This is a study of an over-the-counter, capsaicin-based (0.25%) topical analgesic for management of osteoarthritis knee pain meeting the US Food and Drug Administration's (FDAs) Tentative Final Monograph (TFM) guidance for "External Analgesic Drug Products For Over-the-Counter Human Use," published in the Federal Register on February 8, 1983 (final proposed 21 CFR 348). Subjects meeting the inclusion criteria and not meeting the exclusion criteria were randomized into one of four groups: once daily treatment with active product, once daily treatment with product vehicle (no capsaicin), twice daily treatment with active product, and twice daily treatment with product vehicle (no capsaicin), all for 7 consecutive days of treatment. The twice daily treatments were spaced approximately 12 hours apart. Osteoarthritis knee pain was assessed by the 100 mm visual analog scale. Osteoarthritis knee pain assessments were done each day for 28 days. Tolerability data were also collected.

This is a study of a over-the-counter, capsaicin-based (0.25%) topical analgesic for management of osteoarthritis knee pain meeting the US Food and Drug Administration's (FDAs) Tentative Final Monograph (TFM) guidance for "External Analgesic Drug Products For Over-the-Counter Human Use," published in the Federal Register on February 8, 1983 (final proposed 21 CFR 348). Subjects meeting the inclusion criteria and not meeting the exclusion criteria were randomized into one of four groups: once daily treatment with active product, once daily treatment with product vehicle (no capsaicin), twice daily treatment with active product, and twice daily treatment with product vehicle (no capsaicin), all for 7 consecutive days of treatment. The twice daily treatments were spaced approximately 12 hours apart. Both knees received study drug treatment but only one knee per subject was assigned as the "study knee".

Osteoarthritis knee pain was assessed by the 100 mm visual analog scale and the response criterion was a 50% or greater reduction in osteoarthritis knee pain from baseline. Baseline was defined as the visual analog scale recorded not more than 30 minutes before the first study drug application (on Study Day 1). For subjects in the once daily (QD) groups the osteoarthritis knee pain assessments were at 12 hrs after the initial application (during Study Day 1) and 24 hours (Study Day 2) after the initial application and then once in the morning on Study Days 3 - 28. For subjects in the twice daily (BID) groups the osteoarthritis knee pain assessments were at 12 hrs after the initial application (during Study Day 1) and 24 hours(Study Day 2) after the initial application and then once in the morning and once 12 hours later on Study Days 3 - 28.

Tolerability data were also collected as reported burning-stinging pain, erythema and pruritus at the site of application.

Inclusion Criteria:

1. Subject has granted written informed consent.
2. Subject is at least 18 years of age.
3. Subject has knee pain with radiographic evidence of osteoarthritis in at least one knee (including an x-ray within the previous 2 years).
4. Subject's osteoarthritis knee pain has been present for ≥ 6 months.
5. Subject has osteoarthritis knee pain of ≥ 50 mm in one knee based on the visual analog scale at screening.
6. Subject has regularly used topical over-the-counter pain relief products or over-the-counter oral medication (acetaminophen or ibuprofen) to treat/manage pain from osteoarthritis in the previous 3 months.
7. Subject is in good general health and free of any disease state or physical condition which, in the investigator's opinion, exposes the subject to an unacceptable risk by study participation.
8. Subject is capable of understanding and complying with all instructions and study procedures, including the ability to accurately evaluate their symptoms.
9. Subject must be a male or non-pregnant female. If female, subject must be past childbearing age or otherwise must test negative for pregnancy. Males and females must agree to use effective birth control during the study or for at least 30 days after last dose of study investigational product, if unable to complete the study.

Exclusion Criteria:

1. Subject has spontaneously improving or rapidly deteriorating osteoarthritis or knee pain.
2. Subject has rheumatoid or psoriatic arthritis, or a form of arthritis inconsistent with a diagnosis of osteoarthritis.
3. Subject has used any topical steroids on or in the vicinity of the knees within 1 week prior to Screening, or has had a knee injection within 1 month prior to Screening.
4. Subject is currently taking prescription pain medication.
5. Subject has shaved their knees within 2 days of first day of treatment (Day 1).
6. Subject has used any capsaicin containing product on or in the vicinity of the knees within 2 weeks prior to first day of treatment (Day 1).
7. Subject has used any topically applied products (including emollient/moisturizer) on or in the vicinity of the knees within 2 weeks prior to first day of treatment (Day 1).
8. Subject has used topical therapy on the knees that, in the investigator's opinion, might affect the study evaluations of signs and/or symptoms.
9. Subject has broken or damaged skin on their knees, or an open wound near the knees.
10. Subject has a history of allergy/sensitivity to topical substances.
11. Subject is not able to understand the nature, importance, or consequences of the study.
12. Subject has a psychiatric disorder or has significant anxiety or depression that, in the investigator's opinion, could interfere with the subject's ability to accurately assess their pain, adhere to study instructions, or complete the study.
13. Subject has hypertension that is not adequately controlled (medication to treat hypertension is allowed), vascular disease, psychological disorder, or other condition that, in the investigator's opinion, contraindicate the use of medication.
14. Is obese with a Body Mass Index (BMI) of greater than 40 kg/m2.
15. Subject requires a surgical procedure in the immediate future.
16. Subject is pregnant or nursing.
17. Subject has been treated with an investigational drug, device, or therapy within 30 days prior to first day of treatment (Day 1).

Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.

Adverse events were collected from the start of study drug treatment (Day 1) to the end of treatment (Day 28).

Definition of adverse events were consistent with clinicaltrials.gov definitions. Application site adverse events were specifically collected at pre-application of study drug (-30 min (± 5 min), and at 15 (± 5 min), 30 (± 5 min), 45 (± 5 min), and 60 minutes (± 5 min) and after leaving the clinic on each day at home at the same time (± 2 hours) for 7 days.

Study medications were number coded only and identical in physical characteristics. Randomization coding was held only at the manufacturing site until data base lock.