A Study To Evaluate The Effect Of CP-690,550 On Measures Of Kidney Function In Patients With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of study is to explore the effect of CP-690,550 (Tofacitinib) on measures of kidney function in patients with active rheumatoid arthritis (RA).

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Two-Period, Fixed Sequence Study To Evaluate The Effect Of CP-690,550 On Measured Glomerular Filtration Rate In Patients With Active Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: CP-690,550 or Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient must meet the American College of Rheumatology (ACR) classification criteria for the diagnosis of rheumatoid arthritis by satisfying at least four of the seven criteria. The patient must have active disease at both Screening and predose on Day 1 of Period 1. Patient must have had an inadequate response to at least one disease-modifying antirheumatic drug (DMARD), non-biologic or biologic, due to ineffectiveness or intolerance. Exclusion Criteria: Pregnant or lactating women Serious medical conditions that would make treatment with CP-690,550 potentially unsafe. A patient who has a history of asthma, multiple allergies or severe allergy (eg, anaphylaxis) to any substance. In particular, a history of allergy to iodine, povidone-iodine, iohexol or other iodinated contrast media.

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sequence 1<br> | Drug: CP-690,550 or Placebo<br>* CP-690,550 10 mg twice a day (BID) orally or placebo BID orally, approximately 72 days<br>|
| Placebo Comparator: Sequence 2<br> | Drug: Placebo<br>* Placebo BID orally, approximately 72 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Geometric (Geo) Mean-Fold Change at End of Period 1 From Baseline in Measured Glomerular Filtration Rate (mGFR) | Glomerular filtration rate (GFR) is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. mGFR was determined using iohexol serum clearance using compartmental modeling of the iohexol serum concentration-time data. mGFR values were normalized to 1.73 meters squared (m^2) body surface area. A normal GFR is greater than (>)90 milliliters per minute (mL/min), although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR <15 mL/min is consistent with kidney failure. Baseline was defined as the mean of the values obtained at Run-in and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 43 of Period 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Geometric Mean-Fold Change at the End of Period 2 From Baseline in mGFR | mGFR was determined using iohexol serum clearance using compartmental modeling of the iohexol serum concentration-time data. mGFR values were normalized to 1.73 m^2 body surface area. Baseline was defined as the mean of the values obtained at Run-in and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From End of Period 1 in mGFR | mGFR was determined using iohexol serum clearance using compartmental modeling of the iohexol serum concentration-time data. mGFR values were normalized to 1.73 m^2 body surface area. | Day 43 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 1 From Baseline in Estimated Glomerular Filtration Rate (eGFR) Using Modified Diet in Renal Disease (MDRD) | eGFR was calculated using the MDRD equation and normalized to 1.73 m^2 body surface area. Baseline was defined as the mean of the values obtained at Screening and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 43 of Period 1 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From Baseline in eGFR Using MDRD | eGFR was calculated using the MDRD equation with eGFR values normalized to 1.73 m^2 body surface area. Baseline was defined as the mean of the values obtained at Screening and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From End of Period 1 in eGFR Using MDRD | eGFR was calculated using the MDRD equation with eGFR values normalized to 1.73 m^2 body surface area. | Day 43 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 1 From Baseline in eGFR Using the Cockcroft-Gault Equation | eGFR was calculated using the Cockcroft-Gault equation normalized to 1.73 m^2 body surface area. Baseline was defined as the mean of the values obtained at Screening and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 43 of Period 1 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From Baseline in eGFR Using the Cockcroft-Gault Equation | eGFR was calculated using the Cockcroft-Gault equation normalized to 1.73 m^2 body surface area. Baseline was defined as the mean of the values obtained at Screening and on predose in Period 1/Day 1. | Day 1 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From End of Period 1 in eGFR Using the Cockcroft-Gault Equation | eGFR was calculated using the Cockcroft-Gault equation normalized to 1.73 m^2 body surface area. | Day 43 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 1 From Baseline in Serum Creatinine | Blood samples were collected from participants at screening, predose on Day 1 of Period 1, on the last day of Period 1 and on the last day of Period 2 for assessment of serum creatinine levels. Serum creatinine values in milligrams per deciliter (mg/dL) reported by the central laboratory were used. Baseline for serum creatinine was defined as the mean of values obtained at screening and predose on Day 1 of Period 1. | Day 1 of Period 1, Day 43 of Period 1 | 
| Adjusted Geometric Mean-Fold Change From End of Period 2 From Baseline in Serum Creatinine | Blood samples were collected from participants at screening, predose on Day 1 of Period 1, on the last day of Period 1 and on the last day of Period 2 for assessment of serum creatinine levels. Serum creatinine values in mg/dL reported by the central laboratory were used. Baseline for serum creatinine was defined as the mean of values obtained at screening and predose on Day 1 of Period 1. | Day 1 of Period 1, Day 29 of Period 2 | 
| Adjusted Geometric Mean-Fold Change at End of Period 2 From End of Period 1 in Serum Creatinine | Blood samples were collected from participants at screening, predose on Day 1 of Period 1, on the last day of Period 1 and on the last day of Period 2 for assessment of serum creatinine levels. Serum creatinine values in mg/dL reported by the central laboratory were used. | Day 43 of Period 1, Day 29 of Period 2 | 
| Percentage of Participants Achieving an American College of Rheumatology 20% (ACR20) Response | ACR20 response: greater than or equal to (≥)20 percent (%) improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Day 1 of Period 1 to Day 43 of Period 1, Day 1 of Period 1 to Day 29 of Period 2 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response | ACR50 response: ≥50% improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) participant's assessment of disease activity, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a HAQ, and 5) CRP at each visit. | Day 1 of Period 1 to Day 43 of Period 1, Day 1 of Period 1 to Day 29 of Period 2 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response | ACR70 response: ≥70% improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) participant's assessment of disease activity, 3) participant's assessment of pain, 4) participant' assessment of functional disability via a HAQ, and 5) CRP at each visit. | Day 1 of Period 1 to Day 43 of Period 1, Day 1 of Period 1 to Day 29 of Period 2 | 
