Fleischmann R, Furst DE, Connolly-Strong E, Liu J, Zhu J, and Brasington R—Rheumatology and Therapy, 2020
Acthar Gel was assessed in a Phase 4, two-part, multicenter, randomized withdrawal study of 259 patients1*
Disclosure statement: Funding to support the preparation of this content was provided by Mallinckrodt Pharmaceuticals.
STUDY OBJECTIVE
To evaluate the efficacy, safety, and tolerability of Acthar Gel in patients with persistently active rheumatoid arthritis (RA) despite treatment with a glucocorticoid and 1 or 2 DMARD(s)
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 a stable low-dose glucocorticoid and required biologic/nonbiologic DMARD(s)
- Patients were on stable background medication throughout the study
- Patients received Acthar Gel 80 U SC twice a week for 12 weeks, a dosage that previous studies suggest is effective
- Patients who did not achieve low disease activity (LDA) defined as DAS28-ESR <3.2 at Week 12 were discontinued from the study
Part 2: 12-week, randomized, double-blind withdrawal period
- Patients who achieved LDA at Week 12 were entered into the second portion of the study
- Patients were randomly assigned to receive either Acthar Gel 80 U SC twice a week or placebo (1 mL) SC twice a week
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; DMARD=disease-modifying antirheumatic drug; SC=subcutaneous.
*In a randomized withdrawal study, patients who have an apparent response to treatment in an open-label period or in the treatment arm of a randomized trial are randomized to continued drug treatment or placebo.2
Study Design
Multicenter, two-part study
†The proportion of patients who achieved LDA (DAS28-ESR <3.2) at Week 12.
Study Assessments
- Primary endpoint: Proportion of patients who achieved LDA (DAS28-ESR <3.2) at Week 12
- Selected secondary and exploratory endpoints:
- Proportion of patients who maintained LDA (DAS28-ESR <3.2) from Weeks 12 to 24
- Proportion of patients who achieved remission (DAS28-ESR <2.6) at Weeks 12 and 24
- Time to disease activity flare from Weeks 12 to 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 with CDAI score ≤10 at Weeks 12 and 24
- Proportion of patients who met ACR20, ACR50, and ACR70 criteria at Weeks 12 and 24‡
- Changes in HAQ-DI, FACIT-F, and WPAI scores from baseline to Weeks 12 and 24
- Changes in key markers of bone turnover from baseline to Weeks 12 and 24
- Safety endpoints evaluated by study period and throughout study:
- AEs
- Vital signs
- Laboratory test results
ACR20=American College of Rheumatology, 20% improvement; ACR50=American College of Rheumatology, 50% improvement; ACR70=American College of Rheumatology, 70% improvement; AEs=adverse events; CDAI=Clinical Disease Activity Index; DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI=Health Assessment Questionnaire-Disability Index; LDA=low disease activity; WPAI=Work Productivity and Activity Impairment.
‡ACR50 and ACR70 responses at Week 24 were evaluated post hoc.
Study Limitations
- All patients were aware that they were being treated with Acthar Gel during the open-label period. This may have led to higher responses to treatment
- Sample bias may exist, limiting the extrapolation of the results to the general population:
- >80% of study participants were of Hispanic or Latino ethnicity
- Patients with other rheumatic autoimmune diseases, clinically significant infections, or malignancies were excluded from the study
- The results may not be solely attributed to Acthar Gel because patients were on different stable background medications at the start of the trial, and there were no washout periods. Acthar Gel has not been formally studied in combination with other treatments
Patient Overview1
| Key Inclusion Criteria |
| Men and nonpregnant, nonlactating women aged ≥18 years |
| Met the 2010 ACR/EULAR criteria for having RA that was active, defined as DAS28-ESR >3.2 |
| Use of a glucocorticoid 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 study):
|
| 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 |
| Use of intra-articular glucocorticoids in the 14 days before screening or use of B-cell-mediated therapies in the 24 weeks before screening |
| Known contraindications to Acthar Gel, 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, current type 1 or type 2 diabetes mellitus, a history of chronic active hepatitis or tuberculosis, a solid tumor or hematologic malignancy, drug/alcohol abuse, or a clinically significant infection |
| Key Inclusion Criteria |
| Men and nonpregnant, nonlactating women aged ≥18 years |
| Met the 2010 ACR/EULAR criteria for having RA that was active, defined as DAS28-ESR >3.2 |
| Use of a glucocorticoid 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 study):
|
| 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 |
| Use of intra-articular glucocorticoids in the 14 days before screening or use of B-cell-mediated therapies in the 24 weeks before screening |
| Known contraindications to Acthar Gel, 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, current type 1 or type 2 diabetes mellitus, a history of chronic active hepatitis or tuberculosis, a solid tumor or hematologic malignancy, drug/alcohol abuse, or a clinically significant infection |
ACR=American College of Rheumatology; DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; DMARD=disease-modifying antirheumatic drug; EULAR=European League Against Rheumatism.
