| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ACTIVE OSTEOARTHRITIS OF THE KNEE |
|
| MedDRA Classification |
| 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 |
| To establish efficacy and safety of PLA-695 in subjects with active OA of the knee. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PLA-695 among number of dose levels.
To assess health outcome measures.
To assess the effect of PLA-695 on biomarkers related to clinical responses.
To assess PLA-695 exposure-response relationship on PD, efficacy, and safety measures.
To assess pharmacogenomics (PGX) analysis in OA (not in Europe). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Men or women 50 to 75 years of age.
a) Women must be of non-childbearing potential; women < or = 55 years must have a negative serum β-HCG pregnancy test.
b)Sexually active men who are not surgically sterile must agree and commit to use of barrier contraception during the study and for at least 12 weeks after the last dose of TA.
- Diagnosed with idiopathic OA of the knee for at least 3 months duration in accordance with [1986] American College of Rheumatology (ACR) clinical and radiographic criteria:
knee pain, the presence of osteophytes, and any one of the following:
age >50 years, crepitus, or morning stiffness <30 minutes.
- Radiographic confirmation of OA at the target joint (weight-bearing anteroposterior and lateral views) within 1 year of screening.
- Must be ambulatory.
- Must be currently treated for OA with a stable daily dose of 1 NSAID, including COX-2 inhibitors, not exceeding the maximum recommended dose in the product label, and taken as prescribed by the physician, starting at least 4 weeks before the screening visit.
- Must be willing to discontinue use of all NSAIDs/COX-2 inhibitors during the study
- At the baseline visit (2 to 14 days after after discontinuation of NSAID therapy), the scores of the following 3 measures must be at least 3 on a 1 to 5 point categorical scale and demonstrate a 1 category worsening (“flare”) in all three measures at the baseline visit as compared with the screening values:
a)Walking pain (5-point categorical scale: none, mild pain, moderate pain, severe pain, very severe pain)
b)Investigator’s overall evaluation of the subject’s condition (5-point categorical scale: very good, good, fair, poor, very poor)
c)Subject’s overall evaluation of his/her condition (5-point categorical scale: very good, good, fair, poor, very poor)
- The subject’s overall assessment of walking pain (Question 1 of the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] Visual Analog Scale [VAS]) must be ≥40 mm (0 as “no pain” to 100 mm as “severe pain”) |
|
| E.4 | Principal exclusion criteria |
- Subjects who have previously not been able to tolerate NSAIDs/COX-2 inhibitors, or have not had a therapeutic response to NSAIDs for OA.
- History of known hypersensitivity or allergic reaction to any of the components of PLA-695, sulfonamides, 5-lipoxygenase inhibitors, LT receptor antagonists, acetaminophen/paracetamol, or COX-2 inhibitors/NSAIDs, including aspirin.
- History of any surgery at the target knee, including arthroscopic interventional surgical procedure, or anticipated need for any surgery during the study.
- Arthroscopy for diagnostic purposes or lavage at the target knee within 1 year of screening, or any invasive procedures anticipated during the study.
- Orthopedic surgery of the lower extremities other than the target knee within 6 months of screening, or an anticipated need for such surgery during the study.
- History of or suspected current esophageal or gastrointestinal bleeding, ulcers, obstruction, or perforation, or pancreatitis.
- Grade 4 severity on the Kellgren
-Lawrence Scale on the screening target knee radiograph.
- Concomitant inflammatory arthropathy or other diseases or conditions that may affect joints (eg, RA or other auto-immune diseases, metabolic bone disease, psoriatic arthritis, gout, pseudogout, infection of the target knee, chondrocalcinosis in the target knee, Paget’s disease, neuropathic conditions, hemochromatosis).
- History of acute trauma leading to secondary OA of the target knee.
- Cancer, or a history of cancer (other than successfully resected cutaneous basal and squamous cell carcinoma) within 5 years before the screening visit.
- Any significant cardiovascular, hematologic, blood dyscrasia, endocrine, respiratory, neurologic, psychiatric, metabolic, immunologic, infectious, hepatic, or renal condition that the investigator considers detrimental to the subject’s participating in the study or that may prevent the successful completion of the study, including the following:
a)Cardiovascular disease:
i)History of myocardial infarction.
ii)History of angina pectoris.
iii)Cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormality, such as ischemia.
iv)History of stroke or transient ischemic attack. v)Congestive heart failure (CHF) New York Heart Association classification for CHF: Class III or IV.
vi)Uncontrolled hypertension (systolic blood pressure [SBP] ≥140 mmHg or diastolic blood pressure [DBP] ≥90 mmHg).b)Poorly controlled diabetes.
c)Known or suspected untreated infections with Helicobacter pylori infection.
d)History of human immunodeficiency virus (HIV) infection or known risk of HIV disease.
- Any clinically significant laboratory abnormality, including those listed below:
a)Liver function abnormality (total bilirubin >1.5 x the upper limit of normal [ULN], aspartate aminotransferase [AST/SGOT] > 1.2 x ULN, alanine aminotransferase [ALT/SGPT] > 1.2 x ULN).
b)Anemia (hemoglobin or hematocrit below the lower limit of normal).
c)Thrombocytopenia or thrombocytosis (platelets <125,000/mm3 or ≥1,000,000/mm3 [SI units:<125 x 109/L or ≥ 1,000 x 109/L])
d)Renal function abnormality, including serum creatinine level greater than the upper limit of normal.
e)Positive qualitative serologic findings for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies.
f)Fasting serum triglyceride levels > 500 mg/dL (SI units:>5.65 mmol/L).
g)Serum amylase or serum lipase ≥ 1.25 x ULN.Screening laboratory tests with abnormal results may be repeated once to confirm abnormal results.
- History of poor compliance to treatment regimens or history of drug abuse/alcohol abuse, or excessive alcoholic beverage consumption (ie, 2 or more alcohol-containing drinks per day).
- Oral or parenteral corticosteroids, intra-articular injection, or arthrocentesis in target joint within 3 months before screening.
- Injections of hyaluronic acid or its derivatives in the target joint within 6 months before screening.
- History of a need for use of chronic narcotic analgesics.
- Chronic aspirin use, including low dose aspirin for cardiac prophylaxis.
- Lithium therapy within 4 weeks before screening.
- Oral or parenteral anticoagulant (eg, warfarin, heparin) within 4 weeks before screening.
- Anti-platelet agents (eg, clopidogrel) within 4 weeks before screening.
- Anti-LT agents (eg, montelukast) within 4 weeks before screening.
- Other investigational medications or therapies within 1 month before screening.
- At the baseline visit no NSAIDs should have been ingested (including nonprescription NSAIDs), within 2 days or 5 half-lives, which ever is longer, before the baseline visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| WOMAC VAS walking pain (question 1) at week 6 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
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 | |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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