| Least Squares (LS) Mean Change at End of Period 1 From Baseline in Disease Activity Score Based on 28-Joint Count CRP (DAS28-3 [CRP]) | DAS28 calculated from the tender/painful joint count, swollen joint count (SJC) using the 28 joints count, and CRP value. DAS28 less than or equal to (≤)3.2 equals (=) low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in DAS28-3 (CRP) | DAS28 calculated from the tender/painful joint count, SJC using the 28 joints count, and CRP value. DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in DAS28-3 (CRP) | DAS28 calculated from the tender/painful joint count, SJC using the 28 joints count, and CRP value. DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline DAS28-4 (CRP) | DAS28 calculated from the number of SJC and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline DAS28-4 (CRP) | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR (mm/hour) and PGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 DAS28-4 (CRP) | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR (mm/hour) and PGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity. | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline in Tender/Painful Joint Count | 68 joints were assessed by a joint assessor to determine the number of joints that were considered tender or painful Assessed joints included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb interphalangeal [IP], PIP, and distal interphalangeals [DIP]), and lower extremity (hip, knee, ankle, tarsus, metatarsophalangeals [MTP], great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in Tender/Painful Joint Count | 68 joints were assessed by a joint assessor to determine the number of joints that were considered tender or painful Assessed joints included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb IP, PIP, and DIP), and lower extremity (hip, knee, ankle, tarsus, MTP, great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in Tender/Painful Joint Count | 68 joints were assessed by a joint assessor to determine the number of joints that were considered tender or painful Assessed joints included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb IP, PIP, and DIP), and lower extremity (hip, knee, ankle, tarsus, MTP, great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline in Swollen Joint Count | Swollen joint count included 66 joints. Assessor assessed joints for swelling using the following scale: present/absent/not done/not applicable (to be used for artificial joints). Joints assessed included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb IP, PIP, and DIP), and lower extremity (knee, ankle, tarsus, MTP, great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in Swollen Joint Count | Swollen joint count included 66 joints. Assessor assessed joints for swelling using the following scale: present/absent/not done/not applicable (to be used for artificial joints). Joints assessed included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb IP, PIP, and DIP), and lower extremity (knee, ankle, tarsus, MTP, great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in Swollen Joint Count | Swollen joint count included 66 joints. Assessor assessed joints for swelling using the following scale: present/absent/not done/not applicable (to be used for artificial joints). Joints assessed included: upper body (temporomandibular, sternoclavicular, acromioclavicular), upper extremity (shoulder, elbow, wrist, MCP, thumb IP, PIP, and DIP), and lower extremity (knee, ankle, tarsus, MTP, great toe IP, proximal and distal interphalangeals combined [PIP]). | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline in CRP |  | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in CRP |  | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in CRP |  | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline in Patient Global Assessment of Arthritis (PGAA) | Participants answered the following question, Considering all the ways your arthritis affects you, how are you feeling today? Participants responded by using a 0 - 100 millimeter (mm) visual analog scale (VAS), where 0 mm = very well and 100 mm = very poorly. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in PGAA | Participants answered the following question, Considering all the ways your arthritis affects you, how are you feeling today? The participants responses were recorded using a 100 mm VAS, where 0 mm = very well and 100 mm = very poorly. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in PGAA | Participants answered the following question, Considering all the ways your arthritis affects you, how are you feeling today? The participants responses were recorded using a 100 mm VAS, where 0 mm = very well and 100 mm = very poorly. | Day 43 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline in Physician Global Assessment of Arthritis | A physician assessed how the participant's overall arthritis appeared at the time of the visit. This was an evaluation based on the participant's disease signs, functional capacity and physical examination. The physician's response was recorded using a 100 mm VAS, where 0 mm = very good and 100 mm = very poor. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in Physician Global Assessment of Arthritis | A physician assessed how the participant's overall arthritis appeared at the time of the visit. This was an evaluation based on the participant's disease signs, functional capacity and physical examination. The physician's response was recorded using a 100 mm VAS, where 0 mm = very good and 100 mm = very poor. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in Physician Global Assessment of Arthritis | A physician assessed how the participant's overall arthritis appeared at the time of the visit. This was an evaluation based on the participant's disease signs, functional capacity and physical examination. The physician's response was recorded using a 100 mm VAS, where 0 mm = very good and 100 mm = very poor. | Day 43 of Period 1, Day 29 of Period 1 | 
| LS Mean Change at End of Period 1 From Baseline in Patient Assessment of Arthritis Pain | Participant's assessed the severity of their arthritis pain using a 100 mm VAS placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponded to the magnitude of their pain. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline in Patient Assessment of Arthritis Pain | Participant's assessed the severity of their arthritis pain using a 100 mm VAS placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponded to the magnitude of their pain. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 in Patient Assessment of Arthritis Pain | Participant's assessed the severity of their arthritis pain using a 100 mm VAS placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponded to the magnitude of their pain. | Day 43 of Period 2, Day 29 of Period 2 | 
| LS Mean Change at End of Period 1 From Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) Score | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. | Day 1 of Period 1, Day 43 of Period 1 | 
| LS Mean Change at End of Period 2 From Baseline HAQ-DI Score | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. | Day 1 of Period 1, Day 29 of Period 2 | 
| LS Mean Change at End of Period 2 From End of Period 1 HAQ-DI Score | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. | Day 43 of Period 1, Day 29 of Period 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1