Clinical trial NCT03561779: Clinical Trial of YYD302 (Phase3) for Treatment of Osteoarthritis of the Knee
Official title: A Randomized, Double-blind, Active-controlled, Multi-center, Phase 3 Study to Evaluated the Safety and Efficacy of Intraarticular Hyalurinic Acid(YYD302) for Osteoarthritis of the Knee After 12 Weeks of Treatment and Retreatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteoarthritis, Knee
Keywords: Osteoarthritis
Lead sponsor: Yooyoung Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2018-06-19
Enrollment: 184
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The Subjects are injected investigational Product (YYD302 or Synovian Inj.)
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, active-controlled, multi-center, phase 3 study to evaluate the safety and efficacy of intraarticular hyaluronic acid(YYD302) for osteoarthritis of the knee after 12 weeks of treatment and retreatment

Detailed description: First Injection: A multicenter, active-controlled, randomized, evaluator and subject bllinded, parallel, phase 3 study Re-Injection: A multicenter, active-controlled, randomized, parallel

Eligibility criteria: Inclusion Criteria:

\[Visit 1, 2 Inclusion Criteria\]

1. Males or Females 40 years and older
2. According to the clinical diagnosis standard of the American College of Rheumatology (ACR), someone, diagnosed as a single/both sides of osteoarthritis, who corresponds to over 3 conditions of followings.

1) Over 50 years of age 2) Less than 30 minutes of morning stiffness 3) Crepitus on active motion 4) 4 bony tenderness 5) Bony enlargement 6) Nopalpable warmth of synvium 3. Within 6 months from screening visit, someone who diagnosed with Kellgren \& Lawrence Grade I\~III by the radioactive examination.

4. By the Weight-bearing pain(100mm-VAS) examination, someone who has a outcome of the single or both sides of the osteoarthritis is over 40mm 5. Patient (No-responder) who has experienced steady pain in spite of dosing NSAIDs or other pain-killers in the past.

6. Patient who can walk by themselves without helper like cane or walker etc. (If the patient who has used helper routinely from previous 6 months, evaluating the patient including the helper is possible. In this case, patient needs to use same helper continuously by end of the clinical trial test.) 7. Patient who agrees to participate in this clinical trial by themselves.

\[Visit 6, 7 Inclusion criteria\] 1. According to the clinical diagnosis standard of the American College of Rheumatology (ACR), someone, diagnosed as a single/both sides of osteoarthritis, who corresponds to over 3 conditions of followings.

1. Over 50 years of age
2. Less than 30 minutes of morning stiffness
3. Crepitus on active motion
4. 4 bony tenderness
5. Bony enlargement
6. Nopalpable warmth of synvium 2. At Re-screening visit, someone who diagnosed with Kellgren \& Lawrence Grade I\~III by the radioactive examination.

3. Patient who can walk by themselves without helper like cane or walker etc. (If the patient who has used helper routinely from previous 6 months, evaluating the patient including the helper is possible. In this case, patient needs to use same helper continuously by end of the clinical trial test.) 4. Patient who are confirmed for Responder by efficacy at visit 5.

Exclusion Criteria:

1. Someone who has BMI≥32kg/m² at the screening visit.
2. Patient who has an experience dosing psychoactive drug, narcotic analgesic which can have an effect on pain sense over 3 months habitually.
3. Patient who has been administrated gastrointestinal drug(for example H₂-blockers, misoprostol or proton pump inhibitors) regularly, who can't stop injecting for clinical study period.
4. Patient has attended abnormal values from screening test(2 times excess at upper limit of the normal values at ALT, AST, BUN, Serum Creatinine).
5. Patient who has rheumarthritis or other inflammatory metabolic arthritis.
6. Patients having serious gastrointestinal, liver, renal, heart disease.
7. When the inflammatory disease is occurred on joint area to patient like septic arthritis.
8. Patients having skin ailment at the injecting site of the joint region.
9. Patients having secondary osteoarthritis according to the Ochronosis, Hemochromatosis or systemic disease.
10. Patients who have severe pain like Sudek's atrophy, Paget's disease, Spinal disc herniation.
11. Poly-articular patients who have suffered seriously by osteoarthritis at other parts affect judge of the knee joint pain.
12. Patients who diagnosed clear interval disappearance at the knee joint by X-ray.
13. Patients who were administrated below drugs before baseline visit. 1) Patients who were injected HA at the target knee joint or other parts of knee joint in recent 9 months.

