Investigating Clinical Efficacy of Ofatumumab in Adult Rheumatoid Arthritis (RA) Patients Who Had an Inadequate Response to MTX Therapy

The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR20 if he experienced >=20% improvement from baseline in TJC and SJC and a >=20% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR50 if he experienced >=50% improvement from baseline in TJC and SJC and a >=50% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

The ACR score was based on improvement from baseline in tender (TJC) and swollen joint counts (SJC). A participant had achieved ACR70 if he experienced >=70% improvement from baseline in TJC and SJC and a >=70% improvement from baseline in 3 out of 5 of the following assessments: participant pain assessment on a 100 millimeter (mm) visual analog scale (VAS), participant global assessment on a 100 mm VAS scale, physician global assessment on a 100 mm VAS scale, participant self-assessed disability, and C-reactive protein.

ACRn = the largest integer n for which a participant (par.) met the criteria requiring an improvement of n%. ACRn is a measure characterizing percent (%) improvement from baseline (IFBL). A par. with an ACRn of X had an improvement of >=X% in tender/swollen joints (TJC/SJC), and an improvement of >=X% in 3 of the 5 parameters (patient [pt] pain assessment, pt global assessment [GA], physician GA, pt self-assessed disability, acute phase reactant). ACRn = minimum(TJC % IFBL, SJC % IFBL, composite measure % IFBL). Composite measure % IFBL is the 3rd highest value of % IFBL for the 5 parameters.

The DAS28 is a clinical index of rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of DA can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. APRs are a class of proteins that are useful markers for inflammation.

The DAS28 is a clinical index of RA disease activity that combines information from swollen joints, tender joints, the acute phase reactant, and general health (patient global assessment). Change from baseline in DAS28 is calculated as the Week 4, 8, 12, 16, 20, and 24 values minus the baseline value.

The DAS28 is a clinical index of rheumatoid arthritis disease activity (DA) that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of DA can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. APRs are a class of proteins that are useful markers for inflammation.

The DAS28 is a clinical index of RA disease activity that combines information from swollen joints, tender joints, the acute phase reactant, and general health (patient global assessment). Change from baseline in DAS28 is calculated as the Week 4, 8, 12, 16, 20, and 24 values minus the baseline value.

The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 <=3.2 to >5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=3.2 to <=5.1); non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1.

The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 <=3.2; moderate responders: change from baseline >1.2 with DAS28 <=3.2 to >5.1 or change from baseline >0.6 to <=1.2 with DAS28 <=3.2 to <=5.1); non-responders: change from baseline <=0.6 or change from baseline >0.6 and <=1.2 with DAS28 >5.1.

The HAQ-DI is a 20-question instrument used to assess the degree of difficulty a participant had in accomplishing tasks in 8 functional areas (FAs): dressing, arising, eating, walking, hygiene, reaching, gripping, and errands/chores. Responses for each FA were scored from 0 (no difficulty) to 3 (inability to perform a task). The total score (range of 0-3) was calculated by adding the 8 individual FA scores, then dividing this sum by the total number of components answered. Responders were defined as participants achieving an improvement from baseline in the HAQ-DI score at Week 24 of >=0.22.

Participants achieving clinical remission were defined as those with a low disease activity, i.e., DAS28 score (using CRP) <2.6 at Week 24.

Change from baseline in tender joint count was calculated as the Week 24 count minus the baseline count. A total of 68 joints were assessed. Joints were classified as either tender or not tender by an independent assessor, who had documented experience in performing joint assessments.

Change from baseline in swollen joint count was calculated as the Week 24 count minus the baseline count. A total of 66 joints were assessed. Joints were classified as either swollen or not swollen by an independent assessor, who had documented experience in performing joint assessments.

A horizontal VAS of 100 mm was used to report the participant's level of joint pain. The scale ranged from 0 (no pain) to 100 (unbearable pain). Participants were instructed to draw a vertical line through the horizontal line to indicate how much joint pain they had. The distance from the "no pain" end to the vertical line drawn by the participant was the joint pain score. Change from baseline was calculated as the Week 24 value minus the baseline value.

The participant used a horizontal VAS of 100 mm for overall assessment of disease. The scale ranged from 0 (very well) to 100 (very poor). Participants were instructed to draw a vertical line through the horizontal line to indicate the state of the arthritis. The distance from the "very well" end to the vertical line drawn by the participant was the global disease assessment score. Change from baseline in participant-assessed global disease was calculated as the Week 24 value minus the baseline value.

