Rheumatoid Arthritis (RA)

Fleischmann R, Furst DE, Brasington R, Connolly-Strong E, Liu J, and Barton ME —Presented at ACR, 2018

Acthar Gel was studied in patients who needed an alternative treatment to biologic/nonbiologic DMARDs and corticosteroids1

INTERIM RESULTS

An open-label phase of an ongoing, multicenter 2-part* study of 116 patients with persistently active RA despite receiving 1 to 2 DMARDs and corticosteroids1

 

Part 1: 12-week open-label treatment phase

  • Persistently active RA defined as:
    • DAS28-ESR Score >3.2 despite treatment with required biologic/nonbiologic DMARD(s) and a corticosteroid
  • Patients must be on stable background medication throughout the study
  • Patients received Acthar Gel 80 U subcutaneously twice a week for the entire 12-week period

Part 2: Double-blind randomized phase

  • Patients who achieved LDA as defined as DAS28-ESR Score ≤3.2 at Week 12 were entered into the second portion of the study
    • Patients received either Acthar Gel 80 U or placebo (1 mL) subcutaneously twice a week
  • Patients who did not achieve LDA at Week 12 or who experienced an RA flare were discontinued from the study
    • RA flare is defined as an increase of >0.6 DAS28-ESR from Week 0 sustained over 2 consecutive visits or an increase of >1 DAS28-ESR from Week 0 at a single visit

DAS28-ESR=Disease Activity Score with 28 joint count and Erythrocyte Sedimentation Rate; DMARD=disease-modifying antirheumatic drug; LDA=low disease activity.

*This interim report summarizes data collected through May 10, 2018.

Study Design

The proportion of patients who achieved LDA (DAS28-ESR ≤3.2) at Week 12.

Interim Study Assessments

Efficacy was evaluated at baseline and Weeks 4, 8, and 12

  • Primary endpoint:
    • Proportion of patients who achieved LDA at Week 12 defined as DAS28-ESR ≤3.2
  • Secondary endpoints:
    • DAS28-ESR scores, including:
      • Tender and swollen joint count
      • General Health Visual Analogue Scale (VAS)
      • Erythrocyte Sedimentation Rate (ESR)
  • ACR response criteria with improvements of 20%, 50%, or 70%
  • Clinical Disease Activity Index (CDAI) responders (defined as patients with remission [>2.8] and LDA [≤10])
  • Patient-Reported Outcomes (PROs)
    • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
    • Health Assessment Questionnaire-Disability Index (HAQ-DI)
    • Work Productivity and Activity Impairment (WPAI) questionnaire
    • Patient assessment of pain (ACR criteria)
    • Patient global assessment of disease activity (ACR criteria)
    • Adverse events were monitored and recorded throughout the study

Study Limitations

  • Data reported here are from a pre-planned 50% data review of the open-label phase of an ongoing study. This is an interim analysis of 116 patients in a larger 2-part study with no comparator arm in Part 1. The trial is now fully enrolled with 232 patients. Because this is an interim report, significance tests were not conducted, and therefore P values are not reported. Full results of this study may vary from the interim analysis1,2
  • Sample bias may exist since this was an open-label phase of an ongoing study, and patients were aware that they were receiving Acthar Gel1
  • Examiner bias may also exist as the patient had to reach low disease activity in order to enter the second phase of the study1
  • The results cannot be solely attributed to Acthar Gel since patients were on different medications at the start of the trial and no washout periods were undertaken. Acthar Gel has not been formally studied in combination with other treatments1

Patient Overview

Key Inclusion Criteria
Age ≥18 years
Meet the criteria for RA as defined by the 2010 ACR/EULAR classification
Have persistently active RA defined as a DAS28-ESR >3.2 despite treatment with required biologic/nonbiologic DMARD(s) and a corticosteroid
Currently taking a corticosteroid in the 12 weeks prior to the screening visit and on a stable dose of 5–10 mg of prednisone (or prednisone equivalent) for 4 weeks prior to the screening visit 