DMARDs Permitted During the Study
| Nonbiologic DMARDs |
| Sulfasalazine |
| Hydroxychloroquine |
| Methotrexate |
| Leflunomide |
| Tofacitinib§ |
| Biologic DMARDs |
| Infliximab |
| Etanercept |
| Golimumab |
| Adalimumab |
| Certolizumab |
| Abatacept |
| Nonbiologic DMARDs | Biologic DMARDs | ||
| Sulfasalazine | Hydroxychloroquine | Infliximab | Etanercept |
| Methotrexate | Leflunomide | Golimumab | Adalimumab |
| Tofacitinib§ | __ | Certolizumab | Abatacept |
DMARD=disease-modifying antirheumatic drug.
Most common (≥3% of patients) DMARDs included:
- Biologic DMARDs: adalimumab,||¶ etanercept,||¶ abatacept,||¶ certolizumab pegol,||¶ tocilizumab,|| and infliximab||
- Nonbiologic DMARDs: hydroxychloroquine,||¶ sulfasalazine,||¶ leflunomide,||¶ chloroquine,||¶ and tofacitinib||
DMARD=disease-modifying antirheumatic drug.
§Targeted synthetic DMARD (tsDMARD).
||Prior DMARDs.
¶Concomitant DMARDs.
Patient Disposition
AE=adverse event; LDA=low disease activity.
#Patients met withdrawal criteria if they developed a condition that met any of the study exclusion criteria or failed to meet any inclusion criteria during the study that was not considered an AE, or if they were noncompliant.
Patient Demographics and Baseline Characteristics, Safety Population
| Characteristic | Open-label period |
| Acthar Gel (N=259) | |
| Age, y, mean (SD) | 51.0 (12.2) |
| Female, n (%) | 231 (89.2) |
| Weight, kg, mean (SD) | 72.9 (17.0) |
| Disease duration, y, mean (SD) | 10.3 (8.0) |
| Prednisone (or equivalent) dose, mg/day, mean (SD) | 6.3 (5.0) |
| DAS28-ESR, mean (SD) | 6.3 (1.0) |
| ESR, 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 (87.0) |
| Weight, kg, mean (SD) | 70.8 (15.7) |
| Disease duration, y, mean (SD) | 10.1 (6.8) |
| Prednisone (or equivalent) dose, mg/day, mean (SD) | 5.9 (1.7) |
| DAS28-ESR, mean (SD) | 6.2 (0.9) |
| ESR, 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=77) | |
| Age, y, mean (SD) | 50.9 (11.3) |
| Female, n (%) | 69 (89.6) |
| Weight, kg, mean (SD) | 72.4 (14.5) |
| Disease duration, y, mean (SD) | 9.4 (8.8) |
| Prednisone (or equivalent) dose, mg/day, mean (SD) | 6.9 (8.7) |
| DAS28-ESR, mean (SD) | 6.2 (1.0) |
| ESR, 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=77) | |
| Age, y, mean (SD) | 51.0 (12.2) | 50.1 (12.2) | 50.9 (11.3) |
| Female, n (%) | 231 (89.2) | 67 (87.0) | 69 (89.6) |
| Weight, kg, mean (SD) | 72.9 (17.0) | 70.8 (15.7) | 72.4 (14.5) |
| Disease duration, y, mean (SD) | 10.3 (8.0) | 10.1 (6.8) | 9.4 (8.8) |
| Prednisone (or equivalent) dose, mg/day, mean (SD) | 6.3 (5.0) | 5.9 (1.7) | 6.9 (8.7) |
| DAS28-ESR, mean (SD) | 6.3 (1.0) | 6.2 (0.9) | 6.2 (1.0) |
| ESR, 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) |
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; ESR=erythrocyte sedimentation rate; SD=standard deviation.
