Phase 2a Clinical Trial of HL237 for Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this clinical trial is to determine the optimal dose of HL237 tablets in rheumatoid arthritis patients by comparing the efficacy and safety of the three dose groups of HL237 tablets and the control group.

Official Title
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For 12 Weeks, the Multi Center, Randomized, Double Blinded, Placebo Controlled, Parallel, Dose-finding Clinical Study for the Therapeutic Exploration of Safety and Efficacy Assessment of HL237 Tablet in Patients With Rheumatoid Arthritis (Phase IIa)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: HL237 tablet
* Drug: Placebo of HL237 tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female, 19 years ≤ age ≤ 80 years In the case of women of childbearing age, those who have a negative pregnancy test before randomization Patients who agree to use a medically accepted method of contraception during the clinical trial Patients corresponding to ACR functional class Ⅰ,Ⅱ,Ⅲ Patients with active rheumatoid arthritis with DAS28-ESR > 3.2 in the evaluation of DAS28-ESR identified at the screening Patients who were diagnosed with rheumatoid arthritis according to the 2010 ACR/EULAR classification criteria at least 3 months prior to the screening, and showed insufficient response or refractory to treatment with one or more DMARDs. Among the subjects who have previously been continuously administering the following rheumatoid arthritis drugs without stopping, those who have used them according to the conditions before randomization and can maintain the current administration regimen and dose during the clinical trial. cDMARDs : Patients who received the same cDMARDs for 12 weeks or more continuously and did not change the dosage and administration of the cDMARDs for 4 weeks or more until the 2nd visit(ex. methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, bucillamine etc.) Prednisolone : Patients who received corticosteroids with a daily dose of 10mg or less of oral prednisolone equivalent continuously, and did not change the dosage and administration for more than 2 weeks until the 2nd visit. Tramadol or NSAIDs : Patients who did not change the dosage and administration for more than 2 weeks consecutively until the 2nd visit Patients who have completed the wash-out period as follows until the 2nd visit including the screening period (each period refers to the case where it continues consecutively, and these drugs are contraindicated from the screening). bDMARDs abatacept, adalimumab, certolizumab pegol, golimumab : 10 weeks or more anakinra : 10 days or more etanercept : 3 weeks or more infliximab : 8 weeks or more tocilizumab : 5 weeks or more rituximab : 6 months or more JAK inhibitors tofacitinib, baricitinib : 2 weeks or more immunosuppressants tacrolimus, cyclosporin, azathioprine, cyclophosphamide mizoribine etc : 4 weeks or more tramadol, analgesics and anti-inflammatory analgesic other than NSAIDs : 4 days or more Volunteer, be willing and able to provide written informed consent for the trial Patients who can read and understand written instructions Exclusion Criteria: Patients corresponding to ACR functional class Ⅳ Patients with acquired immune deficiency syndrome or autoimmune diseases other than rheumatoid arthritis Severe heart failure, congestive heart failure (NYHA II～IV), ischemic heart disease, peripheral artery disease and/or cerebrovascular disease Patients with a history of gastrointestinal bleeding or perforation due to treatment of nonsteroidal anti-inflammatory drugs Patients with bleeding or a current history of blood coagulation disorder Patients suffering from infectious disease (including tuberculosis, shingles, etc.) at the time of screening or undergoing treatment with the medical history Patients with a history of malignant tumors within 5 years prior to screening Patients with peptic ulcer confirmed by endoscopy or radiographic examination within 6 months prior to screening Patients with a history of gastric or duodenal perforation or obstruction, patients with a history of gastrointestinal surgery (except appendicitis), and patients with a history of upper or lower gastrointestinal bleeding (excluding simple hemorrhoids) within the past year Patients with symptoms or signs of pyloric obstruction Patients diagnosed with malabsorption within 12 weeks prior to the screening Patients with hypersensitive reaction or history of clinically significant hypersensitive reaction to investigational product or its excipients Patients with aspirin asthma (asthma attacks caused by nonsteroidal anti-inflammatory drugs) or a history of the same Patients with inflammatory bowel disease such as crohn's disease or ulcerative colitis