An Open-label Extension Study Evaluating the Safety and Efficacy of Upadacitinib (ABT-494) in Adults With Rheumatoid Arthritis (BALANCE-EXTEND)

• ClinicalTrials.gov Identifier: NCT02049138
• Recruitment Status: Completed
• First Posted: January 30, 2014
• Results First Posted: July 12, 2022
• Last Update Posted: July 12, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: January 28, 2014
• First Posted Date: January 30, 2014
• Results First Submitted Date: June 15, 2022
• Results First Posted Date: July 12, 2022
• Last Update Posted Date: July 12, 2022
• Actual Study Start Date: January 24, 2014
• Actual Primary Completion Date: July 29, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 15, 2022)

• Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria:

  1. ≥ 20% improvement in 68-tender joint count;
  2. ≥ 20% improvement in 66-swollen joint count; and
  3. ≥ 20% improvement in at least 3 of the 5 following parameters:
     • Physician global assessment of disease activity
     • Patient global assessment of disease activity
     • Patient assessment of pain
     • Health Assessment Questionnaire - Disability Index (HAQ-DI)
     • High-sensitivity C-reactive protein (hsCRP).
• Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria:

  1. ≥ 50% improvement in 68-tender joint count;
  2. ≥ 50% improvement in 66-swollen joint count; and
  3. ≥ 50% improvement in at least 3 of the 5 following parameters:
     • Physician global assessment of disease activity
     • Patient global assessment of disease activity
     • Patient assessment of pain
     • Health Assessment Questionnaire - Disability Index (HAQ-DI)
     • High-sensitivity C-reactive protein (hsCRP).
• Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria:

  1. ≥ 70% improvement in 68-tender joint count;
  2. ≥ 70% improvement in 66-swollen joint count; and
  3. ≥ 70% improvement in at least 3 of the 5 following parameters:
     • Physician global assessment of disease activity
     • Patient global assessment of disease activity
     • Patient assessment of pain
     • Health Assessment Questionnaire - Disability Index (HAQ-DI)
     • High-sensitivity C-reactive protein (hsCRP).
• Percentage of Participants With Satisfactory Humoral Response to PCV-13 Four Weeks After Vaccination [ Time Frame: Vaccination Baseline (defined as the last non-missing observation on or before the date of receiving PCV-13 vaccination) and 4 weeks after vaccination ]
  Satisfactory humoral response is defined as greater than or equal to 2-fold increase in antibody concentration from the vaccination Baseline in at least 6 out of the 12 pneumococcal antigens 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).

Original Primary Outcome Measures (submitted: January 28, 2014)

