Lubricin-inspired Osteoarthritis Treatment: a Unique Solution (LOTUS)

Inclusion Criteria:

1. Male or female at least 40years of age
2. Knee OA with Kellgren-Lawrence (KL) Grade 2 to 4 of the target knee on X-ray

3. Inadequate pain relief with 1st line treatment, consisting of any of the following

   1. conservative non-pharmacological treatment AND/OR
   2. stable dose NSAIDs for at least the past 30 days OR
   3. use of NSAID treatment is contraindicated
4. Target knee pain on most days (at least 15 days per month in the preceding month)
5. Symptomatic knee OA with moderate to severe pain (NRS ≥4 and <9 on Numeric Rating Scale (NRS) with target knee significantly worse than the other knee with a minimum difference of 2-point between knees.
6. Possess cognitive and language ability to complete informed consent and questionnaires
7. Willingness to follow protocol instructions and maintain appointment schedule of the study
8. Willingness to maintain their existing stable regimen (defined as the same regimen for at least the past 30 days) of complementary and non-pharmacological knee OA treatments for trial duration (if any)
9. If participant is taking a stable regimen of NSAIDs - they are willing to maintain their existing stable regimen (defined as taking the same dose for at least the past 30 days) of NSAIDs and not anticipate to change for the duration of the study.
10. Willingness to stop any 'as needed' (PRN) NSAIDs or paracetamol or opioids (except for protocol-permitted rescue pain medication) for the duration of the trial
11. Willingness to stop taking any rescue pain meds 24 hours prior to scheduled follow up clinic visits (except for their stable NSAIDs therapy)

Exclusion Criteria:

1. Pregnant or lactating
2. Other significant knee pathologies of target knee from medical history or radiographic method(s)
3. Severe malalignment > 10 degree in the target knee (either varus or valgus) measured using standardized knee x-ray at screening or based on previous medical records
4. Severe inflammatory arthritis or other joint disease with warm, red, and swollen knee in the target knee
5. History of knee surgery or significant knee trauma of target knee in the past 12 months
6. Received intraarticular injection in the targeted knee joint within the past 6 months
7. Knee surgery or intraarticular injection in the target knee planned in the next 8 months
8. Allergy to rescue pain medication (paracetamol)
9. Unstable/ poorly controlled coagulopathy[CH1.1][LC1.2]
10. Severe anxiety, depression or psychiatric disorder based on self -reported medical history
11. Chronic pain conditions other than knee OA (e.g. cancer, fibromyalgia, pain due to hip OA, etc.) which may interfere with the outcomes of the study, at the discretion of the investigator
12. History of or current substance abuse, self-reported
13. Significant systemic medical comorbidities, e.g. uncontrolled diabetes or hypertension, immunocompromised, cancer, severe cardiovascular disease, neuropathic pain/disorder, etc.
14. ModifiedPainDETECT Questionnaire (mPDQ) >18
15. Current use of any non-opioids centrally acting analgesics including gabapentin, pregabalin, duloxetine, tricyclic antidepressants (e.g. amitriptyline) for pain management within 12 weeks prior to screening.
16. Started taking oral or injectable GLP-1 products in the past 6 months as new regimen. Current use of a GLP-1 product is permitted if the participant has been on the product for > 6 months and plans to continue the product at its current stable dose for the duration of the trial.
17. Started taking another concomitant medication within the past 12 weeks or changed dose of a concomitant medication within the past 12 weeks which could, in the opinion of the Principal Investigator or delegate, impact the participant's safety on the trial or the reliability of the outcome assessments.
18. Participate in another clinical trial and received study intervention currently or in the past 3 months