Have been on at least 1 of the following for at least 12 weeks prior to the screening visit and must remain on same doses throughout the study:

  • Methotrexate ≤20 mg per week and 1 additional allowed biologic or nonbiologic DMARD
  • One allowed biologic DMARD
Key Exclusion Criteria
Have taken any investigational treatment for RA or biologic investigational agent within 24 weeks or any nonbiologic investigational agent within 6 weeks prior to the first dose of study drug
History of use of Acthar Gel for treatment of RA or sensitivity to Acthar Gel
Currently has other rheumatic autoimmune or inflammatory joint disease
Used intra-articular corticosteroids within 14 days prior to screening visit
Used B-cell–mediated therapies (eg, rituximab) within 24 weeks prior to screening visit
Have known contraindications to Acthar Gel
Key Inclusion Criteria Key Exclusion Criteria
Age ≥18 years Have taken any investigational treatment for RA or biologic investigational agent within 24 weeks or any nonbiologic investigational agent within 6 weeks prior to the first dose of study drug
Meet the criteria for RA as defined by the 2010 ACR/EULAR classification
Have persistently active RA defined as a DAS28-ESR >3.2 despite treatment with required biologic/nonbiologic DMARD(s) and a corticosteroid History of use of Acthar Gel for treatment of RA or sensitivity to Acthar Gel
Currently taking a corticosteroid in the 12 weeks prior to the screening visit and on a stable dose of 5–10 mg of prednisone (or prednisone equivalent) for 4 weeks prior to the screening visit  Currently has other rheumatic autoimmune or inflammatory joint disease
Used intra-articular corticosteroids within 14 days prior to screening visit

Have been on at least 1 of the following for at least 12 weeks prior to the screening visit and must remain on same doses throughout the study:

  • Methotrexate ≤20 mg per week and 1 additional allowed biologic or nonbiologic DMARD
  • One allowed biologic DMARD
Used B-cell–mediated therapies (eg, rituximab) within 24 weeks prior to screening visit
Have known contraindications to Acthar Gel

DMARDs Permitted During the Study

Nonbiologic DMARDs Biologic DMARDs
Sulfasalazine
Leflunomide
Hydroxychloroquine
Methotrexate
Infliximab
Adalimumab
Etanercept
Certolizumab
Golimumab
Abatacept
Tofacitinib
Nonbiologic DMARDs Biologic DMARDs
Sulfasalazine
Leflunomide
Hydroxychloroquine
Methotrexate
Infliximab
Adalimumab
Etanercept
Certolizumab
Golimumab
Abatacept
Tofacitinib

Targeted synthetic DMARD (tsDMARD). 

Patient Demographics and Characteristics

  • As of May 10, 2018, 100 patients out of the 116 patients enrolled in the study had completed the 12-week open-label treatment phase (Part 1)
  • 14 patients had discontinued due to:
    • Withdrawal by the patient (n=9)
    • Met withdrawal criteria (n=1)
    • Other reasons (n=4)
  • 2 patients had not completed Part 1 of the study

Patients Who Completed the 12-week Open-label Treatment Phase (n=100)

Baseline Characteristics Patients
Age, y, mean (SD) 54.2 (11.53)
Female, n (%) 84 (84.0)
Weight, kg, mean (SD) 72.0 (14.51)
DAS28-ESR score, mean (SD) 6.3 (1.04)
Tender joint count, mean (SD) 14.8 (7.60)
Swollen joint count, mean (SD) 11.1 (5.31)
CDAI, mean (SD) 38.4 (12.93)

Baseline Characteristics Patients
Age, y, mean (SD) 54.2 (11.53)
Female, n (%) 84 (84.0)
Weight, kg, mean (SD) 72.0 (14.51)
DAS28-ESR score, mean (SD) 6.3 (1.04)
Tender joint count, mean (SD) 14.8 (7.60)
Swollen joint count, mean (SD) 11.1 (5.31)
CDAI, mean (SD) 38.4 (12.93)

SD=standard deviation. 