Primary Endpoint1
- Efficacy results are presented for the modified intent-to-treat (mITT) population, which includes all patients who received ≥1 dose of study drug and contributed any efficacy data to the study
Open-label treatment period (Part 1)
63% (n=163) of patients treated with Acthar Gel achieved LDA (DAS28-ESR <3.2) at Week 12 during the open-label period, mITT population**††
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; LDA=low disease activity.
**Percentages above bars are rounded to the nearest whole number.
††P values from 1-sample binomial test (open-label period). P values denote differences from baseline for the open-label period.
‡‡P<.0001.
- 19% (n=49) of patients treated with Acthar Gel achieved remission (DAS28-ESR <2.6) at Week 12
Key Secondary Endpoints1,3
Open-label treatment period (Part 1)
65% (n=169) of patients treated with Acthar Gel achieved LDA defined by CDAI scores ≤10 at Week 12 during the open-label period, mITT population**††
CDAI=Clinical Disease Activity Index; LDA=low disease activity; mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
††P values from 1-sample binomial test (open-label period). P values denote differences from baseline for the open-label period.
‡‡P<.0001.
Open-label treatment period (Part 1)
ACR20/50/70 response was achieved by 83% (n=215), 63% (n=162), and 30% (n=78) of patients, respectively, assessed at Week 12 during the open-label period, mITT population**††
ACR20=American College of Rheumatology, 20% improvement; ACR50=American College of Rheumatology, 50% improvement; ACR70=American College of Rheumatology, 70% improvement; mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
††P values from 1-sample binomial test (open-label period). P values denote differences from baseline for the open-label period.
‡‡P<.0001.
§§P≤.05.
Double-blind withdrawal period (Part 2)
61% (n=47) of patients treated with Acthar Gel sustained LDA (DAS28-ESR <3.2) at Week 24 during the double-blind withdrawal period, mITT population**||||
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; LDA=low disease activity; mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
||||P values from Pearson’s chi-square test (double-blind period). P values denote differences from placebo for the double-blind period.
§§P≤.05.
- 30% (n=23) of patients treated with Acthar Gel and 30% (n=23) of patients who received placebo achieved remission (DAS28-ESR <2.6) at Week 24¶¶
¶¶P=.828.
Double-blind withdrawal period (Part 2)
At Week 24, a significantly greater proportion of patients treated with Acthar Gel maintained LDA (CDAI score ≤10) compared with patients who received placebo during the double-blind withdrawal period, mITT population**||||
CDAI=Clinical Disease Activity Index; LDA=low disease activity; mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
||||P values from Pearson’s chi-square test (double-blind period). P values denote differences from placebo for the double-blind period.
##P≤.01.
Double-blind withdrawal period (Part 2)
At Week 24, the cumulative disease activity flare rate was significantly lower for patients treated with Acthar Gel (17%) than with placebo (30%; P=.049) during the double-blind withdrawal period, mITT population** ***
mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
***Cumulative disease activity flare rate data from Fleischmann R, Furst DE, Connolly-Strong E, Liu J, Zhu J, Brasington R. A multicenter study assessing the efficacy and safety of repository corticotropin injection in patients with persistently active rheumatoid arthritis. Poster presented at: European Congress of Rheumatology; June 12-15, 2019; Madrid, Spain.
