Randomized, Double-blind, Vehicle Controlled, Repeat Dose Comparative Study in RA Patients Managed With DMARDs

Study Overview
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Brief Summary
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This is a randomized, vehicle controlled, double-blind, repeat dose comparative study in patients with rheumatoid arthritis (RA) under management with DMARDs and with persistent disease activity. The goal of this study is to evaluate the safety, tolerability and pharmacokinetics of 6 weekly repeat doses of ORTD-1.

Official Title
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A Randomized, Double-blind, Parallel, Vehicle Controlled, Repeat Dose Comparative Phase 1b Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ORTD-1 in Rheumatoid Arthritis Patients With Mild Disease Managed With DMARDs

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Low dose ORTD-1
* Drug: Low dose vehicle control
* Drug: High dose ORTD-1
* Drug: High dose vehicle control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age or older, males or females. Diagnosed rheumatoid arthritis per the American Rheumatism Association 1987 classification criteria of at least 6 months duration. Disease activity defined as: erythrocyte sedimentation rate (ESR) > 24 mm or serum C-reactive protein level ≥ 1.2 times (X) the upper limit of normal (ULN), and DAS28-CRP score ≥ 2.6 and < 5.1 Current regimen of DMARDs that may include methotrexate, sulfasalazine, hydroxychloroquine, leflunomide and/or azathioprine, alone or in combination. No change in DMARD dose(s) within 4 weeks prior to Screening. May be receiving a stable regimen (of at least 4 weeks duration) of concomitant NSAIDs. Women of child-bearing potential (WOCBP), defined as a sexually mature woman not surgically sterilized, or not post-menopausal for at least 12 consecutive months. Female subjects must: Not be lactating; not be pregnant upon enrollment. Agree to use highly effective methods of birth control throughout the study. Highly effective methods of contraception include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation by oral, intravaginal, or transdermal administration; progestogen-only hormonal contraception associated with inhibition of ovulation by oral, injectable, or implantable administration; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; partner vasectomy; or total abstinence (only if total abstinence is an established method and lifestyle of the subject). Patients already using hormonal contraception at the time of screening will be eligible but will not initiate hormonal contraception in order to participate in the study. Agree to use highly effective methods of birth control for at least 6 months after the last dose of investigational product. Male subjects must refrain from donating sperm or fathering a child during the study. Male subjects must use barrier contraception throughout the course of the study. Signed and dated informed consent. Exclusion Criteria: Prior therapy with any biologic therapeutic within 3 months prior to enrollment, or in the case of Rituxan (rituximab), this period must be at least 12 months. History of or current clinical fibromyalgia or Juvenile Idiopathic Arthritis (JIA). Positive diagnosis of SLE. Patients with Type 1 or Type 2 Diabetes Mellitus. Patients with psoriasis. Patients with skin condition(s) or visible abnormalities at or near potential sites of injection (right and left abdomen; right and left thigh) that could mask the assessment of safety. Acute illness including current or chronic infections requiring antibiotics, or symptoms of a resolving illness, within 2 weeks prior to study. Any investigational drug within 3 months prior to study. Patients may not be receiving systemic corticosteroid therapy with the exception of inhaled corticosteroids for the treatment of asthma. Any clinically relevant abnormality as assessed by the Investigator, on screening history, physical exam, clinical laboratory, chest X-ray, or ECG, other than values consistent with rheumatoid arthritis, with the exception that liver function tests (ALP, ALT, AST) may be up to 1.5 times (X) the upper limit of normal (ULN). Positive serological test for HCV, HBsAg, HBcAg, HIV. QuantiFERON-positive patients may be enrolled with documented evidence that they have completed a prescribed course of antituberculous therapy. History of cardiovascular disease with New York Heart Association (NYHA) functional class II or greater; or history of stroke, or uncontrolled hypertension. History of lymphoproliferative disease, or organ allograft. Pregnancy or lactation, or WOCBP not currently using contraceptives or male partners of WOCBP not currently using contraceptives. History of cancer (except for in situ cancer, or limited stage cancer of the cervix, head and neck (squamous cell), thyroid, or skin (non-melanomatous) curatively treated with no sign of disease for > 5 years). Any physical or psychological condition that might prevent complete participation in the study, in the view of the investigator.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ORTD-1-Low Dose<br>5.6 mg/0.45 mL of active study drug | Drug: Low dose ORTD-1<br>* Once weekly, single subcutaneous injection of ORTD-1 at a volume of 0.45 mL. Six weekly treatments; 28-day follow-up period.<br>* Other names: ORTD-1;|
| Placebo Comparator: Vehicle Control -Low Dose<br>Vehicle (Identical formulation without the active DP) | Drug: Low dose vehicle control<br>* Once weekly subcutaneous injection of vehicle at a volume of 0.45 mL. Six weekly treatments; 28-day follow-up period.<br>* Other names: Placebo;|
| Experimental: ORTD 1-High Dose<br>22.5 mg/1.8 mL of active study drug | Drug: High dose ORTD-1<br>* Two subcutaneous injections of ORTD-1 at two injection sites once weekly; 0.90 mL of ORTD-1 per each subcutaneous injection. Six weekly treatments; 28-day follow-up period.<br>* Other names: ORTD-1;|
| Placebo Comparator: Vehicle Control -High Dose<br>Vehicle (Identical formulation without the active DP) | Drug: High dose vehicle control<br>* Two subcutaneous injections of vehicle at two injection sites once weekly; 0.90 mL of vehicle per each subcutaneous injection. Six weekly treatments; 28-day follow-up period.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of ORTD-1 measured by the number of patients with adverse events | Safety will be assessed throughout the duration of the study (weeks 1 through 10) by monitoring of adverse events. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity by measurement of anti-drug antibodies | Immunogenicity is the measurement of anti-drug (ORTD-1) antibodies (ADA) in serum. ADA samples will be analyzed from the change in baseline (Visit 1) using descriptive statistics (mean, median, range and standard deviation). | Weeks 1, 3, 5, and 10 | 
| Serum concentration of ORTD-1 from baseline | Serum concentration will be measured from the change in baseline (Visit 1) using descriptive statistics (mean, median, range and standard deviation). | 10 weeks | 
| Cmax of ORTD-1 | Cmax (maximum plasma concentration) will be measured using the arithmetic mean, standard deviation (SD), coefficient of variation (CV) (%), median, minimum, and maximum. | Week 1 through week 6 | 
| Tmax of ORTD-1 | Tmax (time of maximum plasma concentration) will be measured using the arithmetic mean, standard deviation (SD), coefficient of variation (CV) (%), median, minimum, and maximum. | Week 1 through week 6 |