Interim Results of an Open-Label Phase of an Ongoing Study1

Primary Endpoint

61% (n=70) of patients treated with Acthar Gel achieved LDA (DAS28-ESR score <3.2) at Week 12

Key Secondary Endpoints

Mean DAS28-ESR scores of patients (N=116) treated with Acthar Gel decreased over time through Week 12

ACR 20/50/70 response was achieved by 85% (n=98), 66% (n=76), and 34% (n=39) of patients, respectively, assessed at Week 12

Mean PRO Scores Improved From Week 4 Through Week 12 During Treatment With Acthar Gel

PRO Assessment Baseline Week 4
Mean (SD)
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 22.6 (8.69) 17.2 (8.08)
Health Assessment Questionnaire-Disability Index (HAQ-DI) 1.6 (0.54) 1.1 (0.64)
Work Productivity and Activity Impairment (WPAI)
Percent work time missed due to RA 17.1 (22.77) 17.6 (25.55)
Percent impairment while working due to RA 46.2 (26.39) 30.7 (25.95)
Percent overall work impairment due to RA 52.8 (27.55) 39.4 (30.68)
Percent activity impairment due to RA 62.0 (22.96) 45.9 (26.75)
Patient assessment of pain 64.8 (19.55) 47.0 (22.94)
Patient global assessment of disease activity 60.8 (19.58) 45.9 (19.93)
PRO Assessment
Week 8 Week 12
Mean (SD)
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 16.1 (8.24) 13.8 (7.36)
Health Assessment Questionnaire-Disability Index (HAQ-DI) 0.9 (0.66) 0.7 (0.60)
Work Productivity and Activity Impairment (WPAI)
Percent work time missed due to RA 13.1 (16.88) 8.8 (13.76)
Percent impairment while working due to RA 25.6 (18.88) 20.4 (20.09)
Percent overall work impairment due to RA 34.6 (23.71) 26.6 (23.62)
Percent activity impairment due to RA 36.1 (22.69) 28.2 (23.88)
Patient assessment of pain 34.8 (21.00) 24.4 (21.55)
Patient global assessment of disease activity 35.3 (21.66) 24.4 (20.47)
PRO Assessment Minimum Clinically Important Difference (MCID)
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 3–43,‖
Health Assessment Questionnaire-Disability Index (HAQ-DI) 0.223
Work Productivity and Activity Impairment (WPAI)
Percent work time missed due to RA ND
Percent impairment while working due to RA ND
Percent overall work impairment due to RA ND
Percent activity impairment due to RA ND
Patient assessment of pain 114
Patient global assessment of disease activity 15% (absolute)/20% (relative improvement)5,¶
PRO Assessment Baseline Week 4 Week 8 Week 12 Minimum
Clinically Important
Difference (MCID)
Mean (SD)
Functional Assessment
of Chronic Illness
Therapy-Fatigue
(FACIT-F)
22.6 (8.69) 17.2 (8.08) 16.1 (8.24) 13.8 (7.36) 3–43,‖
Health Assessment
Questionnaire-Disability
Index (HAQ-DI)
1.6 (0.54) 1.1 (0.64) 0.9 (0.66) 0.7 (0.60) 0.223
Work Productivity and Activity Impairment (WPAI)
Percent work time
missed due to RA
17.1 (22.77) 17.6 (25.55) 13.1 (16.88) 8.8 (13.76) ND
Percent impairment
while working due to
RA
46.2 (26.39) 30.7 (25.95) 25.6 (18.88) 20.4 (20.09) ND
Percent overall work
impairment due to RA
52.8 (27.55) 39.4 (30.68) 34.6 (23.71) 26.6 (23.62) ND
Percent activity
impairment due to RA
62.0 (22.96) 45.9 (26.75) 36.1 (22.69) 28.2 (23.88) ND
Patient assessment of
pain
64.8 (19.55) 47.0 (22.94) 34.8 (21.00) 24.4 (21.55) 114
Patient global
assessment of disease
activity
60.8 (19.58) 45.9 (19.93) 35.3 (21.66) 24.4 (20.47) 15% (absolute)/
20% (relative
improvement)5,¶

Values represent the minimally important difference (MID) of 3–4 on a scale of 0–52.