Double-blind withdrawal period (Part 2)
More patients treated with Acthar Gel maintained ACR20/50/70 criteria at Week 24 than placebo during the double-blind withdrawal period, mITT population**||||‡
ACR20=American College of Rheumatology, 20% improvement; ACR50=American College of Rheumatology, 50% improvement; ACR70=American College of Rheumatology, 70% improvement; mITT=modified intent-to-treat.
**Percentages above bars are rounded to the nearest whole number.
||||P values from Pearson’s chi-square test (double-blind period). P values denote differences from placebo for the double-blind period.
‡ACR50 and ACR70 responses at Week 24 were evaluated post hoc.
§§P≤.05.
Key Exploratory 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 | Baseline, mean |
| DAS28-ESR | 6.3 |
| C-reactive protein (μg/mL) |
19.7 |
| Swollen joint count | 10.9 |
| Tender joint count | 14.7 |
| FACIT-F | 22.8 |
| HAQ-DI | 1.7 |
| Outcome | Change from baseline, mean |
| Week 4 | |
| DAS28-ESR | -1.4††† |
| C-reactive protein (μg/mL) |
— |
| Swollen joint count | -5.3‡‡‡ |
| Tender joint count | -7.0‡‡‡ |
| FACIT-F | -5.0‡‡‡ |
| HAQ-DI | -0.5‡‡‡ |
| Outcome | Change from baseline, mean |
| Week 8 | |
| DAS28-ESR | -2.0††† |
| C-reactive protein (μg/mL) |
— |
| Swollen joint count | -6.9‡‡‡ |
| Tender joint count | -8.9‡‡‡ |
| FACIT-F | -6.6‡‡‡ |
| HAQ-DI | -0.6‡‡‡ |
| Outcome | Change from baseline, mean |
| Week 12 | |
| DAS28-ESR | -2.8††† |
| C-reactive protein (μg/mL) |
-2.3 |
| Swollen joint count | -8.1‡‡‡ |
| Tender joint count | -10.7‡‡‡ |
| FACIT-F | -8.9‡‡‡ |
| HAQ-DI | -0.8‡‡‡ |
| Outcome | MID/MCID |
| DAS28-ESR | 1.24 |
| C-reactive protein (μg/mL) |
ND |
| Swollen joint count | ND |
| Tender joint count | ND |
| FACIT-F | 3–45 |
| HAQ-DI | 0.22–0.255 |
| Outcome | Baseline, mean | Change from baseline, mean | MID/MCID | ||
| Week 4 | Week 8 | Week 12 | |||
| DAS28-ESR | 6.3 | -1.4††† | -2.0††† | -2.8††† | 1.24 |
| C-reactive protein (μg/mL) |
19.7 | — | — | -2.3 | ND |
| Swollen joint count | 10.9 | -5.3‡‡‡ | -6.9‡‡‡ | -8.1‡‡‡ | ND |
| Tender joint count | 14.7 | -7.0‡‡‡ | -8.9‡‡‡ | -10.7‡‡‡ | ND |
| FACIT-F | 22.8 | -5.0‡‡‡ | -6.6‡‡‡ | -8.9‡‡‡ | 3–45 |
| HAQ-DI | 1.7 | -0.5‡‡‡ | -0.6‡‡‡ | -0.8‡‡‡ | 0.22–0.255 |
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI=Health Assessment Questionnaire-Disability Index; MCID=minimal clinically important difference; MID=minimal important difference; ND=not determined.
††P values from 1-sample binomial test (open-label period). P values denote differences from baseline for the open-label period.
†††P≤.001.
‡‡‡P<.001.