The physician used a horizontal VAS of 100 mm for overall assessment of disease. The scale ranged from 0 (very well) to 100 (very poor). Physicians were instructed to draw a vertical line through the horizontal line to indicate the state of the arthritis. The distance from the "very well" end to the vertical line drawn by the participant was the global disease assessment score. Change from baseline in the physician-assessed global disease was calculated as the Week 24 value minus the baseline value.

The self-assessed HAQ-DI is a 20-question instrument used to assess the degree of difficulty a participant had in accomplishing tasks in 8 functional areas (FAs): dressing, arising, eating, walking, hygiene, reaching, gripping, and errands/chores. Responses for each FA were scored from 0 (no difficulty) to 3 (inability to perform a task). The total score (range of 0-3) was calculated by adding the 8 individual FA scores, then dividing this sum by the total number of components answered. Change from baseline was calculated as the value at Week 24 minus the baseline value.

Blood samples for the determination of CRP were taken at pre-specified visits and were sent to the central laboratory for analysis. Change from Baseline in CRP was calculated as the Week 24 value minus the baseline value. CRP is an acute-phase protein whose plasma concentration increases in response to inflammation. CRP is a useful marker of inflammation.

ESR is measured by a blood test that shows the rate at which red blood cells sediment in a period of 1 hour. Blood samples for the determination of ESR were taken at pre-specified visits and were measured immediately at the trial site. Change from baseline in ESR was calculated as the Week 24 value minus the baseline value.

The SF-36v2 is a standardized questionnaire used to measure overall subjective health status by measuring 8 health-related parameters (each scored from 0 [poorer health] to 100 [better health]): body pain, general mental health (MH), perception of general health, physical functioning, role limitations (RL) caused by mental condition, RL caused by a physical condition, social functioning, and vitality. It yields an 8-scale profile of functional health and well-being scores, as well as psychometrically based physical and MH summary measures and a preference-based health utility index.

The SF-36v2 is a standardized questionnaire used to measure overall subjective health status by measuring 8 health-related parameters (each scored from 0 [poorer health] to 100 [better health]): body pain, general mental health (MH), perception of general health, physical functioning, role limitations (RL) caused by mental condition, RL caused by a physical condition, social functioning, and vitality. It yields an 8-scale profile of functional health and well-being scores, as well as psychometrically based physical and MH summary measures and a preference-based health utility index.

The FACIT-F score has a valid range of values from 0 to 52, with a higher score indicating a lower burden of fatigue. The subset determining fatigue contains 13 questions. Responses to each question were scored from 0, indicating "Not at all fatigued," to 4, indicating "Very much fatigued."

The following biomarkers were assessed: Anti-Cyclic Citrullinated Peptide 3 antibody (Anti-CCP), Rheumatoid factor IgA (RF-IgA), RF IgG (RF-IgG), and RF IgM (RF-IgM). Measurements of RF were used to characterize participants' disease activity and immune status. Anti-CCP was used to characterize the disease type and the immune status of the participants. Assessments for which results were below the lower limit of quantification (LLQ) were reported using a value of LLQ/2. Assessments for which results were above the upper limit of quantification (ULQ) were reported using a value of ULQ.

The following biomarkers were assessed: Interleukin 6 (IL-6) and Serum Amyloid A. These biomarkers were used to further characterize disease activity.

The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. The values summarized are the minimum DAS28 score (i.e. lowest level of disease activity) achieved by each participant within the first 24 weeks of each treatment course (TC), assessed using erythrocyte sedimentation rate (ESR; rate at which red blood cells sediment in 1 hour).

The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. The values summarized are the minimum DAS28 score (i.e. lowest level of disease activity) achieved by each participant within the first 24 weeks of each treatment course, assessed using C-reactive Protein (CRP: used to monitor acute inflammatory phases of rheumatoid arthritis).