• American College Rheumatology (ACR) 20 Response Rate [ Time Frame: Up to Week 96 ]
  ACR criteria measures improvement in tender or swollen joint counts.
• ACR 50 Response Rate [ Time Frame: Up to Week 96 ]
  ACR criteria measures improvement in tender or swollen joint counts.
• ACR 70 Response Rate [ Time Frame: Up to Week 96 ]
  ACR criteria measures improvement in tender or swollen joint counts.
• Change in Tender Joint Count [ Time Frame: From Week 0 to Week 96 ]
  Tender Joint Count will be assessed by a qualified Independent Joint Assessor or Principal Investigator using the Joint Evaluation Worksheet.
• Change in Swollen Joint Count [ Time Frame: From Week 0 to Week 96 ]
  Swollen Joint Count will be assessed by a qualified Independent Joint Assessor or Principal Investigator using the Joint Evaluation Worksheet.
• Change in Patient's Assessment of Pain [ Time Frame: From Week 0 to Week 96 ]
  Determined by the Joint Evaluation, Visual Analog Scale (VAS), EuroQoL-5D (EQ-5D)
• Change in Patient's Global Assessment of Disease Activity [ Time Frame: From Week 0 to Week 96 ]
  Determined by VAS
• Change in High-Sensitivity C-Reactive Protein (hsCRP) [ Time Frame: From Week 0 to Week 96 ]
  Determined by hsCRP lab test
• Change in Health Assessment Questionnaire Disability Index [ Time Frame: From Week 0 to Week 96 ]
  Determined by the Health Assessment Questionnaire (HAQ-DI)
• Proportion of subjects achieving Low Disease Activity [ Time Frame: Up to Week 96 ]
  Determined by disease activity score using 28 joint counts (DAS28) [CRP] or clinical disease activity index (CDAI) criteria
• Proportion of subjects achieving Clinical Remission [ Time Frame: Up to Week 96 ]
  Determined by DAS28 [CRP] and CDAI criteria
• Change in DAS28 [CRP] [ Time Frame: From Week 0 to Week 96 ]
  DAS28 [CRP] calculation
• Change in CDAI [ Time Frame: From Week 0 to Week 96 ]
  The sum of tender and swollen joint counts [28 joints] and patient and physician global assessments
• Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scale [ Time Frame: From Week 0 to Week 96 ]
  Using the FACIT Fatigue Scale
• Change in Work Instability Scale - Rheumatoid Arthritis (RA-WIS) [ Time Frame: From Week 0 to Week 96 ]
  Using RA-WIS scale
• Change in EQ-5D [ Time Frame: From Week 0 to Week 96 ]
  Using the EuroQol-5D scale
• Incidence of Adverse Events [ Time Frame: Up to 30 day follow-up visit (30 days after last dose of study drug) ]
• Change in Vital Signs [ Time Frame: From Week 0 to 30 day follow-up visit (30 days after the last dose of study drug) ]
  Vital Signs include blood pressure, pulse rate, respiratory rate and body temperature
• Change in Physical Examination [ Time Frame: From Week 0 through 30 day follow-up visit (30 days after last dose of study drug) ]
  A symptom-directed physical exam will be performed when necessary, as per Investigator's judgment.
• Change in Clinical Laboratory Data [ Time Frame: From Week 0 through 30 day follow-up visit (30 days after last dose of study drug) ]
  Clinical Laboratory Data include hematology, clinical chemistry and urinalysis

Current Secondary Outcome Measures (submitted: June 15, 2022)