Open-label treatment period (Part 1)
Most bone turnover markers were stable during the open-label period, mITT population§§§||||||
| Time point | Marker, mean (SD) |
| CTX, µg/L | |
| Baseline | 4.79 (2.09) |
| Week 12 | 4.76 (1.93) |
| Time point | Marker, mean (SD) |
| CTX-I, µg/L | |
| Baseline | 0.39 (0.21) |
| Week 12 | 0.39 (0.21) |
| Time point | Marker, mean (SD) |
| CTX-II, µg/L | |
| Baseline | 3.46 (2.31) |
| Week 12 | 2.99¶¶¶ (2.17) |
| Time point | Marker, mean (SD) |
| CTX-II CRT, ng/mmol |
|
| Baseline | 452.4 (325.4) |
| Week 12 | 362.5‡‡‡ (273.1) |
| Time point | Marker, mean (SD) |
| OPG, pmol/L |
|
| Baseline | 4.71 (1.80) |
| Week 12 | 4.68 (1.98) |
| Time point | Marker, mean (SD) |
| PINP, µg/L | |
| Baseline | 52.23 (28.21) |
| Week 12 | 47.37¶¶¶ (26.21) |
| Time point | Marker, mean (SD) |
| sRANKL, pmol/L | |
| Baseline | 2057.70 (3592.90) |
| Week 12 | 2107.55 (3794.56) |
| Time point | Marker, mean (SD) | ||||||
| CTX, µg/L | CTX-I, µg/L | CTX-II, µg/L | CTX-II CRT, ng/mmol |
OPG, pmol/L | PINP, µg/L | sRANKL, pmol/L | |
| Baseline | 4.79 (2.09) | 0.39 (0.21) | 3.46 (2.31) | 452.4 (325.4) |
4.71 (1.80) | 52.23 (28.21) | 2057.70 (3592.90) |
| Week 12 | 4.76 (1.93) | 0.39 (0.21) | 2.99¶¶¶ (2.17) | 362.5‡‡‡ (273.1) |
4.68 (1.98) | 47.37¶¶¶ (26.21) |
2107.55 (3794.56) |
- During Week 12 of the open-label period, levels of cartilage degeneration markers, CTX-II and CTX-II CRT, and bone formation marker, PINP, significantly decreased
CTX=C-terminal crosslinking telopeptide; CTX-I=C-terminal crosslinking telopeptide of type I collagen; CTX-II=C-terminal crosslinking telopeptide of type II collagen; CTX-II CRT=creatinine-adjusted CTX-II; mITT=modified intent-to-treat; OPG=osteoprotegerin; PINP=N-terminal peptide of type I collagen; SD=standard deviation; sRANKL=soluble receptor activator of nuclear kappa B ligand.
§§§Data do not include bone density imaging and should not be used to conclude that Acthar Gel is safe for the bone in RA.
||||||P values from 1-sample t test for Week 12 versus baseline.
¶¶¶P<.01.
‡‡‡P<.001.
Double-blind withdrawal period (Part 2)
Acthar Gel therapy was associated with improvements in swollen and tender joint counts and measures of fatigue (FACIT-F) and physical function (HAQ-DI) during the double-blind withdrawal period, mITT population (Acthar Gel [n=77], placebo [n=76])||||
| Outcome | Baseline, mean | |
| Acthar Gel |
Placebo | |
| DAS28-ESR | 6.2 | 6.2 |
| C-reactive protein (μg/mL) | 12.1 | 21.8 |
| Swollen joint count | 9.7 | 10.1 |
| Tender joint count | 13.5 | 13.5 |
| FACIT-F | 22.7 | 22.6 |
| HAQ-DI | 1.7 | 1.7 |