Pregnant or breast-feeding Patients administered intraarticular, intramuscular, intravenous corticosteroids within 4 weeks priro to the screening. Patients with significant psychiatric disorders or taking antidepressants, anticonvulsants, or sedatives Patients with substance or alcohol abuse or dependence Patients who participate in other clinical trials within 12 weeks prior to the screening and administer investigational drugs or apply clinical trial medical devices Patients expected to inevitably administer contraindicated drugs during the clinical trial Patients with severe renal dysfuntion(seurum creatinine is 2.0 times higher than the upper limit of normal (based on the institution)) Patients with severe liver dysfuntion(ALT, AST or total bilirubin is 2.0 times higher than the upper limit of normal (based on the institution)) Patients that the investigator deems unsuitable for participation in the clinical trial

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>HL237 tab. 200mg/day | Drug: HL237 tablet<br>* Treatment A : HL237 100mg, twice a day, Treatment B : HL237 200mg, twice a day, Treatment C : HL237 400mg, twice a day<br>|
| Experimental: Treatment B<br>HL237 tab. 400mg/day | Drug: HL237 tablet<br>* Treatment A : HL237 100mg, twice a day, Treatment B : HL237 200mg, twice a day, Treatment C : HL237 400mg, twice a day<br>|
| Experimental: Treatment C<br>HL237 tab. 800mg/day | Drug: HL237 tablet<br>* Treatment A : HL237 100mg, twice a day, Treatment B : HL237 200mg, twice a day, Treatment C : HL237 400mg, twice a day<br>|
| Placebo Comparator: Placebo<br>Placebo of HL237 tab. | Drug: Placebo of HL237 tablet<br>* Placebo of HL237, twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR20(american college of rheumatology 20) response rate | ACR20(american college of rheumatology 20) response rate at 12 weeks after administering investigational products | at 12 weeks after administering investigational products | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR20(american college of rheumatology 20) response rate | ACR20(american college of rheumatology 20) response rate at 4, 8 weeks after administering investigational products | at 4, 8 weeks after administering investigational products | 
| DAS28-ESR(Disease Activity Score 28- erythrocyte sedimentation rate) score | Change of DAS28-ESR(Disease Activity Score 28- erythrocyte sedimentation rate) score | at 4, 8, 12 weeks after administering investigational products | 
| DAS28-CRP(Disease Activity Score 28-C-reactive protein) score | Change of DAS28-CRP(Disease Activity Score 28-C-reactive protein) score Change of DAS28-ESR(Disease Activity Score 28- erythrocyte sedimentation rate) score | at 4, 8, 12 weeks after administering investigational products | 
| Tender joint count | Change of Tender joint count | at 4, 8, 12 weeks after administering investigational products | 
| Swollen joint count | Change of Swollen joint count | at 4, 8, 12 weeks after administering investigational products | 
| Investigator's composite assessment of disease activity | Change of Investigator's composite assessment of disease activity (100 mm visual analog scale (0: not active at all, 100: most severely active)) | at 4, 8, 12 weeks after administering investigational products | 
| Subject's composite assessment of disease activity | Change of Subject's composite assessment of disease activity (100 mm visual analog scale (0: not active at all, 100: most severely active)) | at 4, 8, 12 weeks after administering investigational products | 
| Subject's assessment of pain (visual analog scale) | Change of Subject's assessment of pain (100 mm visual analog scale(0: no pain, 100: severe pain)) | at 4, 8, 12 weeks after administering investigational products | 
| Subject's assessment of physical function (Korean health assessment questionnaire) | Change of Subject's assessment of physical function (Korean health assessment | at 4, 8, 12 weeks after administering investigational products | 
| Erythrocyte Sedimentation Rate (ESR) | Change of Erythrocyte Sedimentation Rate (ESR) | at 4, 8, 12 weeks after administering investigational products | 
| C-Reactive Protein (CRP) | Change of C-Reactive Protein (CRP) | at 4, 8, 12 weeks after administering investigational products | 
| morning stiffness duration | Change of morning stiffness duration | at 4, 8, 12 weeks after administering investigational products | 
| The average number of times of use the remedy per day | Change of The average number of times of use the remedy per day | at 4, 8, 12 weeks after administering investigational products | 
| The percentage of subjects who use the remedy | Change of the percentage of subjects who use the remedy | at 4, 8, 12 weeks after administering investigational products |