| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoarthritis of the knee |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10031165 |
| E.1.2 | Term | Osteoarthritis knee |
|
| 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 evaluate the clinical efficacy of GW842166 versus placebo in the treatment of pain associated with osteoarthritis of the knee. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of GW842166 administered orally to subjects
with osteoarthritis of the knee.
• To evaluate the dose response of GW842166 (incorporating 2 dose levels) and
placebo in the primary efficacy endpoint.
• To explore the clinical efficacy of GW842166 versus naproxen 500mg BID in the
treatment of pain associated with osteoarthritis of the knee.
• To evaluate the pharmacokinetic (PK) parameters of GW842166 in subjects with
osteoarthritis of the knee.
• To characterise the relationship between plasma concentrations and analgesic effect of GW842166 (PK-PD). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria – general
1. Subject is male or female outpatient, ≥ 40 years of age.
A female is eligible to participate in this study if she is of:
a. Non-childbearing potential (i.e., physiologically incapable of becoming
pregnant, including any female who is post-menopausal); or,
b. Child-bearing potential, has a negative pregnancy test and is not lactating at the
Screening and Baseline/Randomisation Visits and agrees to satisfy one of the
requirements listed in Appendix 1: Acceptable Methods of Contraception.
2. Subject is able and willing to give written informed consent
3. Subject is able to read, comprehend and record information required in the protocol e.g. complete assessments using an electronic device.
Inclusion criteria – related to OA
1. Meets ACR clinical and radiographic criteria for classification of idiopathic
(primary) osteoarthritis of the knee as defined by: knee pain and radiographic
osteophytes and at least one of the following:
i. Age > 50 years
ii. Morning stiffness < 30 minutes in duration
iii. Crepitus on active motion of the weight-bearing knee
2. A diagnosis of primary osteoarthritis of the knee for at least 3 months in symptom
duration prior to screen
3. Documented anteroposterior radiographic evidence of tibio-femoral osteoarthritis
within past 12 months (grade 2 or 3 according to the Kellgren & Lawrence scale
[Kellgren, 1963] in Table 4)
4. American Rheumatism Association (ARA) functional class I, II or III (Appendix 2:
American College of Rheumatology: Classification of global functional status)
5. Has ≤80 mm for the WOMAC pain subscale score at screen
6. Has ≥40 mm for the WOMAC pain subscale score at baseline
7. Has a minimum worsening between screen and baseline of at least 10mm for the
WOMAC pain subscale score
8. Subject has taken analgesics for the treatment of their knee OA for at least 4 out of 7 days in each of the 4 weeks preceding screen. Examples of suitable analgesics
include non-selective NSAIDs, COX-2 selective NSAIDs, paracetamol, tramadol
and opioid-containing preparations. Other preparations may be considered on a
case-by-case basis (to be discussed with the study sponsor). |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria – general:
1. Known history of hypersensitivity or intolerance to NSAIDs or aspirin, unless
subject has subsequently taken at least two separate NSAIDs for at least 1 month
without reaction. History of aspirin/NSAID-sensitive asthma, rhinitis, urticaria or
nasal polyps.
2. Intolerance to paracetamol.
3. Any clinical or biological abnormality found at screening (other than those related to the disease under investigation) which, in the opinion of the investigator, is clinically significant and would preclude safe participation in this study (e.g. current
malignancy, human immunodeficiency virus (HIV) infection, significant mental illness).
4. QTc ≥450msecs or QTc >480msecs for subjects with bundle branch block (based on a 12-lead ECG); single or average QTc value of triplicate ECGs, obtained over a
brief recording period. This applies to QTc intervals measured either by Bazett’s or
Fridericia’s formula (machine or manual over-read, male or female subjects).
5. Uncontrolled hypertension at screen SBP >160mmHg and/or sitting diastolic blood pressure DBP >90mmHg). Hypertension controlled by medications is acceptable, as long as stable for at least one month prior to screening (view protocol).
6. Presence of congestive heart failure (NYHA functional class II-IV)
7. History or presence of the following gastrointestinal disorders:
a peptic ulceration
b gastrointestinal bleeding
Note: (view protocol)
8. Subjects with any one of creatinine, bilirubin, alanine aminotransferase (ALT) or
aspartate aminotransfarase (AST) > 1.5 times the upper limit of normal (ULN) at
screen are excluded. Subjects with two or more of bilirubin, ALT or AST above the
ULN are excluded
9. Chronic Hepatitis B and C, as evidenced by positive Hepatitis B surface antigen
(HbsAg) or Hepatitis C antibody
10. History of chronic alcoholic liver disease
11. Renal dysfunction, defined as estimated glomerular filtration rate <30 ml/min
(calculated by central laboratory from the 4-variable Modification of Diet in Renal
Disease (MDRD) formula
12. Use of potent CYP3A4 inhibitors (please view protocol).
13. Use of methotrexate is prohibited. For other substrates for the organic anion
transporting peptide (OATP1B1) (see protocol section 5.6.2.1 Prohibited medications)
14. Use of a combination of a diuretic with either an angiotensin-converting enzyme
(ACE) inhibitor or an angiotensin receptor blocker (ARB). Please view protocol.
15. Use of anticoagulants (warfarin, heparin) or anti-platelet aggregation agents
(excluding low-dose aspirin) or a condition associated with decreased haemostasis
16. A history of clinically significant drug or alcohol abuse, as defined by Diagnostic
and Statistical Manual of Mental Disorders, (please view protocol).
17. Participation in another investigational drug or device study during the 3 months
prior to the Baseline/Randomisation Visit, (please view protocol).
Exclusion criteria related to OA:
1. Secondary causes of arthritis of the knee, please view protocol.
2. Had lower extremity surgery (including arthroscopy) within 6 months prior to
screening or scheduled for surgery of any kind during the study period
3. Significant prior injury to the index knee within 12 months prior to screen
4. Use of lower extremity assistive devices other than a cane or knee brace (use of a
‘shoe lift’ is permitted)
5. Disease of the spine or other lower extremity joints of sufficient degree to affect the index knee.
6. Any other arthritic condition that may affect the interpretation of clinical efficacy
and/or safety data or otherwise contraindicates participation in this clinical study, (please view protocol).
7. Use of any analgesic [including topical NSAIDs; excluding low-dose aspirin
(≤325mg per day)], other than protocol defined rescue therapy (paracetamol), within
5× half-life (in hours) prior to the first dosing day or during the study
8. Corticosteroid use prior to screen as follows:
i. Intra-articular injection of steroids to the index knee within the previous 3 months
ii. Intra-articular steroid injections into any site other than the index knee within the
previous 1 month.
iii. Intra-muscular corticosteroid injections within the previous 3 months.
iv. Oral corticosteroids within the previous 1 month.
9. Received hyaluronan injections into index knee within the previous six months prior to screen.
10. Initiation of or change to an established physiotherapy program within 2 weeks prior to screen or during the study period. An established physiotherapy program may be continued throughout the study period if unchanged in frequency and intensity.
11. Recent start or change in dose regimen (≤3 months prior to baseline) of any
OA-specific therapies (i.e., nutraceutical products) including but not limited to
chondroitin or keratin sulfate, s-adenosyl methionine (SAMe) and glucosamine
preparations.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change from baseline to Day 28 LOCF in Western Ontario and McMasters Universities OA Index (WOMAC) pain subscale score. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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