| Outcome | Change from baseline, mean | |
| Week 12 | ||
| Acthar Gel |
Placebo | |
| DAS28-ESR | -3.5 | -3.5 |
| C-reactive protein (μg/mL) | 2.2 | -4.9 |
| Swollen joint count | -8.8 | -9.2 |
| Tender joint count | -12.0 | -12.1 |
| FACIT-F | -10.0 | -10.3 |
| HAQ-DI | -1.0 | -1.0 |
| Outcome | Change from baseline, mean | |
| Week 16 | ||
| Acthar Gel |
Placebo | |
| DAS28-ESR | -3.4 | -3.1 |
| C-reactive protein (μg/mL) | — | — |
| Swollen joint count | -8.6 | -8.3 |
| Tender joint count | -11.9 | -10.9 |
| FACIT-F | -8.7 | -8.7 |
| HAQ-DI | -0.9 | -0.9 |
| Outcome | Change from baseline, mean | |
| Week 20 | ||
| Acthar Gel |
Placebo | |
| DAS28-ESR | -3.4§§ | -3.1 |
| C-reactive protein (μg/mL) | — | — |
| Swollen joint count | -8.7 | -8.1 |
| Tender joint count | -12.0 | -10.8 |
| FACIT-F | -10.1 | -10.0 |
| HAQ-DI | -0.9 | -0.9 |
| Outcome | Change from baseline, mean | |
| Week 24 | ||
| Acthar Gel |
Placebo | |
| DAS28-ESR | -3.0 | -2.8 |
| C-reactive protein (μg/mL) | 4.3 | -1.8 |
| Swollen joint count | -8.1 | -7.8 |
| Tender joint count | -11.1 | -10.4 |
| FACIT-F | -9.2 | -10.2 |
| HAQ-DI | -0.8 | -0.9 |
| Outcome | MID/MCID | |
| DAS28-ESR | 1.24 | |
| C-reactive protein (μg/mL) | ND | |
| Swollen joint count | ND | |
| Tender joint count | ND | |
| FACIT-F | 3–45 | |
| HAQ-DI | 0.22–0.255 | |
| Outcome | Baseline, mean | Change from baseline, mean | MID/ MCID |
||||||||
| Week 12 | Week 16 | Week 20 | Week 24 | ||||||||
| Acthar Gel | Placebo | Acthar Gel | Placebo | Acthar Gel | Placebo | Acthar Gel | Placebo | Acthar Gel | Placebo | ||
| DAS28-ESR | 6.2 | 6.2 | -3.5 | -3.5 | -3.4 | -3.1 | -3.4§§ | -3.1 | -3.0 | -2.8 | 1.24 |
| C-reactive protein (μg/mL) |
12.1 | 21.8 | 2.2 | -4.9 | — | — | — | — | 4.3 | -1.8 | ND |
| Swollen joint count | 9.7 | 10.1 | -8.8 | -9.2 | -8.6 | -8.3 | -8.7 | -8.1 | -8.1 | -7.8 | ND |
| Tender joint count | 13.5 | 13.5 | -12.0 | -12.1 | -11.9 | -10.9 | -12.0 | -10.8 | -11.1 | -10.4 | ND |
| FACIT-F | 22.7 | 22.6 | -10.0 | -10.3 | -8.7 | -8.7 | -10.1 | -10.0 | -9.2 | -10.2 | 3–45 |
| HAQ-DI | 1.7 | 1.7 | -1.0 | -1.0 | -0.9 | -0.9 | -0.9 | -0.9 | -0.8 | -0.9 | 0.22–0.255 |
DAS28-ESR=Disease Activity Score with 28 joint count and erythrocyte sedimentation rate; FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; HAQ-DI=Health Assessment Questionnaire-Disability Index; MCID=minimal clinically important difference; MID=minimal important difference; mITT=modified intent-to-treat; ND=not determined.
||||P values from Pearson’s chi-square test (double-blind period). P values denote differences from placebo for the double-blind period.
§§P≤.05.