• Percentage of Participants Achieving Low Disease Activity (LDA) Based on Disease Activity Score-28 (DAS28[CRP]) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The DAS28(CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (measured on a VAS from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0 to approximately 10, where higher scores indicate more disease activity. LDA is defined as a DAS28(CRP) score ≤ 3.2.
• Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score-28 (DAS28[CRP]) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The DAS28 (CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (measured on a VAS from 0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 (CRP) range from 0 to approximately 10, where higher scores indicate more disease activity. Clinical remission is defined as a DAS28(CRP) score < 2.6.
• Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, and Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. LDA is defined as a CDAI score ≤ 10.
• Percentage of Participants Achieving Clinical Remission (CR) Based on Clinical Disease Activity Index (CDAI) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, and Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Clinical remission is defined as a CDAI score ≤ 2.8.
• Percentage of Participants Achieving Low Disease Activity (LDA) Based on Simplified Disease Activity Index (SDAI) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The simplified disease activity index (SDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm and hsCRP (mg/dL). The total SDAI score ranges from 0 to 86 with higher scores indicating higher disease activity. LDA is defined as a SDAI score ≤ 11.0.
• Percentage of Participants Achieving Clinical Remission (CR) Based on Simplified Disease Activity Index (SDAI) Over Time [ Time Frame: Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The simplified disease activity index (SDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm and hsCRP (mg/dL). The total SDAI score ranges from 0 to 86 with higher scores indicating higher disease activity. Clinical remission is defined as a SDAI score ≤ 3.3.
• Change From Baseline in Disease Activity Score Based on CRP (DAS28 [CRP]) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The disease activity score-28-CRP (DAS28 [CRP]) assesses RA disease activity based on a continuous scale of combined measures of 28 tender joint counts (TJC28), 28 swollen joint counts (SJC28), C-reactive protein (CRP), and the patient global assessment of disease activity (measured on a visual analog scale from 0 to 100 mm). DAS28(CRP) scores range from 0 to approximately 10 where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity.
• Change From Baseline in Clinical Disease Activity Index (CDAI) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, and Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity.
• Change From Baseline in SimplifiedDisease Activity Index (SDAI) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The simplified disease activity index (SDAI) is a composite index for assessing disease activity based on the summation of the counts of tender joint count (out of 28 evaluated joints) and swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm, Physician's Global Assessment of Disease Activity measured on a VAS from 0 to 10 cm and hsCRP (mg/dL). The total SDAI score ranges from 0 to 86 with higher scores indicating higher disease activity. A negative change from Baseline indicates improvement in disease activity.
• Change From Baseline in Tender Joint Count (TJC68) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Sixty-eight joints were assessed by an evaluator for tenderness or pain. The presence of tenderness was scored as a "1" and absence of tenderness as a "0". The total tender joint count is the sum of the scores, and ranges from 0 to 68 (worst).
• Change From Baseline in Swollen Joint Count (SJC66) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Sixty-six joints were assessed by an evaluator for swelling. The presence of swelling was scored as a "1" and absence of swelling as a "0". The total swollen joint count is the sum of the scores, and ranges from 0 to 66 (worst).
• Change From Baseline in Physician's Global Assessment of Disease Activity Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The physician rated the participant's current global RA disease activity (independently from the participant's assessment) on a visual analog scale (VAS) from 0 to 100 mm, where 0 mm indicates no disease activity and 100 mm indicates severe disease activity
• Change From Baseline in Patient's Global Assessment of Disease Activity Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The participant was asked to rate their current RA disease activity over the past 24 hours on a 100 mm VAS, where 0 mm indicates very low disease activity and 100 mm indicates very high disease activity.
• Change From Baseline in Patient's Assessment of Pain Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale from 0 to 100 mm. A score of 0 mm indicates "no pain" and a score of 100 mm indicates "worst possible pain."
• Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability.
• Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
• Change From Baseline in in Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The FACIT Fatigue scale is a 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better quality of life. A positive change from Baseline indicates improvement.
• Change From Baseline in Work Instability Scale for RA (RA-WIS) Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  RA-WIS is a tool to evaluate work instability (the consequence of a mismatch between an individual's functional ability and their work tasks). RA-WIS consists of 23 questions relating to the participant's functioning in their work environment, each answered as Yes or No. The total score is the number of questions answered Yes, and ranges from 0 to 23. A score < 10 means low risk, scores between 10 and 17 indicate medium risk, and scores > 17 indicate high risk of work instability. A negative change from Baseline indicates improvement in work instability.
• Change From Baseline in EuroQoL-5D (EQ-5D) Index Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The EQ-5D-5L is a generic measure of health status consisting of two parts. The first part (the descriptive system) assesses health in five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) each of which is rated on 5 levels of severity (1: no problem, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems). A health state index score was calculated from individual health profiles using a UK scoring algorithm. Health state index scores generally range from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher scores indicating higher health utility. The higher the score the better the health status. A positive change from baseline indicates improvement in health status.
• Change From Baseline in EuroQoL-5D VAS Score Over Time [ Time Frame: Baseline (of the preceding RCT study) and Weeks 6, 12, 24, 36, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, and 312 ]
  The EQ-5D-5L is a generic measure of health status consisting of two parts. The second part of the questionnaire consists of a visual analog scale (VAS) on which the participant rates his/her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health). A positive change from baseline indicates improvement.
• Percentage of Participants With Satisfactory Humoral Response to PCV-13 12 Weeks After Vaccination [ Time Frame: Vaccination Baseline and 12 weeks after vaccination ]
  Satisfactory humoral response is defined as greater than or equal to 2-fold increase in antibody concentration from the vaccination Baseline in at least 6 out of the 12 pneumococcal antigens 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F).
• Geometric Mean Fold Rise (GMFR) of Anti-pneumococcal Antibody Levels to Each of the 12 Pneumococcal Antigens 4 and 12 Weeks After Vaccination [ Time Frame: Vaccination Baseline and 4 and 12 weeks after vaccination ]

