Rheumatoid Arthritis (RA)

Fleischmann R, Furst DE, Connolly-Strong E, Liu J, Zhu J, and Brasington R—Presented at EULAR, 2019

Acthar Gel was assessed in a Phase 4, two-part, multicenter randomized withdrawal study of 259 patients1

STUDY OBJECTIVE

To evaluate the efficacy and safety of Acthar Gel in patients with persistently active RA despite receiving 1 to 2 DMARDs and corticosteroids

 

Part 1: 12-week open-label treatment period

  • Patients were required to have persistently active RA defined as:
    • DAS28-ESR >3.2 despite treatment with required biologic/nonbiologic DMARD(s) and a corticosteroid
  • Patients were 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 period

  • Patients who achieved Low Disease Activity (LDA) defined as DAS28-ESR <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.

 

Study Design

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

Study Assessments1

  • Primary endpoint:
    • Proportion of patients who achieved LDA at Week 12 defined as DAS28-ESR ≤3.2
  • Secondary and exploratory endpoints:
    • Disease activity flare rate at Week 24, defined as fulfillment of any of the following criteria:
      • DAS28-ESR <3.2 and an increase of 1.2 from Week 12
      • DAS28-ESR ≥3.2 and an increase of >0.6 from Week 12, sustained for 2 consecutive study visits
      • DAS28-ESR ≥3.2 and an increase of >1 from Week 12 at a single visit
    • Proportion of patients who maintained LOA (defined by DAS28-ESR <3.2) from Weeks 12 to 24
    • Proportion of patients with CDAI score ≤10 at Week 12, and who maintained CDAI score ≤10 from Weeks 12 to 24
    • Proportion of patients who met ACR20, ACR50, and ACR70 criteria
  • Safety endpoints: Serious and nonserious AEs

Study Limitations

  • Data reported here are results from the open-label period and top-line results from the double-blind withdrawal period. Full results from double-blind period may vary from top-line analysis
  • Sample bias may exist in the open-label period, as patients were aware that they were receiving Acthar Gel
  • Examiner bias may also exist as the patient had to reach low disease activity in order to enter the second phase of the study
  • 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 treatments

Patient Overview

Key Inclusion Criteria
Age ≥18 years
Meet criteria for RA as defined by the 2010 ACR/EULAR classification at screening
Persistently active RA defined as a DAS28-ESR >3.2 despite prior biologic/nonbiologic DMARD(s) and a corticosteroid at screening and baseline
Use of a corticosteroid in 12 weeks prior to screening and on a stable dose of 5-10 mg of prednisone (or equivalent) for 4 weeks before screening

Use of 1 of the following for ≥12 weeks prior to screening (and must remain on same doses throughout the study):

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

Use of 1 of the following for ≥12 weeks prior to screening (and must remain on same doses throughout the study):

  • Methotrexate ≤20 mg per week and 1 biologic/nonbiologic DMARD
  • 1 allowed biologic DMARD
Used B-cell–mediated therapies (eg, rituximab) in the 24 weeks before screening
Known contraindications to Acthar Gel

DMARDs Permitted During the Study

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

Targeted synthetic DMARD (tsDMARD). 

