Clinical trial: A Study to Evaluate the Efficacy and Safety of X0002 Spray in Subjects With Osteoarthritis of the Knee (NCT03081806)

Eligibility criteria:
Inclusion Criteria:

          1. Ability to read and provide written, personally signed, and dated informed consent to
             participate in the study, in accordance with the ICH GCP Guideline E6 and applicable
             regulations, before completing any study related procedures.

          2. An understanding, ability, and willingness to fully comply with study procedures and
             restrictions.

          3. Subject must be a male or female between 35 and 85 years of age, inclusive.

          4. Female subjects must either not be of childbearing potential (defined as
             postmenopausal for at least 1 year or surgically sterile [bilateral tubal ligation,
             bilateral oophorectomy, or hysterectomy]) or be willing to Practice at least 1 of the
             following medically acceptable methods of birth control.

          5. Subject must have a body mass index (BMI) between 18.5 and 40 kg/m2, inclusive.

          6. Subject must have a diagnosis of idiopathic OA according to the American College of
             Rheumatology clinical and radiographic criteria with knee pain, osteophytes, and
             fulfillment of at least one of the 3 criteria:

               -  age of ≥50 years

               -  stiffness lasting <30 minutes after getting up in the morning

               -  crepitus

          7. A subject must have a Kellgren Lawrence Grade of 2 or 3 as determined by a central
             radiologist at the first screening visit.

          8. Subject must have a history of clinically symptomatic OA of the knee for ≥6 months.

          9. Subject must have had knee pain while standing, walking, and/or in motion for at least
             14 days during the month prior to Screening.

         10. Subject must have a knee pain score ≥4 and <9 on 0-10 pain intensity NRS (without
             analgesic medication) on at least 7 of the 10 days prior to randomization.

         11. Subject must be willing to discontinue any NSAIDs or other analgesic (eg, aspirin,
             acetaminophen) or potentially confounding concomitant treatments (eg, physiotherapy,
             acupuncture) starting on the first screening visit until completing participation in
             the study. (The use of ≤325 mg acetylsalicylic acid per day as cardiac prophylaxis is
             permitted.) The subject will be allowed to take rescue medication (acetaminophen) for
             pain during the study except during the 24 hours prior to the Second Screening Visit,
             Baseline (Day1), Week 2, Week 4, Week 8, Week 12, Week 22, Week 32, Week 42, and Week
             52/EOS.

         12. Subject must be willing to discontinue applying any topical preparations containing
             Vitamin A acids (including all trans retinoic acid (tretinoin), 13 cis retinoic acid
             [isotretinoin], 9 cis retinoic acid [alitretinoin], vitamin A [retinol], retinal, and
             their derivatives) to the lower limbs starting on the first screening visit until
             completing participation in the study. (Topical preparations containing Vitamin A
             acids or retinol may be applied to areas of the skin above the waist, but should not
             be applied to areas of the skin exposed to study medication.)

         13. Subject must be willing to avoid unaccustomed physical activity (eg, starting a new
             weight lifting routine) for the duration of the study starting on the first screening
             visit.

         14. With the exception of OA of the knee, the subject must be in good general health with
             no clinically significant findings from medical history, vital signs, physical
             examination, ECG, and routine laboratory tests that could interfere with subject
             safety, or pain and functional assessments, as determined by the Investigator.

        Exclusion Criteria:

          1. Has worker's compensation injuries affecting the knee or back.

          2. Has a history of or is currently in litigation regarding joint injuries.

          3. Has secondary OA of the target knee or OA of lower limb joints other than the knee
             that, in the investigator's opinion, could interfere with pain and functional
             assessments related to the target knee.

          4. Has a history of total or partial knee replacement, arthroplasty, or other knee
             surgery on the target knee.

          5. In the investigator's opinion, has had significant injury involving the target knee
             within the 6 months before Screening.

          6. Has skin lesions or wounds on or near the target knee at Screening or at Baseline (Day
             1) that, in the investigator's opinion, would affect absorption of the medication.

          7. Has used opiates (including tramadol or tapentadol) or systemic corticosteroids within
             30 days before Screening or requires treatment with chronic opiates or systemic
             corticosteroids.

          8. Subjects with a placebo response exceeding 25% improvement in the average Western
             Ontario and McMaster Osteoarthritis Index [WOMAC] pain subscale score from Screening
             Visit to Day 1 will be excluded.

          9. Has used gabapentin, pregabalin, antiepileptics, or specific antidepressants (i.e.,
             tricyclics, serotonin norepinephrine reuptake inhibitors, or selective serotonin
             reuptake inhibitors) to treat pain in the 14 days before Screening. Other uses not
             related to the pain treatment may be permitted at the medical monitor's discretion
             provided they have been at a stable dose for at least 90 days.

         10. Has had intra articular (IA) injections of corticosteroids, hyaluronic acid, or
             viscosupplements (e.g., Synvisc®) to the target knee within the 12 weeks before
             Screening

         11. Has had IA or intravenous (IV) stem cell therapy in the 6 months prior to Screening

         12. Is receiving or is planning to receive concomitant nonpharmacologic treatments (e.g.,
             physiotherapy, acupuncture) that in the investigator's opinion could confound efficacy
             assessments within 14 days of Day 1.

