Rheumatoid Arthritis
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and effectiveness of LY3337641 in adults with rheumatoid arthritis (RA).
Interventions
DRUGLY3337641
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 6 Weeks | 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. |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | Baseline, Week 12 | 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. |
| Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | Week 12 | 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. |
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | Week 12 | 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. |
| Pharmacokinetics (PK): Clearance Parameter of LY3337641 | 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) | 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. |
| Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | Week 12 | 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. |
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | Week 12 | 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. |
Countries
Argentina, Australia, Austria, Italy, Japan, Mexico, Poland, Puerto Rico, Slovakia, South Africa, South Korea, Spain, United States
Participant flow
Pre-assignment details
The study consist of 2-parts. Part A included participants with at least mildly active rheumatoid arthritis (RA) and Part B included participants with moderately to severely active RA. Long-term extension (LTE) period allowed eligible participants who completed Part B of study to receive LY3337641 up to an additional 52 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo Participants received oral dose of placebo once daily (QD) for 4 weeks. | 9 |
| Part A: 5 mg LY3337641 Participants received oral dose of 5 mg LY3337641 QD for 4 weeks. | 9 |
| Part A: 10 mg LY3337641 Participants received oral dose of 10 mg LY3337641 QD for 4 weeks. | 10 |
| Part A: 30 mg LY3337641 Participants received oral dose of 30 mg LY3337641 QD for 4 weeks. | 8 |
| Part B: Placebo Participants received oral dose of placebo QD for 12 weeks. | 62 |
| Part B: 5 mg LY3337641 Participants received oral dose of 5 mg LY3337641 QD for 12 weeks. | 63 |
| Part B: 10 mg LY3337641 Participants received oral dose of 10 mg LY3337641 QD for 12 weeks. | 62 |
| Part B: 30 mg LY3337641 Participants received oral dose of 30 mg LY3337641 QD for 12 weeks. | 63 |
| Total | 286 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Dosing Period | Adverse Event | 0 | 0 | 0 | 0 | 2 | 1 | 3 | 2 |
| Dosing Period | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Dosing Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 0 |
| Dosing Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Dosing Period | Other | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 4 |
| Dosing Period | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Dosing Period | Site Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Dosing Period | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 7 | 6 | 7 | 7 |
| Dosing Period | Withdrawal by Subject | 0 | 0 | 1 | 0 | 2 | 4 | 1 | 1 |
| Long-term Extension (LTE) Period | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 3 |
| Long-term Extension (LTE) Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 1 |
| Long-term Extension (LTE) Period | Other | 0 | 0 | 0 | 0 | 0 | 3 | 4 | 3 |
| Long-term Extension (LTE) Period | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 52 | 51 | 51 |
| Long-term Extension (LTE) Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 | 3 | 3 |
Baseline characteristics
| Characteristic | Part A: Placebo | Part A: 5 mg LY3337641 | Part A: 10 mg LY3337641 | Part A: 30 mg LY3337641 | Part B: Placebo | Part B: 5 mg LY3337641 | Part B: 10 mg LY3337641 | Part B: 30 mg LY3337641 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 11.43 | 54.0 years STANDARD_DEVIATION 11.75 | 56.9 years STANDARD_DEVIATION 6.44 | 51.9 years STANDARD_DEVIATION 5.72 | 50.5 years STANDARD_DEVIATION 8.75 | 50.1 years STANDARD_DEVIATION 9.2 | 51.7 years STANDARD_DEVIATION 9.36 | 51.9 years STANDARD_DEVIATION 8.91 | 51.5 years STANDARD_DEVIATION 9.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 34 Participants | 26 Participants | 23 Participants | 21 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 7 Participants | 6 Participants | 24 Participants | 29 Participants | 26 Participants | 23 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 8 Participants | 13 Participants | 19 Participants | 44 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 14 Participants | 9 Participants | 10 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 9 Participants | 7 Participants | 53 Participants | 46 Participants | 50 Participants | 51 Participants | 229 Participants |
| Region of Enrollment Argentina | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 15 Participants | 13 Participants | 15 Participants | 14 Participants | 57 Participants |
| Region of Enrollment Australia | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Austria | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Italy | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 10 Participants |
| Region of Enrollment Japan | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 6 Participants | 6 Participants | 7 Participants | 25 Participants |
| Region of Enrollment Mexico | 3 Participants | 3 Participants | 2 Participants | 0 Participants | 10 Participants | 6 Participants | 7 Participants | 4 Participants | 35 Participants |
| Region of Enrollment Poland | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 9 Participants | 9 Participants | 4 Participants | 7 Participants | 32 Participants |
| Region of Enrollment Puerto Rico | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 2 Participants | 3 Participants | 5 Participants | 14 Participants |
| Region of Enrollment Slovakia | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment South Africa | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 3 Participants | 13 Participants |
| Region of Enrollment South Korea | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Spain | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants | 6 Participants | 13 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 6 Participants | 7 Participants | 12 Participants | 13 Participants | 15 Participants | 6 Participants | 71 Participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 9 Participants | 5 Participants | 54 Participants | 53 Participants | 56 Participants | 53 Participants | 246 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 8 Participants | 10 Participants | 6 Participants | 10 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 10 | 0 / 8 | 0 / 62 | 0 / 63 | 0 / 62 | 1 / 63 | 0 / 61 | 0 / 58 | 0 / 61 |
| other Total, other adverse events | 3 / 9 | 1 / 9 | 6 / 10 | 2 / 8 | 7 / 62 | 10 / 63 | 12 / 62 | 19 / 63 | 11 / 61 | 12 / 58 | 10 / 61 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 10 | 0 / 8 | 2 / 62 | 0 / 63 | 0 / 62 | 3 / 63 | 1 / 61 | 3 / 58 | 1 / 61 |
Outcome results
Primary
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.
