Long-term Efficacy and Safety of Repeated Ofatumumab Treatment Courses in RA Patients Who Previously Received Ofatumumab or Placebo in Trial Hx-CD20-403

Study Overview
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Brief Summary
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A 3-year open-label trial for patients who previously participated in Trial Hx-CD20-403 and who fulfill the eligibility criteria for this trial (GEN413) . Th e primary purpose of the trial is to evaluate the long-term effectiveness of repeated courses ( a maximum of 9 treatment courses) of ofatumumab in RA patients who previously received ofatumumab or placebo in Trial Hx-CD20-403.

Detailed Description
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All patients who fulfill the eligibility criteria for this trial , will initiate at least one treatment course of ofatumumab, and depending of subsequent worsening in disease activity will be eligible to received further treatment through the 156 week treatment period: a maximum of a further 8 treatment courses will be given at individualized time intervals . The interval between each treatment course will be at least 16 weeks with the last treatment course given no later than week 130 after baseline (Visit 2A). After each treatment course the patients will attend their next trial visit 8 weeks after Infusion 1, followed by trial visits every 4 weeks up to Week 24, and subsequently every 8 weeks until the next treatment course. After completing the Treatment Period or after withdrawing from the Treatment Period prematurely patients will be followed every 12 weeks (Follow-up Period) until CD19+ cells &/or IgG levels have returned to baseline or normal levels.

Official Title
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An Open-label, International, Multi-center, Phase II, Extension Trial Investigating Long-term Efficacy and Safety of Repeated Treatment Courses of Ofatumumab, a Fully Human Monoclonal Anti-CD20 Antibody, in Adult Patients With Active Rheumatoid Arthritis Who Previously Received Ofatumumab or Placebo

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously received ofatumumab or placebo in Trial Hx-CD20-403. Patients on methotrexate therapy (7.5 - 25 mg/week, p.o., i.m., and/or s.c.). Oral corticosteroids therapy (≤ 10 mg/day prednisolone or equivalent). Active disease at the time of screening as defined by: 3 swollen joints (of 28 joints assessed) and ≥ 3 tender joints (of 28 joints assessed), DAS28≥3.2 (based on ESR) Exclusion Criteria: Use of DMARDs other than methotrexate or exposure to other cell depleting therapy, including investigational compounds < 6 months prior to Visit 2 A. Patients who have received treatment with any non-marketed drug substance within 4 weeks prior to Visit 1 (screening). Breast feeding women or women with a positive pregnancy test at Visit 1 (screening). Received anti-cancer therapy, corticosteroids (intra-articular, i.m., or i.v.), or live/attenuated vaccinations, or exposure to cyclophosphamide, nitrogen mustard, chlorambucil or other alkylating agents < 5 years prior to screening. Past or current malignancy, except for Cervical carcinoma Stage 1B or less, Non-invasive basal cell and squamous cell skin carcinoma, Malignant melanoma with a complete response of a duration of > 10 years, or other cancer diagnoses with a complete response of a duration of > 5 years. Chronic or ongoing active infectious disease requiring systemic treatment. Clinically significant cardiac disease, or history of significant cerebrovascular disease. Significant concurrent, uncontrolled medical conditions, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease Known or suspected HIV positive, positive serology for hepatitis B (HB), positive test for Hepatitis C, or positive plasma or white cell JC virus (JCV) PCR (either compartment). A circulating IgG level <lower limit of normal. Known hypersensitivity to components of the investigational medicinal product. Patients known or suspected of not being able to comply with a study protocol. Women of child bearing potential not will to use adequate contraception during study