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: An Open-label Extension Study Evaluating the Safety and Efficacy of Upadacitinib (ABT-494) in Adults With Rheumatoid Arthritis
• Official Title: Phase 2 Study, Multicenter, Open-Label Extension (OLE) Study in Rheumatoid Arthritis Subjects Who Have Completed a Preceding Phase 2 Randomized Controlled Trial (RCT) With Upadacitinib (ABT-494)
• Brief Summary: The primary objective of the study is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib in adults with rheumatoid arthritis (RA) who have completed a preceding randomized controlled trial with upadacitinib.

Detailed Description

This is an open-label extension study to assess the long-term safety, tolerability, and efficacy of upadacitinib in adults with RA who have completed Study M13-550 (NCT01960855) or Study M13-537 (NCT02066389) Phase 2 randomized controlled trial (RCT) with upadacitinib.

All participants received treatment with 6 mg upadacitinib twice a day at the start of the study. Participants may have been up-titrated to 12 mg BID based on protocol-specified criteria. In Protocol Amendment 2 (January 2016) the study treatment was changed to a once daily (QD) formulation. Participants receiving 6 mg BID were transitioned to 15 mg QD and participants receiving 12 mg BID were transitioned to 30 mg QD dosing.

An optional 12-week vaccine sub-study was added in Protocol Amendment 3 (November 2017) to assess the impact of upadacitinib treatment (15 mg QD and 30 mg QD) with background methotrexate on immunological responses to pneumococcal 13-valent conjugate vaccine (PCV-13; Prevnar 13®) in RA patients. The vaccine substudy included 111 participants who were enrolled in the main study, the first participant was enrolled on 13 February 2018 and the the last participant completed the sub-study on 9 April 2020.

In Protocol Amendment 5 (December 2019), the protocol was revised to allow a decrease in upadacitinib dosing from 30 mg QD to 15 mg QD, as appropriate, based on investigator's medical decision or for safety/tolerability concerns.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Rheumatoid Arthritis

Intervention

• Drug: Upadacitinib
  Tablet taken orally
  Other Names:

  • ABT-494
  • RINVOQ®
• Biological: Pneumococcal 13-valent conjugate vaccine (PCV-13)
  Administered by intramuscular injection
  Other Name: Prevnar 13®

Study Arms

Experimental: Upadacitinib

Participants received treatment with upadacitinib for up to 312 weeks. The starting dose was 6 mg twice a day (BID). Participants who did not achieve a 20% improvement from RCT Baseline in both Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 6 or Week 12 were up-titrated to 12 mg BID. From January 2017 participants were transitioned to a once-daily (QD) regimen of upadacitinib, either 15 mg QD (participants who were taking 6 mg BID) or 30 mg QD (participants taking 12 mg BID). Starting with Protocol Amendment 5 participants receiving 30 mg QD upadacitinib had the option to decrease the dose to 15 mg QD at the investigator's discretion.

A subset of participants who opted-in to the vaccine substudy received a single-dose of 0.5 mL intramuscular injection of pneumococcal 13-valent conjugate vaccine (PCV-13).

