A Study of LY3337641 in Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to evaluate the safety and effectiveness of LY3337641 in adults with rheumatoid arthritis (RA).

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects With Rheumatoid Arthritis: The RAjuvenate Study

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

Intervention / Treatment
-----------------
* Drug: LY3337641
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female subjects of childbearing potential test negative for pregnancy at screening and agree not to breastfeed Female subjects: agree to use a reliable method of birth control from the start of screening until 28 days after the last dose of study drug or be of nonchildbearing potential Male subjects: agree to use a reliable method of birth control from the start of screening until 2 weeks after the last dose of study drug or have undergone vasectomy Have a diagnosis of RA based on the 2010 American College of Rheumatology (ACR)/European League against Rheumatism criteria Have at least 1 of the following: rheumatoid factor or anti-citrullinated peptide antibodies (ACPA) at screening OR radiographs documenting bony erosions Have active RA, defined as: Part A: ≥3 swollen joints (based on 66-joint counts) Part B: ≥6 swollen joints (based on 66-joint counts) ≥6 tender joints (based on 68-joint counts) hsCRP levels greater than the upper limit of normal (ULN) OR positive for ACPA Part B only: Have had inadequate response, loss of response, or intolerance to at least 1 synthetic OR biologic disease-modifying antirheumatic drug (DMARD) Exclusion Criteria: Have received any of the following: Part B only: any prior treatment with a product directly targeting Bruton's tyrosine kinase (BTK) (marketed or investigational) belimumab, natalizumab, or vedolizumab within 6 months prior to baseline B-cell-depleting agents (such as rituximab) or other cell-depleting biologics (eg, anti-cluster of differentiation 3 (CD3) antibody) within 12 months prior to screening for Part A or at any time prior to screening for Part B Have known hypogammaglobulinemia Have hepatitis C virus, hepatitis B virus or human immunodeficiency virus Have active tuberculosis (TB) Are at high risk of infection or have recent evidence of clinically significant infection Have had lymphoma, leukemia, or any malignancy within the previous 5 years except for treated basal cell or squamous epithelial carcinomas of the skin Have received a live (attenuated) vaccine within 28 days prior to baseline or plan to receive one during the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A 5 mg LY3337641<br>Given once a day for 4 weeks. | Drug: LY3337641<br>* Administered orally<br>|
| Experimental: Part A 10 mg LY3337641<br>Given once a day for 4 weeks. | Drug: LY3337641<br>* Administered orally<br>|
| Experimental: Part A 30 mg LY3337641<br>Given once a day for 4 weeks. | Drug: LY3337641<br>* Administered orally<br>|
| Placebo Comparator: Part A Placebo<br>Given once a day for 4 weeks. | Drug: Placebo<br>* Administered orally<br>|
| Experimental: Part B 5 mg LY3337641<br>Given once a day for 12 weeks and an additional 52 weeks for Long-term extension (LTE) period. | Drug: LY3337641<br>* Administered orally<br>|
| Experimental: Part B 10 mg LY3337641<br>Given once a day for 12 weeks and an additional 52 weeks for Long-term extension (LTE) period. | Drug: LY3337641<br>* Administered orally<br>|
| Experimental: Part B 30 mg LY3337641<br>Given once a day for 12 weeks and an additional 52 weeks for Long-term extension (LTE) period. | Drug: LY3337641<br>* Administered orally<br>|
| Placebo Comparator: Part B Placebo<br>Given once a day for 12 weeks. | Drug: Placebo<br>* Administered orally<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Treatment-Emergent Adverse Events (TEAEs) or Adverse Events of Special Interest (AESIs) or Any Serious AEs (SAEs) in Part A | TEAEs are any untoward medical occurrence that either occurs or worsens at any time after treatment baseline, and in the opinion of the investigators is possibly related to study drug. Skin Rash was the only event that was considered an AESI. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of SAEs and other non-serious AEs, regardless of whether or not they were possibly related to study drug, is located in the Reported Adverse Event section. | Up to 6 Weeks | 
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). ACR20 Responder is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient's Global Assessment of Arthritis Pain using visual analog scale (VAS), Health Assessment Questionnaire - Disability Index (HAQ-DI) and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and /or participants who discontinue study or drug before analysis timepoint are deemed non-responders. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | ACR50 Responder Index is composite of clinical, laboratory, and functional measures in RA. ACR50 Responder is a participant who has at least 50% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient's Global Assessment of Arthritis Pain using VAS, HAQ-DI and hsCRP. Participants with missing responses and/or participants who discontinue study or drug before analysis timepoint are deemed non-responders. | Week 12 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | ACR70 Responder Index is composite of clinical, laboratory, and functional measures in RA. ACR70 Responder is a participant who has at least 70% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Patient's Global Assessment of Arthritis Pain using VAS, HAQ-DI and hsCRP. Participants with missing responses and/or participants who discontinue study or drug before analysis timepoint are deemed non-responders. | Week 12 | 
| Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using VAS. DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. | Baseline, Week 12 | 
| Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using VAS. DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. | Week 12 | 
| Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using visual analog scale (VAS) (participant global VAS). DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Clinical remission is defined as DAS28-hsCRP <2.6. | Week 12 | 
| Pharmacokinetics (PK): Clearance Parameter of LY3337641 | Apparent total body clearance of drug after oral administration based on population PK analysis was evaluated. As prespecified per protocol, an overall population estimate of clearance is generated and data from Part A and B were combined for the analysis. The sparse data was then analyzed using population PK methods in Non linear Mixed Effects Model (NONMEM) to generate an overall population estimate of clearance. | Part A: Weeks 1, 2, and 4, Day 1 (0.5 to 2 hours postdose); Part B: Weeks 2, 4, 8, and 12, Day 1 (0.5 to 2 hours postdose) |