2) Patients who were injected steroids into the intra-articular knee joint in recent 3 months 3) Patients who were administrated steroids systemically by the oral medication (But, except inhalation) 4) Patients who were administerated Osteoarthritis nutrition such as glucosamine/chondroichin sulfate or physical therapy or herbal remedy(acupuncture, yellowish swelling, moxa cautery) for the purpose of pain relief in recent 2 weeks 5) Patients who have administerated steroid/No-steriod NSAIDs or other pain relief drugs (patch or other external medicine) in recents 2 weeks except Acetaminophen or below 300mg/day of Asprin 14. Patients who have joint effusion trouble were judged as a positive by tests like Patella tap test.

15. Patients who have target knee joint gotten surgical operation history including Arthroscopy within past one year (In case of having other side of knee joint or hip joint gotten surgical operation history, excepting the patients if there is possibility which can influence the target knee joint's appraisal.

16. Patients who have an operation history about target knee joint. 17. Patients who do the height weight aerobic exercise or anaerobic exercise. 18. Patients who need to be administrated anticoagulant agent together(But, except 300mg daily dose aspirin) 19. Patients who have hypersensitivity history about Investigational Product.

20. In the midst of women in their childbearing years, patients who disagree to do \* contraception by medically permitted method for 12 weeks from administrating investigational product.

* The contraception by medically permitted method: Condom, In case of using injection or insertion, In case of installing a intrauterine contraception device etc.

  21. Pregnant and lactating women 22. Patients who were injected other investigational product over a time within 30 days before participated in this clinical trail.

  23. Besides that, the patients who have difficulty to be participated in this clinical trial continuously by Principle Investigator (PI)'s decision.
* Exclusion criteria for Re-injection is except for 13-1) Re-injection date is followed by visit 7.

Primary outcomes:
measure: Rate of change of the Weight-bearing pain(100mm-VAS) on 12 weeks after first injection in comparison with baseline
timeFrame: Change of the week 12 from baseline
Secondary outcomes:
measure: Rate of change of the Weight-bearing pain(100mm-VAS) on 2, 4 weeks after administration in comparison with baseline
timeFrame: Change of the week 2, 4 from baseline
measure: Rate of change of the KOOS scales on the 2, 4, 12 weeks after administration in comparison with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Rate of change of the rest pain(100mm-VAS) on the 2, 4, 12 weeks after administration in comparison with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Rate of change of the Motion pain (100mm-VAS) on the 2, 4, 12 weeks after administration in comparison with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Patient global assessment (100mm-VAS) on the 2, 4, 12 weeks after administration with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Investigator global assessment (100mm-VAS) on the 2, 4, 12 weeks after administration with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Change of the swelling in the knee joint from baseline to 2, 4, 12 weeks after administration
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Change of the tenderness on pressure in the knee joint from baseline to 2, 4, 12 weeks after administration
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Variation of the Range Of Motion(ROM) in the knee joint on 2, 4, 12 weeks after administration with baseline
timeFrame: Change of the week 2, 4, 12 from baseline
measure: Responder rate of the Weight-bearing pain on 12 weeks in comparison with baseline
timeFrame: Change of the week 12 from baseline
measure: Responder rate of the OMERACT-OARSI on 12 weeks in comparison with baseline
timeFrame: Change of the week 12 from baseline
measure: Use of rescue medication count and the total amount on each visit after injection
timeFrame: Change of the each visit(2, 4, 12, 24, 36 weeks) after injection
measure: The efficacy of secondary outcome 1~11 after 12 weeks(36weeks) compared with the Re-injection(24weeks) in re-injection subjects
timeFrame: Change of the week 12 (36 weeks) after Re-injection(24weeks)
measure: The efficacy of secondary outcome 1~11 after baseline compared with 2, 4, 12, 24, 36 weeks in Re-injection subjects
timeFrame: Change of the week 2, 4, 12, 24, 36 from baseline
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Samsung Medical Center, Department of Internal Medicine
name: Chul-Won Ha, M.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Park YG, Ha CW, Yoo JH, Lee WS, Lee HJ, In Y, Bae KC, Shon OJ, Kim YM, Seon JK, Song SJ, Chang CB, Kim JM, Kim CW, Kim DH, Bae JH. Intra-Articular Injection of a Novel DVS Cross-Linked Hyaluronic Acid Manufactured by Biological Fermentation (YYD302) in Patients With Knee Osteoarthritis: A Double-Blind, Randomized, Multicenter, Noninferiority Study. Clin Ther. 2021 Nov;43(11):1843-1860. doi: 10.1016/j.clinthera.2021.09.005. Epub 2021 Nov 1.