         13. Has a history of significant hypersensitivity, intolerance, or allergy to ibuprofen or
             any other NSAIDs, aspirin, or acetaminophen.

         14. Has had an active gastrointestinal (GI) ulceration in the 6 months prior to Screening
             or a history of GI bleeding within 5 years of Screening.

         15. Has used an anticoagulant or antiplatelet agent (except aspirin up to 325 mg/day for
             cardiac prophylaxis) in the 30 days prior to Screening.

         16. Has positive results on fecal occult blood testing at Screening or on Day 1.

         17. Has a documented history of chronic inflammatory disease (e.g., rheumatoid arthritis,
             psoriatic arthritis, inflammatory bowel disease, gouty arthritis) OR chronic pain
             condition (e.g., fibromyalgia), OR has other conditions that may affect the target
             joint for the functional and pain assessments (e.g., osteonecrosis,
             chondrocalcinosis).

         18. Has uncontrolled depression or other uncontrolled psychiatric disorder (subjects with
             controlled depression or other psychiatric disorder, if using medication, must be on a
             stable dose of a medication other than an epileptic, tricyclic, serotonin
             norepinephrine reuptake inhibitor, or selective reuptake inhibitor for ≥12 weeks prior
             to Screening to participate in the study).

         19. Has asthma requiring treatment with systemic corticosteroids in the last year prior to
             Screening. Asthmatic subjects using inhaled corticosteroids are eligible.

         20. Has uncontrolled hypertension defined as systolic blood pressure >170 mmHg or
             diastolic blood pressure >90 mmHg at the Screening or Baseline Visit (may be repeated
             after 5 minutes rest to verify).

         21. Is receiving systemic chemotherapy, has an active malignancy, lymphoproliferative
             disorder, or blood dyscrasia of any type, or has been diagnosed with cancer within 5
             years before Screening. Subjects with completely excised squamous or basal cell
             carcinoma of the skin will be allowed.

         22. Has any clinically significant unstable cardiac, respiratory, neurological,
             immunological, hematological, hepatic, or renal disease, or any other condition that,
             in the Investigator's opinion, could confound the study results, compromise the
             subject's welfare, interfere with the ability to communicate with the study staff, or
             otherwise contraindicate study participation.

         23. Has an abnormal clinical laboratory assessment at Screening for any of the following:

               -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline
                  phosphatase or lactate dehydrogenase (LDH) ≥3× the upper limit of normal (ULN)

               -  Total bilirubin or creatinine ≥1.5× ULN

               -  Creatinine ≥1.5 × ULN

               -  Hemoglobin <10 g/dL

         24. Subject has any other clinically significant laboratory finding at Screening that in
             the investigator's opinion contraindicates study participation.

         25. Has clinically significant abnormality at Screening or Baseline (Day 1) on 12-lead
             ECG, including a QT interval calculated using Fridericia's correction (QTcF) interval
             >450 milliseconds (msec) for males and 470 msec for females.

         26. Is pregnant, planning to become pregnant during the study, or lactating. Has a
             positive serum and urine pregnancy test at Screening Visit, or a positive urine
             pregnancy test at Baseline (Day 1).

         27. Has a positive urine drug screen for a nonprescribed drug prohibited by the protocol
             at Screening.

         28. Has known alcohol or other substance abuse in the investigator's opinion.

         29. Has participated in a previous clinical study with X0002.

         30. Has participated in any other clinical trial within the past 30 days or within 5
             half-lives of the study drug prior to Screening, whichever is longer.

         31. Is a participating investigator, sub-investigator, study coordinator, or employee of a
             participating investigator, or is an immediate family member of the aforementioned.

         32. Has any factor that, in the investigator's opinion, would jeopardize the evaluation or
             safety or be associated with poor adherence to the protocol.

         33. Is without access to telephone and/or ability to gain technology access.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 35 Years old.
Subject must be at most 85 Years

Patient description (medical language): A 47-year-old woman comes to the office complaining of pain in the calf and knee when she bends down. The pain limits her activity. Her medical history is significant for osteoarthritis, for which she uses nonsteroidal anti-inflammatory drugs (NSAIDs) for the past two years. She is living with her husband and has 3 children. She doesn't smoke but drinks alcohol occasionally. Her vital signs are normal. On physical examination, there is a small effusion in the right knee. The effusion grew a little larger and she developed a tender swelling in the popliteal fossa and calf. Both the pain and swelling worsened as she bent and straightened her knee.

Patient description (patient's own words): I'm a 47-year-old woman, married with 3 kids. I don't smoke and I drink occasionally. I went to the doctor because of pain in my calf and knee when I was bending down. This has been limiting my daily activities. I have been diagnosed with osteoarthritis for which I have taken anti-inflammatory drugs for the past 2 years. The doctor saw a small fluid buildup in my right knee. This buildup became a bit bigger and I have a swollen calf. The pain is worse when I bend and straighten my knee.

Does the patient match the trial criteria? 1