The level of rheumatoid arthritis disease activity based on the DAS28 score is defined as low if DAS28 <=3.2, moderate if 3.2< DAS28 <=5.1, or high if DAS28 > 5.1. A DAS28 <2.6 corresponds to clinical remission. The values summarized are the minimum change from baseline DAS28 score (i.e. greatest change in disease activity during the treatment course) achieved by each participant within the first 24 weeks of each treatment course, assessed by using ESR. Baseline score was determined at the start of each treatment course. For change from baseline, participants had to have both a baseline DAS28 value for the treatment course (i.e., the latest value on or before the date of infusion A of the treatment course, providing it was done within a 14 day window prior to the date of infusion A) and a DAS28 value during the treatment course (i.e., during first 24 weeks of each treatment course). Change from baseline was calculated as the value during the treatment course minus the baseline value.

The level of rheumatoid arthritis disease activity based on the DAS28 score is defined as low if DAS28 <=3.2, moderate if 3.2< DAS28 <=5.1, or high if DAS28 > 5.1. A DAS28 <2.6 corresponds to clinical remission. The values summarized are the minimum change from baseline DAS28 score (i.e. greatest change in disease activity during the treatment course) achieved by each participant within the first 24 weeks of each treatment course, assessed by using CRP. Baseline score was determined at the start of each treatment course. For change from baseline, participants had to have both a baseline DAS28 value for the treatment course (i.e., the latest value on or before the date of infusion A of the treatment course, providing it was done within a 14 day window prior to the date of infusion A) and a DAS28 value during the treatment course (i.e., during first 24 weeks of each treatment course). Change from baseline was calculated as the value during the treatment course minus the baseline value.

The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. Remission is defined as a DAS28 score <2.6 at any time during the first 24 weeks of each treatment course. Low disease activity is defined as a DAS28 score >=2.6 and <3.2 at any time during the first 24 weeks of each treatment course.

The DAS28 is a clinical index of rheumatoid arthritis disease activity that combines information from swollen and tender joints (jts.), the APR, and general health (patient global assessment). The following jts. were assessed on both sides of the body: shoulder, elbow, wrist, metacarpophalangeal (5 per side), proximal interphalangeal (5 per side), and knee. The level of disease activity can be interpreted as low (DAS28<=3.2), moderate (3.2<DAS28<=5.1), or high (DAS28>5.1); total score, 0-9.4. A DAS28 <2.6 corresponds to remission. Remission is defined as a DAS28 score <2.6 at any time during the first 24 weeks of each treatment course. Low disease activity is defined as a DAS28 score >=2.6 and <3.2 at any time during the first 24 weeks of each treatment course.

Time to retreatment is defined as the time in days between infusion A of each treatment course and infusion A of the following treatment course. For participants randomized to ofatumumab in the Double-blind Period, Treatment Course 1 refers to the course of ofatumumab received in the Double-blind Period. The minimum period allowed per protocol before retreatment was 24 weeks (end of Double-blind Period). For participants randomized to placebo in the Double-blind Period, Treatment Course 1 refers to the first course of ofatumumab received in the Open-label Period. The minimum period allowed per protocol before retreatment during the Open-label Period was 16 weeks.

An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general AE/SAE module for a list of AEs (occurring at a frequency threshold >=2%) and SAEs.

The number of participants with a CD19+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

The number of participants with a CD3+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

The number of participants with a CD4+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

The number of participants with a CD8+ cell count greater than or equal to the lower limit of normal (LLN; reference range 0.11 to 0.66 giga [10^9] per liter) or the baseline value (whichever was lower) is presented. The baseline assessment is defined as the start of the Double-blind Period.

The baseline value for a treatment course is defined as the value before infusion A of each treatment course. The post-baseline visit is defined as any assessment during or after the start of infusion A during the specified treatment course. Pre-defined limits of potential clinical concern for vital signs (Low, High) are: Diastolic blood pressure (DBP) (millimeters of mercury [mmHg]): 40, 110; Systolic blood pressure (SBP) (mmHg): 90, 170; Heart rate (beats per minute): 35, 120. LLN=lower limit of normal; ULN=upper limit of normal.

The number of participants with normal, abnormal clinically significant (CS), and abnormal not clinically significant (NCS) ECG findings, as well as the number of participants with no results (NR), during the OL Period are presented. An overall interpretation of the ECG was made by the investigator, or the investigator could delegate this task to a cardiologist, if applicable.

Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Baseline (BL) value for a treatment course (TC) is defined as the latest value on or before the date of infusion A of the TC. The post-baseline (PBL) visit is defined as any visit after the date of infusion A during the specified TC. Pre-defined limits of potential CC (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) are: Albumin: 0.9, 1.5; Alanine amino transferase (ALT): NA, 2; Alkaline phosphatase (ALP): NA, 1.5; Aspartate amino transferase (AST): NA, 2; Bilirubin total (TBIL): NA, 1.5; Calcium: 0.85, 1.08; CO2 content/bicarbonate (BCO): 0.85/0.75, 1.2/1.3, ; Chloride: 0.9, 1.1; Creatine kinase (CK): NA, 2; Creatinine: NA, 1.2; Gamma glutamyl transferase (GGT): NA, 2; Lactate dehydrogenase (LDH): NA, 2; Potassium: 0.9, 1.1; Sodium: 0.93, 1.07; Total protein: 0.8, 1.15; Urea/blood urea nitrogen (BUN): NA, 1.5; Uric acid: NA, 1.5.

Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. The baseline (BL) value for a treatment course (TC) is defined as the latest value on or before the date of infusion A of the TC. The post-baseline (PBL) visit is defined as any visit after the date of infusion A during the specified TC. Pre-defined limits of potential clinical concern (CC Low [relative to lower limit of normal], CC High [relative to upper limit of normal]) are: Eosinophils: NA, 2; Hematocrit (HCT): 0.75, 1.2; Hemoglobin (Hb): 0.75, 1.2; Lymphocytes: 0.4, 2; Neutrophils total (TNUE): 0.8, 1.6; Platelet count (PC): 0.65, 1.5; Red blood cell count (RBC): 0.75, 2; White blood cell count (WBC): 0.7, 1.6.

Only those parameters for a particular flag (<LLN or >ULN) are summarized if at least one value was outside the specified reference range. The Baseline (BL) value for a TC was defined as the latest value on or before the date of infusion A of the TC. However to be evaluable as a baseline value, assessments must have been conducted within a 14 day window prior to the date of infusion A. The post-baseline (PBL) was any visit after the date of infusion A during the specified TC. The pre-defined LLN for biomarkers are: B-lymphocyte stimulator (B-ls):<486.5 nanograms per Liter (ng/L); Interleukin-6 (IL-6):<0.31ng/L and Serum amyloid A: <1951 ng/mL. LLN was not defined for Rheumatoid factor (RF)-IgA, RF-IgG, RF-IgM or anti- cyclic citrullinated peptide (CCP) antibody and RF. The pre- defined ULN range for biomarkers (RF)-IgA: >6 units; RF-IgG:>6 units; RF-IgM:>6 units; Anti-CCP:>19.9999 units; B-ls:>1343.3 ng/L; IL-6: >5 ng/L; RF:>11.9999 kilounits (KU)/L; Serum amyloid A:>82432 ng/mL.

A serious adverse event is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; or is a congenital anomaly/birth defect. Medical or scientific judgment should have been exercised in other situations. Refer to the general SAE module for a list of SAEs.

The reference ranges for immunoglobulins (LLN, ULN) are defined as: IgA (grams/Liter): 0.81, 4.63; IgG (grams/Liter): 6.94, 16.18; IgM (grams/Liter): 0.48, 2.71.

Time to first CD19+ B-cell repopulation (return to normal or baseline level) relative to the first dose was assessed only for those participants whose B-cells repopulated after receiving ofatumumab. Time to first CD19+ B-cell repopulation relative to the last dose of ofatumumab was assessed only for those participants whose B-cells repopulated during their last ofatumumab treatment course or follow-up.

Blood samples were collected for analysis of plasma/white blood cell JC Virus (JCV) using the polymerase chain reaction (PCR) assay. A positive JC Virus test result indicated the presence of JC Virus.

Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Pre-defined limits of potential clinical concern (CC Low [relative to the lower limit of normal], CC High [relative to the upper limit of normal]) are: ALT: NA, 2; ALP: NA, 1.5; Creatinine: N/A, 1.2; CO2/BCO: 0.85/0.75, 1.2/1.3; CK: NA, 2; GGT: NA, 2; Urea/BUN: NA, 1.5.

Only those parameters for which at least one value of clinical concern (CC) was reported are summarized. Pre-defined limits of potential clinical concern (CC Low [relative to lower limit of normal], CC High [relative to upper limit of normal]) are: Eosinophils: NA, 2; Total neutrophils: 0.8, 1.6; Platelet count: 0.65, 1.5.