A Study of the Safety, Tolerability and Efficacy of Treatment With AP1189 in Early RA Patients With Active Joint Disease

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) > 22, who are to start up-titration with methotrexate.

Detailed Description
-----------------
A multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) > 22, who are to start up-titration with methotrexate. The study will be conducted in two parts separated by an interim analysis. Part 1: The subjects will be randomized in a 1:1:1 ratio into: . AP1189 dose 50 mg AP1189 dose 100 mg placebo INTERIM ANALYSIS Part 2: All subjects will be randomized into either design 1, 2 or 3 based on data from the interim analysis. Design 1: AP1189 dose 50 mg or placebo in a 2:1 ratio Design 2: AP1189 dose 100 mg or placebo in a 2:1 ratio Design 3: Continue with the same doses as in Part 1 The purpose of this study is to determine the safety and efficacy of 2 doses of AP1189 compared with placebo after 4 weeks of treatment.

Official Title
-----------------
A Double-blind, Multicenter, Two-part, Randomized, Placebo-controlled Study of the Safety, Tolerability, and Efficacy of 4 Weeks Treatment With AP1189 in Early Rheumatoid Arthritis (RA) Patients With Active Joint Disease

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: 50 mg AP1189
* Drug: AP1189
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent has been obtained prior to initiating any study specific procedures Male and female subjects, 18 to 85 years of age Confirmed diagnosis of (RA) Rheumatoid Arthritis according to the 2010 ACR/EULAR RA classification criteria Polyarthritis with joint swelling and tenderness of a minimum of three joints out of 68 joints tested Candidate for Methotrexate treatment Is about to begin treatment with MTX (Methotrexate) Tested positive for anti-CCP Anti-cyclic citrullinated peptide) or RF (Rheumatoid Factor) Severe active RA (CDAI > 22) at screening and baseline Negative QFG-IT (QuantiFERON-in-Tube test) Subjects should be able to complete the PRO (Patient Reported Outcome) questionnaires Females of child-bearing potential may only participate if using reliable means of contraception or are post-menopausal. Surgically sterilized women at least 6 months prior to screening Females of childbearing potential must have a negative pregnancy test at screening and baseline Exclusion Criteria: Participation in any other study involving investigational drug(s) within 4 weeks prior to study entry Major surgery within 8 weeks prior to screening or planned surgery within 1 month following randomization Rheumatic autoimmune disease other than RA, including SLE (systemic Lupus Erythematosus), MCTD (Mixed Connective Tissue Disease), scleroderma, polymyositis, or significant systemic involvement secondary to RA. Sjögren syndrome with RA is allowable Functional class IV as defined by the ACR Criteria for Classification of Functional Status in RA or wheelchair/bedbound Prior history of or current inflammatory joint disease other than RA Subjects with fibromyalgia Initiation or change in dose for NSAIDs within 2 weeks prior to dosing with the IMP (Investigational Medicinal Product) Corticosteroids are prohibited within 2 weeks prior to screening (and during the entire treatment period and until the final visit Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease Have prior renal transplant, current renal dialysis or severe renal insufficiency (determined by a derived glomerular filtration rate (GFR) using Cockcroft Gault Formula of ≤30 mL/min/1,73 m2 calculated by the local lab) Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids Evidence of active malignant disease Pregnant women or nursing mothers History of alcohol, drug, or chemical abuse within the 6 months prior to screening Neuropathies or other painful conditions that might interfere with pain evaluation Body weight of >150 kg Exclusion criteria that only applies for Norway Evidence of moderate and/or severe organ dysfunction Abnormal chest x-ray (as per the discretion of the investigator Evidence of positive hepatitis serology Evidence of peptic ulcer disease

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, two-part, randomized, double-blind, placebo-controlled 4-week study with repeated doses of AP1189
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg AP1189<br>50 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water. | Drug: 50 mg AP1189<br>* 50 mg AP1189 powder in bottle<br>* Other names: AP1189;|
| Experimental: 100 mg AP1189<br>100 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water. | Drug: AP1189<br>* 100 mg AP1189 powder in bottle<br>|
| Placebo Comparator: Placebo<br>Placebo. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension i e. the powder will be added 50 ml water. | Drug: Placebo<br>* Placebo powder in bottle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CDAI | The change in CDAI score from severe (CDAI > 22) to moderate (CDAI <= 22) after 4 weeks treatment compared to baseline. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Swollen and tender joints | Proportion of subjects achieving a reduction of more than 10 swollen and/or tender joints compared to baseline | 4 weeks | 
| CDAI score | Proportion of subjects achieving a change in CDAI score compared to baseline | 4 weeks | 
| DAS28 score | Proportion of subjects achieving a change in DAS28 compared to baseline | 4 weeks | 
| HAQ-DI (Health Assessment Questionnaire-Disability Index) questionnaire | Proportion of subjects achieving a change in HAQ-DI | 4 weeks | 
| FACIT-Fatigue questionnaire | Proportion of subjects achieving a change in FACIT-Fatigue | 4 weeks | 
| ACR (American College of Rheumatology) response | Proportion of subjects achieving a response assessed by ACR20, ACR50 and ACR70 | 4 weeks |