2ccPA Study in Patients With Symptomatic Knee Osteoarthritis

Phase 1

Completed

• Conditions: Osteoarthritis (OA) of the Knee
• Interventions: Drug: 2ccPA; Drug: placebo

• Registration Number: NCT04229394
• Lead Sponsor: Orient Europharma Co., Ltd.

Brief Summary

This clinical trial is designed to determine safety and tolerability as well as the MTD of a single-dose 2ccPA and PK data in symptomatic knee OA.

Detailed Description

Osteoarthritis (OA) is a degenerative disease frequently associated with symptoms such as inflammation, stiffness, muscle weakness, joint swollen and joint pain. 2-carba-cyclic phosphatidic acid (2ccPA) is the derivative of natural occurring phospholipid mediator, cyclic phosphatidic acid (cPA). Previous studies suggested that 2ccPA inhibits inflammation and may relieve the pain caused by osteoarthritis.

This clinical study aims to assess the safety, tolerability, and pharmacokinetics as well as the maximal tolerated dose (MTD) of a single-dose 2ccPA in symptomatic knee OA. Safety and efficacy data for the design and conduction of subsequent studies will also be collected.

Study Timeline

• Study Start: 2018-02-13
• Study First Submitted: 2018-04-10
• Study First Submitted QC: 2020-01-12
• Study First Posted: 2020-01-18
• Primary Completion: 2021-03-22
• Study Completion: 2021-03-22
• Status Verified: 2021-04
• Last Update Submitted: 2021-04-29
• Last Update Posted: 2021-04-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

1. Male or female subjects who are aged between 40 and 75 years old (inclusive)
2. Subjects diagnosed with symptomatic knee OA for at least 6 months prior to study entry (randomization)
3. Subjects whose radiographic evidence of knee OA are classified as grade II or III (according to Kellgren and Lawrence grading system)
4. Subjects with OA knee pain on the majority of days in the past 30 days prior to study entry (randomization).
5. A score of over 8 and below 16 out of 20 for the WOMAC pain subscale in the index knee in screening
6. Male subjects must agree to practice medically acceptable contraceptive regimen (i.e., sterilization surgery, barrier method, abstention) from screening visit until at least 1 month after the study treatment.
7. Subjects who are willing to sign the informed consent form (ICF)
8. Subjects with normal liver and renal function:

ALT and AST do not exceed 1.5 ULN (upper limit of normal) Serum Cr levels do not exceed 1.0 ULN

Exclusion Criteria

1. Subjects with known hypersensitivity to study medication
2. Female subjects who are pregnant or lactating. Women of childbearing potential must agree to practice medically acceptable contraceptive regimen from screening visit until at least 1 month after the study treatment and must have a negative urine pregnancy test no earlier than 72 hours prior to study treatment.
3. Intra-articular use of corticosteroid, hyaluronic acid or other intra-articular injection in study knee within 3 months prior to study entry (randomization)
4. Use of chondroitin and/ or glucosamine within 4 weeks prior to study entry (randomization)
5. Subjects with known malignancy
6. History of Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lymphoma, arthritis associated with inflammatory bowel disease, sarcoidosis and amyloidosis
7. Prior arthroscopic or open surgery on the study knee within 6 months prior to study entry (randomization)
8. Clinical signs and symptoms of active knee infection or being treated for knee infection at screening
9. Patients with active inflammation: patients with CRP higher than upper limit of normal range at screening visit will be excluded from the study.
10. Subjects with concurrent medical or arthritic condition that could interfere with evaluation of the index knee joint, including fibromyalgia, based on investigator's clinical judgment
11. More significant pain from the back or the hip than the knee
12. Skin breakdown or lesion on the study knee that is not suitable for injection, based on investigator's discretion
13. Prior knee replacement on the study knee or planned knee replacement during the study period
14. Subjects with (1) meniscus tears which requires repairment surgery OR (2) anterior cruciate ligament rupture based on screening MRI results
15. Patients with known severe synovitis, synovium necrosis in the target knee joint judged by investigator at screening
16. Patients with PT/ APTT higher than the upper limit of normal range at screening
17. History of drug or alcohol dependence in the past 3 years
18. Having known infection with HIV-1, HBV, HCV
19. Use of any investigational drug or participation in any drug study within 4 weeks prior to study entry (randomization)
20. Subjects who are unwilling or unable to comply with study procedures
21. Any clinical condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk to participate in the study or confounds the ability to interpret data from the study as judged by the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2ccPA	2ccPA	Only day 1 Intra-articular injection can be given under direct ultrasound guidance; the only one strength for 2ccPA injection vial is 2,400 μg (1.2 mL per vial). IP name: 2-carba-cyclic phosphatidic acid (2ccPA)
Placebo	placebo	Only day 1 Intra-articular injection can be given under direct ultrasound guidance; placebo

Primary Outcome Measures

Name	Time	Method
Adverse events will be coded with MedDRA and analyzed by system organ class (SOC) and preferred term. The number of subjects who experience DLT will be calculated at each dose level and the result of MTD will be provided.	85 days	To determine safety and tolerability as well as the maximal tolerated dose (MTD) of a single-dose 2ccPA in symptomatic knee OA

Secondary Outcome Measures

Name	Time	Method
20% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales	85 days	Proportion of subjects with a 20% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline
Time to maximum plasma concentration (Tmax) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Area under plasma concentration-time curve (AUC) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Apparent volume of distribution (Vz/F) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Synovial fluid matrix metalloproteinase (MMP)-1 level	before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.	Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment
Synovial fluid matrix metalloproteinase (MMP)-3 level	before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.	Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment
Serum matrix metalloproteinase (MMP)-3 levels	at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment	Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-3,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment
Ectopic bone formation	85 days	To investigate ectopic bone formation by MRI at Day 85, compared with baseline and the placebo group
70% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales	85 days	Proportion of subjects with a 70% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline
Maximum plasma concentration (Cmax) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Serum matrix metalloproteinase (MMP)-13 level	at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment	Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-13,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment
Apparent total body clearance (CL/F) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Plasma concentration of 2ccPA	at pre-dose and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after 2ccPA treatment	Plasma concentration of 2ccPA at pre-dose and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after 2ccPA treatment
Joint space narrowing	85 days	To investigate joint space narrowing by MRI at Day 85, compared with baseline and the placebo group
50% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales	85 days	Proportion of subjects with a 50% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline
Elimination half-life (t1/2) of 2ccPA	at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment.	Pharmacokinetic profile of 2ccPA
Synovial fluid 2ccPA level	before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.	Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment
Serum prostaglandin E2 (PGE2) level	at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment	Changes from baseline (pre-dose) in serum prostaglandin E2 (PGE2) levels at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment
Serum matrix metalloproteinase (MMP)-1 level	at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment	Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-1,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment
Synovial fluid matrix metalloproteinase (MMP)-13 level	before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.	Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment

Trial Locations

Locations (5)

Tri-Service General Hospital; 🇨🇳 Taipei, Taiwan

Mackay Memorial Hospital; 🇨🇳 Taipei, Taiwan

Kaohsiung Chang Gung Memorial Hospital; 🇨🇳 Taipei, Taiwan

Veteran General Hospital Taipei; 🇨🇳 Taipei, Taiwan

National Cheng Kung University Hospital; 🇨🇳 Taipei, Taiwan