A Study in Rheumatoid Arthritis

Multiple-Dose, Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY2439821 in Japanese Patients With Rheumatoid Arthritis on Concomitant Methotrexate Treatment

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01253265

Enrollment

Registered

2010-12-03

Start date

2010-05-31

Completion date

2011-12-31

Last updated

2016-05-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

Brief summary

The purpose of this study is to evaluate the safety and tolerability of multiple doses of LY2439821 in Japanese patients with rheumatoid arthritis.

Interventions

DRUGLY2439821

Administered subcutaneously

DRUGPlacebo

Administered subcutaneously

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

20 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Ambulatory male or female patients between the ages of 20 and 75 years * Male patients: Agree to use a reliable method of birth control during the study including barrier contraceptives or a monogamous relationship with a partner who is not child bearing. Female patients: Are women who test negative for pregnancy at the time of entry based on a pregnancy test and are not breast feeding. Women of child bearing potential must agree to use a reliable method of birth control during the study. * Patients who are between the body weight of 40 and 105 kilogram (kg) * Patients who have an established diagnosis of Rheumatoid Arthritis (RA) * Patients who have C reactive protein (CRP) measurement greater than the upper limit of normal or erythrocyte sedimentation rate of at least 28 millimeters per hour (mm/hr) * Patients who have been treated with regular use of Methotrexate (MTX) for at least 12 weeks, and stable treatment (at least 7.5 milligrams per week (mg/week)) for at least 8 weeks * Patients who have given written informed consent approved by the Sponsor and the Institutional Review Board (IRB) governing the investigational site * Patients who have reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures

Exclusion criteria

* Patients who use oral corticosteroids at average daily doses of \>10 mg/day of prednisone or its equivalent or use of variable doses of oral corticosteroids within the last 4 weeks * Patients who have had a live vaccination within the last 12 weeks, or intend to have a live vaccination during the course of the study, or have participated in a vaccine clinical study within the last 12 weeks * Patients who have a diagnosis of any systemic inflammatory condition other than RA * Patients who have evidence of active vasculitis or uveitis * Patients who have a diagnosis of Felty's syndrome * Patients who have had surgical treatment of a joint within the last 8 weeks, or will require it during the study * Patients who have had lymphoma, leukemia, or any malignancy within the last 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease * Patients who have suffered a serious bacterial infection within the last 12 weeks, or a recent or ongoing infection * Patients who have an evidence or suspicion of active tuberculosis (TB) by medical history, physical examination, and/or chest radiograph or documentation of TB by a positive purified protein derivative (PPD) test * Patients who have uncontrolled arterial hypertension characterized by a systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg * Patients who have an evidence of positive hepatitis B (HBV) surface antigen, positive hepatitis B surface antibody, positive hepatitis B core antibody, or hepatitis B DNA (HBV DNA); an evidence of human immunodeficiency virus (HIV), evidence of hepatitis B; or an evidence of hepatitis C * Patients who have clinical laboratory test results at entry that are outside the normal reference range, or results with unacceptable deviations that are considered clinically significant by the investigator * Patients who have a serum creatinine \>2.0 milligrams per deciliter (mg/dL) * Patients who have known hypogammaglobulinemia or a serum immunoglobulin (Ig) G (IgG), IgM, or IgA concentration less than the lower limit of normal * Patients who have an abnormality in the 12 lead electrocardiogram (ECG). * Patients who have donated of blood more than 200 mL within the past 30 days, or more than 400 milliliters (mL) within the past 90 days * Patients who are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off label use of an investigational drug or device, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. For unapproved Disease-Modifying Anti-Rheumatic Drug (DMARDs), have received 30 days or 5 fold of the half life prior to inclusion whichever is longer * Patients who previously completed or withdrawn from this study or any other study investigating LY2439821 * Patients who have been treated with any biologic DMARD currently or previously for 5 half lives * Patients who have had serious reaction to other biologic Disease-Modifying Anti-Rheumatic Drug (DMARDs) * Patients who have received non biologics DMARDs (other than MTX, sulfasalazine, bucillamine or hydroxychloroquine)

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Clinically Significant Effects	Baseline up to 26 weeks	Clinically significant events were defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module.

Secondary

Measure	Time frame	Description
Percentage Change From Baseline to 16 Week Endpoint in Erythrocyte Sedimentation Rate (ESR)	Baseline, 16 weeks	Erythrocyte Sedimentation Rate (ESR) is a disease related biomarker and measured in millimeters per hour (mm/h).
Change From Baseline to 26 Week Endpoint in Neutrophil Counts	Baseline, 26 weeks	—
Change From Baseline to 26 Week Endpoint in Lymphocyte Counts	Baseline, 26 weeks	—
Percentage Change From Baseline to 16 Week Endpoint in C-Reactive Protein	Baseline, 16 weeks	C-reactive protein (CRP) is a disease related biomarker and measured in milligrams per liter.
Pharmacokinetics - Maximum Plasma Drug Concentration (Cmax) at Steady State (ss)	Week 10 pre-dose up to 2 weeks post-dose (Week 12)	Cmax,ss = maximum observed drug concentration (Cmax) at steady state (ss)
Pharmacokinetics - Time of Maximum Observed Drug Concentration (Tmax) at Steady State (ss)	Week 10 pre-dose up to 2 weeks post-dose (Week 12)	tmax,ss = time of maximum observed drug concentration (tmax) at steady state (ss)
Pharmacokinetics - Area Under the Concentration-time Curve (AUC) at Steady State (ss)	Week 10 pre-dose up to 2 weeks post-dose (Week 12)	AUCτ,ss= area under the concentration versus time curve (τ) at steady state (ss)