Interventions:

• Drug: Upadacitinib
• Biological: Pneumococcal 13-valent conjugate vaccine (PCV-13)

• Publications *: Winthrop K, Vargas JI, Drescher E, Garcia C, Friedman A, Hendrickson B, Li Y, Klaff J, Kivitz A. Evaluation of response to 13-valent conjugated pneumococcal vaccination in patients with rheumatoid arthritis receiving upadacitinib: results from a phase 2 open-label extension study. RMD Open. 2022 Mar;8(1):e002110. doi: 10.1136/rmdopen-2021-002110.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 15, 2022): 493
• Original Estimated Enrollment (submitted: January 28, 2014): 470
• Actual Study Completion Date: July 29, 2021
• Actual Primary Completion Date: July 29, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subjects who have completed Study M13-550 (NCT01960855) or Study M13-537 (NCT02066389) with upadacitinib (ABT-494) and did not develop any discontinuation criteria.
2. If the subject has evidence of new latent tuberculosis (TB) infection, the subject must initiate and complete a minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis before continuing to receive study drug.
3. If female, subject must be postmenopausal, OR permanently surgically sterile, OR for women of childbearing potential practicing at least one protocol-specified method of birth control, that is effective from Study Day 1 through at least 30 days after the last dose of study drug.
4. Subjects must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.

Substudy:

1. Must currently be enrolled in the main study.
2. Must have been receiving a stable dose of upadacitinib (either 15 mg QD or 30 mg QD) for a minimum of 4 weeks prior to the Vaccination visit.
3. Must have been on a stable dose of background methotrexate (no change in dose or frequency) for a minimum of 4 weeks prior to the Vaccination visit.
4. If subject is on corticosteroids, must remain on a stable dose of ≤ 10 mg/day of prednisone or equivalent corticosteroid therapy for at least 4 weeks after the vaccination visit.
5. Must meet the prescribing specifications as per local label requirements to receive Prevnar 13® vaccine.
6. Willing to receive Prevnar13® vaccine.

Exclusion Criteria:

1. Pregnant or breastfeeding female.
2. Ongoing infections at Week 0 that have not been successfully treated. Subjects with ongoing infections undergoing treatment may be enrolled but not dosed until the infection has been successfully treated.
3. Anticipated requirement or receipt of any live vaccine during study participation including up to 30 days after the last dose of study drug.

4. Laboratory values from the visit immediately prior to Baseline Visit (local requirements may apply) meeting the following criteria:

   • Serum aspartate transaminase (AST) or alanine transaminase (ALT) > 3.0 × upper limit of normal (ULN)
   • Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m^2
   • Total white blood cell count (WBC) < 2,000/μL
   • Absolute neutrophil count (ANC) < 1,000/μL
   • Platelet count < 50,000/μL
   • Absolute lymphocytes count < 500/μL
   • Hemoglobin < 8 g/dL
5. Enrollment in another interventional clinical study while participating in this study.
6. Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive study drug.

Substudy:

1. Receiving any conventional synthetic disease modifying antirheumatic drugs (csDMARDs) other than methotrexate
2. Receiving > 10 mg/day of prednisone or equivalent corticosteroid therapy.
3. Receipt of any steroid injection within 4 weeks prior to Vaccination visit.
4. History of severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13®.
5. History of any documented pneumococcal infection within the last 6 months prior to the vaccination visit.
6. Receipt of any vaccine 4 weeks prior to the vaccination visit and/or anticipation of any vaccination for 4 weeks after the vaccination visit.
7. Receipt of any pneumococcal vaccine.
8. Subject is not suitable for the sub-study as per the Investigator's judgment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Bulgaria, Chile, Czechia, Hungary, Israel, Latvia, Mexico, New Zealand, Poland, Puerto Rico, Russian Federation, Slovakia, South Africa, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Australia, Czech Republic

Administrative Information

• NCT Number: NCT02049138
• Other Study ID Numbers: M13-538; 2013-003530-33 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: For details on when studies are available for sharing, please refer to the link below.
• Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Use Agreement (DUA). For more information on the process, or to submit a request, visit the following link.
• URL: https://vivli.org/ourmember/abbvie/

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: June 2022