Double-blind withdrawal period (Part 2)
Most bone turnover markers were stable during the double-blind withdrawal period, mITT population§§§###
| Time point | Marker, mean (SD) | |
| CTX, µg/L | CTX-I, µg/L | |
| Baseline | ||
| Acthar Gel | 4.77 (1.89) | 0.44 (0.22) |
| Placebo | 4.58 (1.98) | 0.38 (0.18) |
| Week 12 | ||
| Acthar Gel | 4.58 (1.40) | 0.45 (0.23) |
| Placebo | 4.61 (1.63) | 0.40 (0.21) |
| Week 24 | ||
| Acthar Gel | 4.79 (2.76) | 0.44 (0.20) |
| Placebo | 4.47 (1.68) | 0.41 (0.20) |
| Time point | Marker, mean (SD) | |
| CTX-II, µg/L | CTX-II CRT, ng/mmol |
|
| Baseline | ||
| Acthar Gel | 3.69 (2.47) | 463.7 (316.9) |
| Placebo | 3.61 (2.42) | 460.5 (368.3) |
| Week 12 | ||
| Acthar Gel | 2.93 (2.19) | 368.0 (228.6) |
| Placebo | 3.21 (2.36) | 382.5 (257.5) |
| Week 24 | ||
| Acthar Gel | 3.13 (1.87) | 339.4 (189.7) |
| Placebo | 3.27 (2.05) | 391.6 (236.0) |
| Time point | Marker, mean (SD) | |
| OPG, pmol/L |
PINP, µg/L | |
| Baseline | ||
| Acthar Gel | 4.86 (1.83) | 54.76 (28.79) |
| Placebo | 4.65 (1.78) | 52.46 (26.38) |
| Week 12 | ||
| Acthar Gel | 4.79 (2.23) | 51.19 (29.06) |
| Placebo | 4.73 (1.89) | 48.69 (25.07) |
| Week 24 | ||
| Acthar Gel | 4.93 (2.04) | 54.34 (40.08) |
| Placebo | 5.12 (2.12) | 53.10 (26.16) |
| Time point | Marker, mean (SD) | |
| sRANKL, pmol/L |
||
| Baseline | ||
| Acthar Gel | 1519.42 (2378.26) | |
| Placebo | 2416.34 (3825.88) | |
| Week 12 | ||
| Acthar Gel | 2451.77**** (4417.55) | |
| Placebo | 2358.63 (4401.72) | |
| Week 24 | ||
| Acthar Gel | 2938.96¶¶¶ (5006.25) | |
| Placebo | 2105.64 (4116.93) | |
| Time point | Marker, mean (SD) | ||||||
| CTX, µg/L | CTX-I, µg/L | CTX-II, µg/L | CTX-II CRT, ng/mmol |
OPG, pmol/L |
PINP, µg/L | sRANKL, pmol/L |
|
| Baseline | |||||||
| Acthar Gel | 4.77 (1.89) | 0.44 (0.22) | 3.69 (2.47) | 463.7 (316.9) | 4.86 (1.83) | 54.76 (28.79) | 1519.42 (2378.26) |
| Placebo | 4.58 (1.98) | 0.38 (0.18) | 3.61 (2.42) | 460.5 (368.3) | 4.65 (1.78) | 52.46 (26.38) | 2416.34 (3825.88) |
| Week 12 | |||||||
| Acthar Gel | 4.58 (1.40) | 0.45 (0.23) | 2.93 (2.19) | 368.0 (228.6) | 4.79 (2.23) | 51.19 (29.06) | 2451.77**** (4417.55) |
| Placebo | 4.61 (1.63) | 0.40 (0.21) | 3.21 (2.36) | 382.5 (257.5) | 4.73 (1.89) | 48.69 (25.07) | 2358.63 (4401.72) |
| Week 24 | |||||||
| Acthar Gel | 4.79 (2.76) | 0.44 (0.20) | 3.13 (1.87) | 339.4 (189.7) | 4.93 (2.04) | 54.34 (40.08) | 2938.96¶¶¶ (5006.25) |
| Placebo | 4.47 (1.68) | 0.41 (0.20) | 3.27 (2.05) | 391.6 (236.0) | 5.12 (2.12) | 53.10 (26.16) | 2105.64 (4116.93) |
- During the double-blind period, levels of osteoclast differentiation marker, sRANKL, significantly increased from baseline to Weeks 12 and 24 in the Acthar Gel group, but not the placebo group
CTX=C-terminal crosslinking telopeptide; CTX-I=C-terminal crosslinking telopeptide of type I collagen; CTX-II=C-terminal crosslinking telopeptide of type II collagen; CTX-II CRT=creatinine-adjusted CTX-II; mITT=modified intent-to-treat; OPG=osteoprotegerin; PINP=N-terminal peptide of type I collagen; SD=standard deviation; sRANKL=soluble receptor activator of nuclear kappa B ligand.
§§§Data do not include bone density imaging and should not be used to conclude that Acthar Gel is safe for the bone in RA.
