Efficacy and Safety of ATB-346 Versus Placebo in Osteoarthritis Patients

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of a 14-day dosing regimen of ATB-346 at doses of 150 mg, 200 mg and 250 mg compared to placebo in reducing osteoarthritis knee pain as measured by changes in the post-treatment WOMAC subscale pain score relative to each patient's pretreatment baseline WOMAC assessment.Safety will be assessed via measurements of vital signs and clinical laboratory tests at baseline and at various time points during the study, patient monitoring, and by the documentation of adverse events.

Detailed Description
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The primary objective of this study is to evaluate the efficacy of a 14-day dosing regimen of once daily administration of ATB-346 at doses of 150 mg, 200 mg and 250 mg compared to placebo in reducing osteoarthritis knee pain as measured by changes in the post-treatment WOMAC subscale pain score relative to each patient's pretreatment baseline WOMAC assessment.A total of 360 evaluable patients are planned in this study: 250 mg (n=120); 200 mg (n=120); 150 mg (n=60); placebo (n=60). Safety will be assessed via measurements of vital signs and clinical laboratory tests at baseline and at various time points during the study, patient monitoring, and by the documentation of adverse events.

Official Title
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A Double-Blind, Placebo-Controlled, Phase 2B Study to Assess the Efficacy and Safety of a 14-Day Dosing Regimen of 3 Doses of ATB-346 Versus Placebo, Orally Administered Once Daily to Patients Diagnosed With Osteoarthritis of the Knee

Conditions
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Osteoarthritis

Intervention / Treatment
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* Drug: ATB-346 low dose
* Other: Placebo
* Drug: ATB-346 mid-dose
* Drug: ATB-346 standard dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis greater than 2 years duration requiring the use of regular therapies, e.g. oral or topical anti-inflammatories, acetaminophen, topical capsaicin Between the ages of 40 to 75 BMI ≤40 Patients must be unlikely to procreate or agree to the use of acceptable contraceptive regimens from first drug administration , during the study, and for at least 30 days after the last dose Patients must not have used aspirin or naproxen-containing medications for 7 days prior to study entry Patients must not have used any anti-inflammatory medications or acetaminophen for 5 days prior to study entry Patients must show a ≥10-point increase in WOMAC Visual Analog Score between their screening visit and baseline study entry visit Exclusion Criteria: Females who are pregnant or breastfeeding Seated and resting pulse rate less than 50 beats per minute (bpm) or more than 100 bpm at screening Seated and resting blood pressure below 100/60 mmHg or higher than 140/90 mmHg at screening History of significant hypersensitivity to naproxen, other non-steroidal anti-inflammatory agents, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Patients with a history of GI bleeding or ulceration Patients refractory to NSAIDs Presence of significant gastrointestinal, liver, or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs or know to potentiate or predispose patients to undesired effects Presence of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic, or dermatologic disease as determined by the investigator Suicidal tendency, history of/or disposition to seizures, state of confusion History of hepatic disease Maintenance therapy with any drug, including gastroprotective agents such as proton pump inhibitors, H2 receptor antagonists, sucralfate, etc., or significant history of drug dependency or alcohol abuse (>3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Any clinically significant illness in the previous 30 days before Day 1 of this study Use of any enzyme-modifying drugs, including strong inhibitors of CYP enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin and St John's Wort) in the previous 30 days before Day 1 of this study Any history of tuberculosis and/or prophylaxis for tuberculosis Positive H. Pylori Urea Breathe Test Positive urine screening of alcohol and/or drugs of abuse at the screening visit Positive results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAg) or anti-Hepatitis C Virus (HCV) tests Females who are pregnant according to a positive serum pregnancy test Patients who took an Investigational Product (in another clinical trial) in the previous 30 days before Day 1 of this study.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo Comparator<br>ATB-346 150 mg overencapsulated tablet taken by mouth once daily for 14 days | Drug: ATB-346 low dose<br>* Double blind comparison of orally administered ATB-346 versus placebo in osteoarthritis patients<br>* Other names: Active comparator;|
| Active Comparator: ATB-346 mid-dose<br>ATB-346 200 mg overencapsulated tablet taken by mouth once daily for 14 days | Drug: ATB-346 mid-dose<br>* Double blind comparison of orally administered ATB-346 versus placebo in osteoarthritis patients<br>* Other names: Active comparator;|
| Active Comparator: ATB-346 standard dose<br>ATB-346 250 mg overencapsulated tablet taken by mouth once daily for 14 days | Drug: ATB-346 standard dose<br>* Double blind comparison of orally administered ATB-346 versus placebo in osteoarthritis patients<br>* Other names: Active comparator;|
| Placebo Comparator: Active Comparator<br>Overencapsulated placebo tablet taken by mouth once daily for 14 days | Other: Placebo<br>* Double blind comparison of orally administered ATB-346 versus placebo in osteoarthritis patients<br>* Other names: Non-active comparator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-item pain intensity measure | Self reported pain intensity over the past 48 hours. Each item is scored 0-10 (0 = no pain; 10 = pain as bad as can be), yielding a total between 0 and 50 | Previous 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-item stiffness intensity measure | Self reported pain intensity over the past 48 hours. Each item is scored 0-10 (0 = no pain; 10 = pain as bad as can be), yielding a total between 0 and 20 | Previous 48 hours | 
| 17-item difficulty performing daily activities measure | Self reported pain intensity over the past 48 hours. Each item is scored 0-10 (0 = no pain; 10 = pain as bad as can be), yielding a total between 0 and 170 | Previous 48 hours | 
| Measurement of whole blood cyclo-oxygenase activity | Thromboxane B2 (TXB2) blood levels (pg/mL) will be measured after 1, 4 and 14 days of treatment. samples taken on days 1, 4 and 14. Decreases (measured in pg/mL) in the blood levels of thromboxane B2 are a direct measure of the effect of treatment on cyclo-oxygenase activity and the reduced production of this inflammatory mediator, i.e., thromboxane B2. | After 1, 4 and 14 days of treatment dosing. | 
| Number of patients with genetic variations in the drug modifying enzyme CYP2C9 that may alter the metabolism of ATB-346 will be investigated. | CYP2C9 isoforms will be measured in one blood sample taken prior to study drug dosing. | Samples will be retained through study completion and analyzed within 1 year of study initiation. | 
| Number of participants with treatment-related adverse events | The safety of ATB-346 will be monitored via on study and two week post study physician and clinical laboratory assessments. | Pre-study and days 4, 14 and 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Knee, WOMAC, NSAID, Pain