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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ofatumumab<br>1000 mL dilution of 35mls ofatumumab in sterile, pyrogen free, 0.9% NaCl | Drug: ofatumumab<br>* 1000 mL dilution of 35mls ofatumumab in sterile, pyrogen free, 0.9% NaCl<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Withdrawal | Time to treatment withdrawal was defined as the time from the first infusion of ofatumumab until the date of treatment withdrawal. The sponsor discontinued the intravenous route of administration development program for rheumatoid arthritis (RA), and this study was terminated early; hence, this primary endpoint was not evaluated. | From Baseline up to 144 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Change From Baseline in Disease Activity Score Based on 28 Joints (DAS28) Over the Course of Weeks (Wk) 1 to 24 in Each Treatment Course (TC), Assessed by Erythrocyte Sedimentation Rate (ESR; Rate at Which Red Blood Cells Sediment in 1 Hour) | DAS28(ESR) is a numeric outcome that measures RA activity based on the ESR (a non-specific general indicator of inflammation), tender joint count (JC), swollen JC, and participant's global assessment of disease activity on a 100 millimeter Visual Analog Scale. DAS28 values range from 0 (no activity) and upwards; increasing values indicate increasing activity (there is no upper limit on the scale). Change from baseline (CFB) was calculated at all visits; however, minimum CFB was calculated as the minimum CFB obtained over the course of weeks 1-24 of each treatment cycle. | Baseline (last visit prior to dosing in each TC) and last visit of each TC (8 wk post infusion, then every 4 wk until Wk 24; up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Minimum Change From Baseline in DAS28 Over the Course of Weeks 1 to 24 in Each Treatment Course, Based on C-reactive Protein (CRP) | DAS28(CRP) is a numeric outcome that measures RA activity based on the CRP (used to monitor acute inflammatory phases of RA), tender JC, swollen JC, and participant's global assessment of disease activity on a 100 millimeter Visual Analog Scale. DAS28 values range from 0 (no activity) and upwards; increasing values indicate increasing activity (there is no upper limit on the scale). Change from baseline (CFB) was calculated at all visits; however, minimum CFB was calculated as the minimum CFB obtained over the course of weeks 1-24 of each treatment cycle. | Baseline (last visit prior to dosing in each TC) and last visit of each TC (8 wk post infusion, then every 4 wk until Wk 24; up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Time to Re-treatment in Each Treatment Course | Time to re-treatment in each treatment course (TC) is defined as the time from the first infusion of ofatumumab until the date of the first infusion of the first re-treatment course. The data presented reflect the time to re-treatment, which is defined as the time in days between the first infusion of each TC and the first infusion of the following TC. For TC 1, time to re-treatment is defined as the time between the first infusion in TC 1 and the first infusion in TC 2; similarly, for TC 2 it is the time between the first infusion of TC 2 and the first infusion of TC 3. The study was terminated by the sponsor after Treatment Course 7; therefore, there are no re-treatment data available for Treatment Course 7. | Week 16 to Week 104 of each treatment course (up to 125 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Ofatumumab Serum Concentration | Blood samples of participants were collected for the measurement of ofatumumab concentration in the blood. The blood samples were collected before infusion (BI) (baseline of that particular treatment course) and at the end of infusion (EI) of ofatumumab. | Before infusion and at the end of infusion for each Treatment Course (8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next TC; up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial vi | 
| Number of Participants Achieving American College of Rheumatology (ACR)20 | ACR20 is achieved if the participant has 20% improvement from Baseline in TJC and SJC and in 3 out of 5 of following assessments (A); participant pain A, participant global A, physician global A on a visual analog scale (VAS: a 10 cm scale ranging from no pain to severe pain; the distance marked by the participant from the no pain end is his joint pain score), participant self-assessed disability, and C-reactive protein. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants Achieving ACR50 | ACR50 is achieved if the participant has 50% improvement from Baseline in: TJC and SJC and in 3 out of 5 of following assessment (A) ; participant pain A , participant global A, physician global A on a visual analogue scale (VAS: a 10 cm scale ranges from 'no pain' to 'severe pain' and the distance marked by the participant from the no pain end is his joint pain score).and participant self-assessed disability and C-reactive protein. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TCand 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants Achieving ACR70 | ACR70 is achieved if the participant has 70% improvement from Baseline in: TJC and SJC and in 3 out of 5 of following assessment (A) ; participant pain A , participant global A, physician global A on a visual analogue scale (VAS: a 10 cm scale ranges from 'no pain' to 'severe pain' and the distance marked by the participant from the no pain end is his joint pain score).and participant self-assessed disability and C-reactive protein. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With the Indicated European League Against Rheumatism (EULAR) Response | EULAR response is based on the DAS score. EULAR response criterion classifies participants as good or moderate responders and non-responders. Good response: DAS28 score <=3.2 and >1.2 improvement from Baseline (IfB) in DAS28 score, Moderate response: DAS28 score <=3.2 and between >0.6 and <=1.2 IfB; DAS28 score between >3.2 and <=5.1 and >1.2 IfB; DAS28 score between >3.2 and <=5.1 and between >0.6 and <=1.2 IfB; DAS28 score >5.1 and >1.2 IfB. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants in the Indicated Categories of the Health Assessment Questionnaire (HAQ) | The HAQ, a 20-question instrument, assesses the degree of difficulty a person has in accomplishing tasks in eight functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores). Responses in each area are scored from 0 (no difficulty) to 3 (inability to perform a task in that area). The index is calculated by adding all scores, then dividing this score by the total number of components answered. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With the Indicated Global Disease Assessment Using the VAS | The participant and the physician independantly used the VAS for overall assessment of the disease. VAS is used to measure the physician's subjective assessment of the participant's RA disease process at the time of the visit. The scale ranged from 0 (extremely well) to 10 (extremely poor). The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With the Indicated Pain Score | The pain score was assessed using the VAS: a 10 cm scale ranging from no pain to severe pain; the distance marked by the participant from the no pain end is his joint pain score. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With HAHA Response | The host immune response was assessed based on Human Anti-Human Antibodies (HAHA). The serum samples of the participants were collected for the assessment of HAHA. The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Whole Blood Transcriptional Profiles | Blood samples were collected for transcriptomic analysis of messenger ribonucleic acid (mRNA). The sponsor discontinued the IV administration development program for RA, and this study was terminated early; hence, this endpoint was not evaluated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Percentage of Cluster of Differentiation (CD)19+, 4+, 3+, and 8+ B-cell Subsets in the Blood | Blood samples of participants were collected for the evaluation of CD19+, CD4+, CD3+, and CD8+ B-cell subsets. These biomarkers are associated with immune functions. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| CD19+, CD4+, CD3+, and CD8+ Cell Counts, Measured in mm^3 | Blood samples of participants were collected for the evaluation of CD19+, CD4+, CD3+, and CD8+ cell counts. These cells are present on white blood cells and are used as markers to associate cells with immune functions. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Ratio of CD 4+/CD8+ | Blood samples of participants were collected for the evaluation of CD4+ and CD8+ cell counts and the ratio was calculated. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With Rheumatoid Factor (RA Factor) >13 International Units Per Milliliter | Blood samples of participants were collected for the evaulation of RA factor. RA factor is an antibody found in the blood of participants with rheumatoid arthritis and is used for the diagnosis of rheumatoid arthritis. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With Anti-cyclic Citrullinated Peptide Antibody (CCP) >6.9 International Units Per Liter | Blood samples of participants were collected for the evaluation of Anti-CCP. Anti-CCP plays an important role in immune response and helps assess the disease condition. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With B-Lymphocyte Stimulator (BLyS) >2.49 Micrograms Per Liter | Blood samples of participants were collected for the evaluation of BLyS. BLyS is a potent co-stimulator of B lymphocytes, and elevated levels of BLyS are observed in automimmune diseases. It regulates the immunnoglobin (antibody produced by B cells that is used by the immune system to indentify bacteria and viruses in the body) secretion of normal B cells (type of cells in the blood). | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With Interleukin 6 (IL-6) >11.9 Picograms Per Milliliter | Blood samples of participants were collected for the evaluation of IL-6. IL-6 plays an important role in immune response and helps assess the disease condition. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Sodium, Potassium, Chloride, Bicarbonate, Calcium, and Uric Acid | Blood samples of participants were collected for the evaluation of uric acid and electrolytes (sodium, potassium, chloride, and calcium), as increased levels may reflect B-cell lysis due to treatment with ofatumumab. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Total Protein (TP) and Albumin | Blood samples of participants were collected to evaluate TP and albumin. TP can vary depending on auto-immune diseases, and TP and albumin can vary depending on debilitating diseases. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Total Bilirubin (TB) and Creatinine | Blood samples of participants were collected to evaluatate TB and creatinine levles. TB evlauation is performed to assess the condition of the liver, and possible hemolytic anemia, and the creatinine evaulation is performed to assess the renal condition (condition of the kidneys). | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Alanine Aminotranferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl-transferase (GGT) | Blood samples of participants were collected for the evaluation of ALT, AST, AP, and GGT. AST, ALT, AP, and GGT are evaluated to assess the condition of the liver. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Blood Urea Nitrogen (BUN) | The blood samples of participants were collected to assess the amount of nitrogen (in the form of urea) in the blood. BUN is evaluated to asssess the renal function of the participants. | Baseline of each TC and 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Assessment of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | The blood pressure (BP) of the participants was measured before infusion (infu) (BI) and post the first (A) and second (B) infusions (PI) during all 7 treatment courses.Timing for taking BP readings: SBP (BP when the heart is contracting): TC1, 2, 3 (infu A) more than 2 hours PI; TC1, 2 ,3 (infu B) 2 hours PI; TC4, 5, 6, 7 (infu A) 2 hours PI; TC4, 7 (infu B) 2 hours PI; TC5, 6 (infu B) 1 hour PI. For DBP (BP when the heart is resting between beats): TC1, 3 (infu A) more than 2 hours PI; TC2, 4, 5, 6, 7 (infu A) 2 hours PI; TC1, 2, 3, 4, 7 (infu A) 2 hours PI; TC5, 6 (infu B) 1 hour PI. | BI and PI A and B for all TCs (8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course [up to 156 weeks, follow-up phase]). TCs were individualized based on clinical status and may not correlate to trial visits/wk | 
| Assessment of Heart Rate (HR) | The HR of the participants was measured to assess the condition of the heart.HR was measured BI and post the first (A) and second (B) infusins during all 7 treatment courses.Timing for measuring HR: TC1, 3 (infu A) more than 2 hours PI; TC1, 2 ,3, 4, 7 (infu B) 2 hours PI; TC2, 4, 5, 6, 7 (infu A) 2 hours PI; TC5, 6 (infu B) 1 hour PI. | BI and PI A and B for all TCs (8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course [up to 156 weeks, follow-up phase]). TCs were individualized based on clinical status and may not correlate to trial visits/wk | 
| Assessment of Body Temperature (BT) | The BT of the participants was measured BI and post the first (A) and second (B) infusions (PI) of each cycle to assess the effect of ofatumumab on the BT.The BT of the participants was measured before BI and PI A and B during all 7 treatment courses.Timing for taking BT reading: TC1, 3 (infu A) more than 2 hours PI; TC1, 2 ,3, 4, 7 (infu B) 2 hours PI; TC2, 4, 5, 6, 7 (infu A) 2 hours PI; TC5, 6 (infu B) 1 hour PI. | BI and PI A and B for all TCs (8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course [up to 156 weeks, follow-up phase]). TCs were individualized based on clinical status and may not correlate to trial visits/wk | 
| Assessment of Lactic Dehydrogenase (LDH) and Creatine Phosphokinase (CPK) | Blood samples of participants were collected to assess LDH and CPK. Both tests are performed to evaluate the injury and damage to the body tissue, potentially from B-cell lysis. | 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. | 
| Number of Participants With Normal and Abnormal Electrocardiogram Readings | Electrocardiograms of the participants were taken. The abnormal clinically significant (CS) and not clinically significant (NCS) reading, as determined by the Investigator, were recorded. | 8 wk post infusion, then every 4 wk until Wk 24, then every 8 wk until next treatment course (up to 144 weeks). TCs were individualized based on clinical status and may not correlate to trial visits or study weeks. |