Patient Disposition

Patient Demographics and Baseline Characteristics

Characteristic Open-Label Period
Acthar Gel (N=259)
Age, y, mean (SD) 51.0 (12.2)
Female, n (%)  
Weight, kg, mean (SD) 72.9 (17.0)
DAS28-ESR score at baseline, mean (SD) 6.3 (1.0)
ESR at baseline, mean (SD) 43.6 (24.8)
DAS28-ESR at Week 12, mean (SD) 3.6 (1.4)
ESR at Week 12, mean (SD) 24.0 (21.5)
Characteristic Double-Blind Withdrawal Period
Acthar Gel (N=77)
Age, y, mean (SD) 50.1 (12.2)
Female, n (%) 67 (87)
Weight, kg, mean (SD) 70.8 (15.7)
DAS28-ESR score at baseline, mean (SD) 6.2 (0.9)
ESR at baseline, mean (SD) 40.3 (21.5)
DAS28-ESR at Week 12, mean (SD) 2.8 (0.4)
ESR at Week 12, mean (SD) 15.8 (12.2)
Characteristic Double-Blind Withdrawal Period
Placebo (N=76)
Age, y, mean (SD) 50.9 (11.3)
Female, n (%) 69 (90)
Weight, kg, mean (SD) 72.4 (14.5)
DAS28-ESR score at baseline, mean (SD) 6.2 (1.0)
ESR at baseline, mean (SD) 42.0 (22.9)
DAS28-ESR at Week 12, mean (SD) 2.7 (0.5)
ESR at Week 12, mean (SD) 15.2 (12.6)
Characteristic Open-Label Period Double-Blind Withdrawal Period
Acthar Gel (N=259) Acthar Gel (n=77) Placebo (n=76)
Age, y, mean (SD) 51.0 (12.2) 50.1 (12.2) 50.9 (11.3)
Female, n (%) 231 (89) 67 (87) 69 (90)
Weight, kg, mean (SD) 72.9 (17.0) 70.8 (15.7) 72.4 (14.5)
DAS28-ESR score at baseline, mean (SD) 6.3 (1.0) 6.2 (0.9) 6.2 (1.0)
ESR at baseline, mean (SD) 43.6 (24.8) 40.3 (21.5) 42.0 (22.9)
DAS28-ESR at Week 12, mean (SD) 3.6 (1.4) 2.8 (0.4) 2.7 (0.5)
ESR at Week 12, mean (SD) 24.0 (21.5) 15.8 (12.2) 15.2 (12.6)

SD=standard deviation. 

Primary Endpoint

  • Efficacy results are presented for the modified intent-to-treat (mITT) population, which include all patients who received ≥1 dose of study drug and contributed any efficacy data to the study

Open-Label Treatment Period (Part 1)

63% of Patients Treated With Acthar Gel Achieved LDA (DAS28-ESR Score <3.2) at Week 12 During the Open-Label Period, mITT Population

Key Secondary Endpoints1

Open-Label Treatment Period (Part 1)

65% of Patients Treated With Acthar Gel Achieved LDA Defined by CDAI Scores ≤10 at Week 12 During the Open-Label Period, mITT Population

§P<.001 from 1-sample binomial test (open-label period) or Pearson’s chi-square test (double-blind withdrawal period).

P values denote differences from baseline for the open-label period and from placebo for the double-blind withdrawal period.

Key Secondary Endpoints1

Open-Label Treatment Period (Part 1)

ACR 20/50/70 Response Was Achieved by 83%, 63%, and 30% of Patients, Respectively, Assessed at Week 12 During the Open-Label Period, mITT Population

||P<.001 from 1-sample binomial test (open-label period) or Pearson’s chi-square test (double-blind withdrawal period).

P values denote differences from baseline for the open-label period and from placebo for the double-blind withdrawal period. 

Percentages above bars are rounded to the nearest whole number.

#P≤.05.

Key Secondary Endpoints1

Open-Label Treatment Period (Part 1)

Acthar Gel Therapy Was Associated With Significant Improvements in Swollen and Tender Joint Counts and Measures of Fatigue (FACIT-F) and Physical Function (HAQ-DI) During the Open-Label Period, mITT Population (N=259)

Outcome Change From Baseline, Mean (SD)
Week 4
DAS28-ESR -1.4 (1.1)**
Swollen joint count -5.3 (5.0)**
Tender joint count -7.0 (6.6)**
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) -5.0 (8.2)**
Health Assessment Questionnaire-Disability Index (HAQ-DI) -0.5 (0.5)**
Outcome Change From Baseline, Mean (SD)
Week 8
DAS28-ESR -2.0 (1.2)**
Swollen joint count -5.3 (5.0)**
Tender joint count -8.9 (7.0)**
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) -6.5 (8.4)**
Health Assessment Questionnaire-Disability Index (HAQ-DI) -0.6 (0.6)**
Outcome Change From Baseline, Mean (SD)
Week 12
DAS28-ESR -2.8 (1.4)**
Swollen joint count -8.1 (5.4)**
Tender joint count -10.7 (7.8)**
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) -8.7 (8.4)**
Health Assessment Questionnaire-Disability Index (HAQ-DI) -0.8 (0.6)**
Outcome MID/MCID
DAS28-ESR 1.23
Swollen joint count ND
Tender joint count ND
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 3-44
Health Assessment Questionnaire-Disability Index (HAQ-DI) 0.22-0.254
Outcome Change From Baseline, Mean (SD) MID/MCID
Week 4 Week 8 Week 12
DAS28-ESR -1.4 (1.1)**  -2.0 (1.2)**  -2.8 (1.4)** 1.23
Swollen joint count -5.3 (5.0)**  -6.9 (5.0)** -8.1 (5.4)** ND
Tender joint count -7.0 (6.6)** -8.9 (7.0)** -10.7 (7.8)** ND
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) -5.0 (8.2)** -6.5 (8.4)** -8.7 (8.4)** 3-44
Health Assessment Questionnaire-Disability Index (HAQ-DI) -0.5 (0.5)** -0.6 (0.6)** -0.8 (0.6)** 0.22-0.254