Time frame: Up to 6 Weeks
Population: All randomized participants who received at least 1 dose of the study drug in Part A.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | 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 | 3 Participants |
| Part A: Placebo | 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 | SAEs | 0 Participants |
| Part A: Placebo | 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 | AESIs | 0 Participants |
| Part A: 5 mg LY3337641 | 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 | 1 Participants |
| Part A: 5 mg LY3337641 | 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 | SAEs | 0 Participants |
| Part A: 5 mg LY3337641 | 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 | AESIs | 0 Participants |
| Part A: 10 mg LY3337641 | 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 | AESIs | 0 Participants |
| Part A: 10 mg LY3337641 | 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 | 6 Participants |
| Part A: 10 mg LY3337641 | 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 | SAEs | 0 Participants |
| Part A: 30 mg LY3337641 | 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 | 2 Participants |
| Part A: 30 mg LY3337641 | 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 | SAEs | 0 Participants |
| Part A: 30 mg LY3337641 | 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 | AESIs | 0 Participants |
Primary
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.
Time frame: Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | 48.1 Percentage of Participants |
| Part A: 5 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | 55.4 Percentage of Participants |
| Part A: 10 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | 44.2 Percentage of Participants |
| Part A: 30 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response in Part B | 50.9 Percentage of Participants |
p-value: 0.473Regression, Logistic
p-value: 0.67Regression, Logistic
p-value: 0.823Regression, Logistic
Secondary
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.
Time frame: Baseline, Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | -1.62 units on a scale | Standard Deviation 1.447 |
| Part A: 5 mg LY3337641 | Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | -1.55 units on a scale | Standard Deviation 1.182 |
| Part A: 10 mg LY3337641 | Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | -1.24 units on a scale | Standard Deviation 1.146 |
| Part A: 30 mg LY3337641 | Change From Baseline in the Disease Activity Score (DAS) 28-high-sensitivity C-reactive Protein (hsCRP) in Part B | -1.80 units on a scale | Standard Deviation 1.453 |
p-value: 0.86395% CI: [-0.53, 0.44]Mixed-effects Model for Repeated Measure
p-value: 0.50395% CI: [-0.32, 0.65]Mixed-effects Model for Repeated Measure
p-value: 0.28995% CI: [-0.77, 0.23]Mixed-effects Model for Repeated Measure
Secondary
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.
Time frame: Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | 27.8 Percentage of Participants |
| Part A: 5 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | 25.0 Percentage of Participants |
| Part A: 10 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | 15.4 Percentage of Participants |
| Part A: 30 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response in Part B | 29.1 Percentage of Participants |
p-value: 0.743Regression, Logistic
p-value: 0.124Regression, Logistic
p-value: 0.858Regression, Logistic
Secondary
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.
Time frame: Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | 16.7 Percentage of Participants |
| Part A: 5 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | 8.9 Percentage of Participants |
| Part A: 10 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | 1.9 Percentage of Participants |
| Part A: 30 mg LY3337641 | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response in Part B | 16.4 Percentage of Participants |
p-value: 0.199Regression, Logistic
p-value: 0.028Regression, Logistic
p-value: 0.863Regression, Logistic
Secondary
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.
Time frame: Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | 20.4 Percentage of Participants |
| Part A: 5 mg LY3337641 | Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | 19.6 Percentage of Participants |
| Part A: 10 mg LY3337641 | Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | 7.7 Percentage of Participants |
| Part A: 30 mg LY3337641 | Percentage of Participants Who Achieve Clinical Remission Using DAS28-hsCRP in Part B | 25.5 Percentage of Participants |
p-value: 0.905Regression, Logistic
p-value: 0.069Regression, Logistic
p-value: 0.547Regression, Logistic
Secondary
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.
Time frame: Week 12
Population: All randomized participants who received at least 1 dose of the study drug, for participants who completed or early discontinued dosing treatment period before the study was terminated in Part B. Missing values due to discontinuation of study or drug, or missing data were imputed using non-responder imputation (NRI).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | 27.8 Percentage of Participants |
| Part A: 5 mg LY3337641 | Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | 32.1 Percentage of Participants |
| Part A: 10 mg LY3337641 | Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | 21.2 Percentage of Participants |
| Part A: 30 mg LY3337641 | Percentage of Participants Who Achieve Low Disease Activity Using DAS28-hsCRP in Part B | 29.1 Percentage of Participants |
p-value: 0.626Regression, Logistic
p-value: 0.418Regression, Logistic
p-value: 0.951Regression, Logistic
Secondary
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.
Time frame: 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)
Population: All randomized participants who received at least 1 dose of the study drug and have evaluable PK data in in Part A and Part B.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Pharmacokinetics (PK): Clearance Parameter of LY3337641 | 29.1 Liter per hour (L/hr) | Standard Error 5.9 |