Countries

Japan

Participant flow

Participants by arm

Arm	Count
30 mg LY2439821 Administered subcutaneously at Week 0, 1, 2, 4, 6, 8 and 10	6
80 mg LY2439821 Administered subcutaneously at Week 0, 1, 2, 4, 6, 8 and 10	6
180 mg LY2439821 Administered subcutaneously at Week 0, 1, 2, 4, 6, 8 and 10	6
120 mg LY2439821 240 mg LY2439821 was administered subcutaneously (loading dose) at Week 0, followed by 120 mg LY2439821 administered subcutaneously weekly from Week 1 through Week 10	6
Placebo Placebo is administered subcutaneously in the same manner as active drug in each dose group	8
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Met Predefined Discontinuation Criteria	1	0	0	0	0
Overall Study	Withdrawal by Subject	0	0	0	0	1

Baseline characteristics

Characteristic	30 mg LY2439821	80 mg LY2439821	180 mg LY2439821	120 mg LY2439821	Placebo	Total
Age, Continuous	53.0 years STANDARD_DEVIATION 15.4	56.8 years STANDARD_DEVIATION 7.2	61.7 years STANDARD_DEVIATION 11.3	52.5 years STANDARD_DEVIATION 14	60.1 years STANDARD_DEVIATION 7.7	57.0 years STANDARD_DEVIATION 11.2
C-Reactive Protein (CRP)	7.950 milligrams per liter (mg/L)	11.750 milligrams per liter (mg/L)	3.500 milligrams per liter (mg/L)	31.000 milligrams per liter (mg/L)	5.650 milligrams per liter (mg/L)	9.700 milligrams per liter (mg/L)
Duration of Rheumatoid Arthritis (RA)	10.9 years STANDARD_DEVIATION 11.8	7.9 years STANDARD_DEVIATION 9.7	6.8 years STANDARD_DEVIATION 12	5.6 years STANDARD_DEVIATION 4.1	3.6 years STANDARD_DEVIATION 3.2	6.8 years STANDARD_DEVIATION 8.5
Erythrocyte Sedimentation Rate (ESR)	28.0 millimeters per hour (mm/h)	53.5 millimeters per hour (mm/h)	26.0 millimeters per hour (mm/h)	42.5 millimeters per hour (mm/h)	25.5 millimeters per hour (mm/h)	29.5 millimeters per hour (mm/h)
Lymphocytes	0.993 10^9 cells per liter (GI/L)	1.156 10^9 cells per liter (GI/L)	1.187 10^9 cells per liter (GI/L)	1.379 10^9 cells per liter (GI/L)	1.295 10^9 cells per liter (GI/L)	1.275 10^9 cells per liter (GI/L)
Neutrophils	6.763 10^9 cells per liter (GI/L)	4.293 10^9 cells per liter (GI/L)	3.857 10^9 cells per liter (GI/L)	6.056 10^9 cells per liter (GI/L)	6.757 10^9 cells per liter (GI/L)	5.261 10^9 cells per liter (GI/L)
Race/Ethnicity, Customized Japanese	6 participants	6 participants	6 participants	6 participants	8 participants	32 participants
Region of Enrollment Japan	6 participants	6 participants	6 participants	6 participants	8 participants	32 participants
Sex: Female, Male Female	4 Participants	6 Participants	3 Participants	4 Participants	5 Participants	22 Participants
Sex: Female, Male Male	2 Participants	0 Participants	3 Participants	2 Participants	3 Participants	10 Participants
Weekly dose of Methotrexate (MTX)	8.33 milligrams per week (mg/wk) STANDARD_DEVIATION 0.82	8.33 milligrams per week (mg/wk) STANDARD_DEVIATION 0.82	8.00 milligrams per week (mg/wk) STANDARD_DEVIATION 0	9.00 milligrams per week (mg/wk) STANDARD_DEVIATION 1.1	9.06 milligrams per week (mg/wk) STANDARD_DEVIATION 1.66	8.58 milligrams per week (mg/wk) STANDARD_DEVIATION 1.1

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	4 / 6	5 / 6	3 / 6	3 / 6	6 / 8
serious Total, serious adverse events	0 / 6	0 / 6	0 / 6	0 / 6	0 / 8

Outcome results

Primary

Number of Participants With Clinically Significant Effects

Clinically significant events were defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Event module.

Time frame: Baseline up to 26 weeks