihypertensive medications must be stable for at least 1 month prior to Screening.

29. Subjects who have evidence of orthostatic hypotension based upon replicate orthostatic blood pressure measurements. If orthostatic blood pressure change is not able to be determined (eg, unable to establish a stable supine systolic and diastolic blood pressure) then subject is not eligible for the study.

30. Subjects with a total impact score of >7 on Survey of autonomic symptoms (SAS)

31. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3.0 times the upper limit of normal, or creatinine exceeding 1.7 mg/dL in men or 1.5 mg/dL in women, or hemoglobin A1c ≥10% at Screening. Repeat confirmatory tests may be performed.

32. Presence of drugs of abuse or illegal drugs in the urine toxicology screen obtained at Screening.

33. Positive Hepatitis B, Hepatitis C, or HIV tests at Screening indicative of current infection.

34. Participation in other studies involving investigational products within 30 days before Screening.

35. Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential who are unwilling or unable to use two highly effective methods of contraception for the duration of the study and for 112 days (16 weeks) after last dose of IP.

36. Other severe acute or chronic medical or psychriatric condition or laboratory abnormality that may increase risk associated with study participation

Interventional

Tanezumab

1. SC placebo once every 8 weeks plus oral NSAID BID (naproxen 500 mg, celecoxib 100mg BID, or diclofenac ER 75 mg BID)  through week 56

2. Tanezumab 2.5 mg SC once every 8 weeks plus placebo oral NSAID BID (to match naproxen, celecoxib, or diclofenac) through week 563. Tanezumab 5mg SC once every 8 weeks plus placebo oral NSAID BID (to match naproxen, celecoxib, or diclofenac) through week 56

None

Randomized

Double Blind

Principal Investigator, site staff, and Patient are blinded

Parallel

Tanezumab is a monoclonal antibody that binds to and inhibits the actions of NGF. The NGFI class may offer an important breakthrough in the treatment of chronic pain and is under clinical investigation for the treatment of pain associated with osteoarthritis or other chronic pain conditions.

Phase III