Values represent the minimum clinically important improvement (MCII).

Safety Findings

Adverse events# and study withdraws
Event Patients (N=116) n (%)
Infections and infestations 17 (14.7)
  Urinary tract infection 4 (3.4)
  Pharyngitis 3 (2.6)
  Nasopharyngitis 2 (1.7)
  Otitis media acute 2 (1.7)
  Upper respiratory tract infection 2 (1.7)
General disorders and administration site conditions 10 (8.6)
  Pain 2 (1.7)
Nervous system disorders 10 (8.6)
  Headache 10 (8.6)
Injury, poisoning, and procedural complications 6 (5.2)
  Contusion 2 (1.7)
  Fall 2 (1.7)
  Joint dislocation 2 (1.7)
Musculoskeletal and connective tissue disorders 6 (5.2)
Skin and subcutaneous tissue disorders 5 (4.3)
Investigations (ie, blood glucose increased, blood pressure increased, systolic blood pressure increased, liver function test increased)   4 (3.4)
Metabolism and nutrition disorders 4 (3.4)
  Hyperglycemia  3 (2.6)
Gastrointestinal disorders 3 (2.6)
Psychiatric disorders 3 (2.6)
Cardiac disorders 2 (1.7)
Ear and labyrinth disorders 2 (1.7)
Renal and urinary disorders 2 (1.7)
Serious adverse events 2 (1.7)
  Chest pain  1 (0.9)
  Pneumonia  1 (0.9)
Study withdrawals 14 (12.1)
  Withdrawals by subject 9 (7.8)
  Adverse event 0 (0.0)
  Met withdrawal criteria 1 (0.9)
  Death 0 (0.0)
  Other 4 (3.4)
Event Patients (N=116)
n (%)
Infections and infestations 17 (14.7)
  Urinary tract infection 4 (3.4)
  Pharyngitis 3 (2.6)
  Nasopharyngitis 2 (1.7)
  Otitis media acute 2 (1.7)
  Upper respiratory tract infection 2 (1.7)
General disorders and administration site conditions 10 (8.6)
  Pain 2 (1.7)
Nervous system disorders 10 (8.6)
  Headache 10 (8.6)
Injury, poisoning, and procedural complications 6 (5.2)
  Contusion 2 (1.7)
  Fall 2 (1.7)
  Joint dislocation 2 (1.7)
Musculoskeletal and connective tissue disorders 6 (5.2)
Skin and subcutaneous tissue disorders 5 (4.3)
Investigations (ie, blood glucose increased, blood pressure increased, systolic blood pressure increased, liver function test increased)   4 (3.4)
Metabolism and nutrition disorders 4 (3.4)
  Hyperglycemia  3 (2.6)
Gastrointestinal disorders 3 (2.6)
Psychiatric disorders 3 (2.6)
Cardiac disorders 2 (1.7)
Ear and labyrinth disorders 2 (1.7)
Renal and urinary disorders 2 (1.7)
Serious adverse events 2 (1.7)
  Chest pain  1 (0.9)
  Pneumonia  1 (0.9)
Study withdrawals 14 (12.1)
  Withdrawals by subject 9 (7.8)
  Adverse event 0 (0.0)
  Met withdrawal criteria 1 (0.9)
  Death 0 (0.0)
  Other 4 (3.4)

#List of adverse events with ≥2 occurrences. Patients with multiple occurrences for an event are counted only once.