 MID=minimally important difference; MCID=minimally important clinical difference; ND=not determined.

**P<.001 from 1-sample t test.

Key Secondary Endpoints1

Double-Blind Withdrawal Period (Part 2)

62% of Patients Treated With Acthar Gel Sustained LDA (DAS28-ESR <3.2) at Week 24 During the Double-Blind Withdrawal Period, mITT Population

††P<.05 vs placebo from Pearson’s chi-square test.

Key Secondary Endpoints1

Double-Blind Withdrawal Period (Part 2)

At Week 24, a Significantly Greater Proportion of Patients Treated With Acthar Gel Achieved LDA (CDAI Score ≤10) Compared With Patients Who Received Placebo, mITT Population

‡‡P≤.05.

  • The cumulative disease activity flare rate was significantly lower for patients treated with Acthar Gel (17.05%) than with placebo (29.73%; P=.049) at Week 24

Key Secondary Endpoints1

Double-Blind Withdrawal Period (Part 2)

More Patients Treated With Acthar Gel Met ACR 20/50/70 Criteria at Week 24 Than Placebo During the Double-Blind Withdrawal Period, mITT Population

 

Flare Activity Through Week 24, mITT Population

Key Secondary Endpoints1

Double-Blind Withdrawal Period (Part 2)

At week 24, the cumulative disease activity flare rate was significantly lower for patients treated with Acthar Gel than with placebo (P=.049)

Disease activity flare rate at Week 24 was defined as any of the following criteria:

  • DAS28-ESR <3.2 and an increase of 1.2 from Week 12
  • DAS28-ESR ≥3.2 and an increase of >0.6 from Week 12, sustained for 2 consecutive study visits
  • DAS28-ESR ≥3.2 and an increase of >1 from Week 12 at a single visit

Safety Findings

AEs of interest

AE Open-Label Period
Acthar Gel (N=259)
Any AE (%) 98 (38)
Diabetes mellitus (%) 1 (0.4)
Glycosylated hemoglobin increased (%) 4 (2)
Liver function test increased (%) 1 (0.4)
Hyperglycemia (%) 3 (1)
Hypertension (%) 4 (2)
Weight increased (%) 0
AE Double-Blind Withdrawal Period
Acthar Gel (N=77)
Any AE (%) 25 (33)
Diabetes mellitus (%) 1 (1)
Glycosylated hemoglobin increased (%) 1 (1)
Liver function test increased (%) 0
Hyperglycemia (%) 3 (4)
Hypertension (%) 3 (4)
Weight increased (%) 0
AE Double-Blind Withdrawal Period
Placebo (N=77)
Any AE (%) 31 (40)
Diabetes mellitus (%) 0
Glycosylated hemoglobin increased (%) 2 (3)
Liver function test increased (%) 1 (1)
Hyperglycemia (%) 2 (3)
Hypertension (%) 0
Weight increased (%) 1 (1)
AE Open-Label Period Double-Blind Withdrawal Period
Acthar Gel (N=259) Acthar Gel (n=77) Placebo (n=77)
Any AE (%) 98 (38) 25 (33) 31 (40)
Diabetes mellitus (%) 1 (0.4) 1 (1) 0
Glycosylated hemoglobin increased (%) 4 (2) 1 (1) 2 (3)
Liver function test increased (%) 1 (0.4) 0 1 (1)
Hyperglycemia (%) 3 (1) 3 (4) 2 (3)
Hypertension (%) 4 (2) 3 (4) 0
Weight increased (%) 0 0 1 (1)
  • AEs observed were consistent with those of previous trials of Acthar Gel
  • Most common AEs observed were: urinary tract infection (n=10), headache (n=9), and pharyngitis (n=7)
  • Three patients reported serious AEs (chest pain, pneumonia, and craniocerebral injury)