Dong-A ST Co., Ltd.

Glycemic control is a mainstay of diabetes management to reduce the risk of microvascular complications and cardiovascular outcomes in people with type 2 diabetes (T2D). However, intensive control to near-normal glycated hemoglobin (HbA1c) yielded complex results in previous landmark trials. Potential risks of intensive glycemic control, such as hypoglycemia and weight gain, may partly contributed to the possible harms associated with this approach. Recent advances in diabetes management with development of newer antidiabetic drugs which minimize possible harms of intensive glycemic control as well as reduce cardiorenal risks enabled safer glycemic reduction. Thus, this randomized trial aims to evaluate the effects of near normalization of HbA1c with novel approaches on microvascular complications and cardiovascular outcomes in people with T2D.

Pharmacokinetics and Safety Profiles After Administration of DA-5221_01 and Co-administration of 5221_01-R1 and DA-5221_01-R2 in Healthy Adult Volunteers

1. **One day (±1 day) before surgery:** The investigator or designated study staff will thoroughly explain the clinical trial process to the participant and their guardian (representative) based on the informed consent form and provide the form so that all participants and their guardians have sufficient time to read, discuss, and decide. Participants who agree to participate in the clinical trial will voluntarily sign the written consent form and receive a copy of the signed consent form before any study-related procedures are conducted. The clinical trial site will assign a screening number to patients who voluntarily provide consent and undergo screening. The screening number can be assigned in the order in which the participants sign the consent within the study site. After confirming eligibility based on inclusion/exclusion criteria, randomization will be performed to assign participants to either the treatment group or the control group (with a 1:1 ratio). If assigned to the treatment group, participants will receive 'Polacoxib (preventive Acelex cap 2mg) once daily, NSAIDs-excluded non-opioid/opioid analgesics - PRN use.' If assigned to the control group, participants will receive NSAIDs-excluded non-opioid or opioid analgesics. Data will be collected by comparing the two groups in a double-arm setup. Pain scores, UCLA/ASES scores, and joint range of motion will be collected, and this data will be valid up to 3 months before the surgery. (For patients taking NSAIDs or Ultracet, the dose will be maintained until v5.)
2. **Two hours before surgery:** Administration of medication begins.
3. **Three days after surgery:** Collect pain scores and the cumulative number of NSAIDs-excluded non-opioid or opioid analgesic doses (post-surgery). Non-opioid or opioid analgesics (e.g., Fentanyl injection or Ultracet) will be used to manage post-surgical pain, and the number of doses will be collected to assess the participant's pain.
4. **Two weeks after surgery:** An outpatient visit will be conducted one week after discharge. Collect pain scores and the cumulative number of NSAIDs-excluded non-opioid or opioid analgesic doses at the two-week mark.
5. **Six weeks after surgery:** Collect pain scores and the cumulative number of NSAIDs-excluded non-opioid or opioid analgesic doses.
6. **Three months after surgery:** MRI will be performed to check for re-tears (optional for participants). This visit will be the study's completion visit, during which pain scores, UCLA/ASES scores, joint range of motion, and cumulative doses of NSAIDs-excluded non-opioid or opioid analgesics will be collected. If adverse events occurring during the treatment period have resolved before this completion visit, no additional safety follow-up will be performed, and this visit will be considered the end of the clinical trial. If adverse events have not resolved by the completion visit, follow-up will continue until the adverse events have either returned to pre-study or baseline levels, or the principal investigator or designee determines that the adverse events have stabilized, or no further follow-up is deemed necessary. This follow-up will mark the completion of the clinical trial.