A Trial of APPA in the Treatment of Knee Osteoarthritis

Study Overview
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Brief Summary
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A placebo controlled study of APPA in 150 participants with Osteoarthritis of the knee

Detailed Description
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This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, 4-week trial of a fixed-dose combination of apocynin and paeonol (APPA) administered orally twice daily versus placebo twice daily. Approximately 150 subjects will be randomized to one of the two treatment groups.

Official Title
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A Placebo-controlled, Double-blinded, Randomized, Trial Using a Combination of Apocynin and Paeonol (APPA) for the Treatment of Knee Osteoarthritis

Conditions
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Osteoarthritis

Intervention / Treatment
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* Drug: APPA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is able to read and understand the language and content of the study material, understand the requirements for study visits, and is willing to provide information at the scheduled evaluations and appropriate written informed consent has been obtained. Femorotibial osteoarthritis of the knee, according the American College of Rheumatology (ACR) clinical and radiographic criteria (Altman et al., 1986) (Appendix A). Radiological OA grade 2 or 3 of the target knee, using the Kellgren-Lawrence method (Kellgren and Lawrence, 1957) as graded by central, independent reading of X-ray obtained during screening, or on a recent (within 6 months) X-ray image which fulfills the protocol specifications for reading. Age between 40 years and 85 years at the time of screening, both included; of either sex. Pain score rated on an 11-point numerical rating scale of the target knee of ≥ 20 and ≤ 45 out of 50 in response to the WOMAC pain sub-score (5 questions), at the time of screening and baseline. The subject should have undergone a washout-period of at least 5 half-lives of any analgesic medication before completing the screening and baseline questionnaires. Women of child-bearing potential must use a highly effective method of contraception(please see Appendix B). Postmenopausal status is defined as being amenorrheic for at least 1 year prior to screening. Sexually active men with a female partner of childbearing potential must ensure that their female partner uses a highly effective method of contraception and agree to use condom from enrolment up to at least 3 months after the study end. Furthermore, male participants must agree not to donate sperm throughout the study and at least 3 months after he study end. Knee pain in the target knee for 14 days of the preceding month (periarticular knee pain due to OA and not due to non-OA conditions such as bursitis, tendonitis, etc.) based on subject report. Inadequate response to or intolerance to analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs) as reported by the subject Exclusion Criteria: Known or suspected hypersensitivity to or previous hypersensitivity reactions to APPA, or any of the excipients in the investigational product. For women of childbearing potential: Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding Failure to agree to practice a highly effective method of contraception (see Appendix B), from enrolment up to at least 3 months after the study end. For sexually active men with a female partner of childbearing potential: Failure to agree to ensure that their female partner uses a highly effective method of contraception, to agree to use condom (see Appendix B) from enrolment up to at least 3 months after the study end, and to agree not to donate sperm throughout the study and at least 3 months after the study end. Intra-articular delivery of corticosteroids within 3 months or hyaluronic acid within 6 months of screening in the target knee or into any other joint within 30 days of screening. Systemic corticosteroid treatment of more than 14 days during the past 6 months prior to screening. Major surgery or arthroscopy of the target knee within the previous year prior to screening. Planned surgery on either knee within the next 3 months. Use of a currently unapproved investigational drug, device or biologic within 3 months prior to screening. Presence of inflammatory arthritis, such as rheumatoid arthritis, psoriatic arthritis, polymyalgia rheumatica, gout or pseudogout with history of clinical attacks. Current malignancy or treatment for malignancy within the past five years, with the exception of treated non-melanoma skin cancer, unless affecting the target knee area, or carcinoma in situ events. Any other abnormal laboratory results or significant medical conditions that the Investigator believes should preclude the subject's participation in the trial. Prior septic arthritis of the target knee. Known osteoarthritis of the hip(s) if pain in either or both hip(s) exceeds that of the target knee using the WOMAC Hip Pain sub-score for that hip at the time of screening Presence of significant radicular back pain, as reported by the subject. Presence of severe pain in either knee, defined as > 45 out of 50 in response to the WOMAC pain sub-score (5 questions), at the time of screening or baseline, regardless of the eligibility of the contralateral knee. Body Mass Index > 40.0 kg/m2. Estimated glomerular filtration rate < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) method. Substantial use of moderate or higher strength opioid medication for the treatment of pain within 6 weeks before the screening visit, as evaluated by the investigator. Use of duloxetine, pregabalin, or gabapentin within 4 weeks before the baseline visit. History of alcohol or drug abuse within the past 5 years prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: APPA<br>APPA, an oral combination of two isomers: 4-hydroxy-3-methoxyacetophenone (4H3MA) & 2-hydroxy-4-methoxyacetophenone (2H4MA) administered to 75 participants as 2 x 400mg capsules b.d. for 28 days . | Drug: APPA<br>* APPA, an oral combination of two isomers: 4-hydroxy-3-methoxyacetophenone (4H3MA) & 2-hydroxy-4-methoxyacetophenone (2H4MA).<br>|
| Placebo Comparator: Placebo<br>2 capsules b.d. for 28 days | Drug: Placebo<br>* Placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC pain score | change from baseline in WOMAC pain sub-score of the target knee as evaluated at week 4. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in WOMAC total score and the WOMAC function and stiffness scores at week 4 |  | 28 days | 
| Changes from baseline in constant, intermittent and total OA pain assessed by ICOAP scores at week 4 Changes from baseline in constant, intermittent and total OA pain assessed by ICOAP scores at week 4 |  | 28 days | 
| Changes from baseline in WOMAC pain weight-bearing score (questions 1, 2, and 5) and non-weight bearing score (questions 3 and 4) at week 4 |  | 28 days | 
| Changes from baseline in physical function assessed by the 20 Meter Walk Test gait speed at week 4 |  | 28 days | 
| Change from baseline in the weekly mean of the average daily pain intensity at Week 4 |  | 28 days | 
| Area-under-effect curves of the weekly mean of the average daily pain intensity at Week 4 |  | 28 days | 
| OMERACT-OARSI responder rate at week 4 |  | 28 days | 
| Total dose of rescue medication calculated as the sum of tablets used, based on pill counts |  | 28 days | 
| Time between baseline and first use of rescue medication |  | 28 days | 
| Changes from baseline in the Patient Global Assessment (PGA) score at week 4 |  | 28 days | 
| Changes from baseline in quality of life assessed by the EQ5D at week 4 |  | 28 days | 
| Safety | Nature, incidence and severity of AEs. Changes in laboratory safety parameters, vital signs, 12-lead ECG parameters, and weight | 28 days |