###P values from 2-sample t test for Acthar Gel time point versus baseline.
****P<.05.
¶¶¶P<.01.
Safety Endpoints1
Summary of AEs, safety population
| Part 1 (Open-label period) | |
| AE | Acthar Gel (N=259) |
| Any AE,†††† n (%) | 98 (37.8) |
| Anemia, n (%) | 5 (1.9) |
| Glycosylated hemoglobin increased, n (%) | 4 (1.5) |
| Headache, n (%) | 9 (3.5) |
| Hypertension, n (%) | 4 (1.5) |
| Nasopharyngitis, n (%) | 4 (1.5) |
| Nausea, n (%) | 5 (1.9) |
| Pharyngitis, n (%) | 7 (2.7) |
| Upper respiratory tract infection, n (%) | 4 (1.5) |
| Urinary tract infection, n (%) | 10 (3.9) |
| AE resulting in study drug withdrawal, n (%) | 3 (1.2) |
| Serious AE, n (%) | 3 (1.2) |
| Serious infectious event, n (%) | 1 (0.4) |
| Opportunistic infections, herpes zoster, n (%) | 1 (0.4) |
| Part 2 (Double-blind period) | |
| AE | Acthar Gel (n=77) |
| Any AE,†††† n (%) | 25 (32.5) |
| Anemia, n (%) | 2 (2.6) |
| Back pain, n (%) | 2 (2.6) |
| Diarrhea, n (%) | 1 (1.3) |
| Dizziness, n (%) | 1 (1.3) |
| Gastritis, n (%) | 1 (1.3) |
| Glycosylated hemoglobin increased,‡‡‡‡ n (%) |
1 (1.3) |
| Headache, n (%) | 5 (6.5) |
| Hyperglycemia, n (%) | 3 (3.9) |
| Hypertension, n (%) | 3 (3.9) |
| Influenza, n (%) | 1 (1.3) |
| Nasopharyngitis, n (%) | 2 (2.6) |
| Rhinitis, n (%) | 0 |
| Upper respiratory tract infection, n (%) | 0 |
| Urinary tract infection, n (%) | 2 (2.6) |
| AE resulting in study drug withdrawal, n (%) |
0 |
| Part 2 (Double-blind period) | |
| AE | Placebo (n=77) |
| Any AE,†††† n (%) | 31 (40.3) |
| Anemia, n (%) | 2 (2.6) |
| Back pain, n (%) | 0 |
| Diarrhea, n (%) | 3 (3.9) |
| Dizziness, n (%) | 1 (1.3) |
| Gastritis, n (%) | 2 (2.6) |
| Glycosylated hemoglobin increased,‡‡‡‡ n (%) |
2 (2.6) |
| Headache, n (%) | 5 (6.5) |
| Hyperglycemia, n (%) | 2 (2.6) |
| Hypertension, n (%) | 0 |
| Influenza, n (%) | 1 (1.3) |
| Nasopharyngitis, n (%) | 2 (2.6) |
| Rhinitis, n (%) | 2 (2.6) |
| Upper respiratory tract infection, n (%) | 3 (3.9) |
| Urinary tract infection, n (%) | 3 (3.9) |
| AE resulting in study drug withdrawal, n (%) |
1 (1.3) |
| Part 1 (Open-label period) | |
| AE | Acthar Gel (N=259) |
| Any AE,†††† n (%) | 98 (37.8) |
| Anemia, n (%) | 5 (1.9) |
| Glycosylated hemoglobin increased, n (%) | 4 (1.5) |
| Headache, n (%) | 9 (3.5) |
| Hypertension, n (%) | 4 (1.5) |
| Nasopharyngitis, n (%) | 4 (1.5) |
| Nausea, n (%) | 5 (1.9) |
| Pharyngitis, n (%) | 7 (2.7) |
| Upper respiratory tract infection, n (%) | 4 (1.5) |
| Urinary tract infection, n (%) | 10 (3.9) |
| AE resulting in study drug withdrawal, n (%) | 3 (1.2) |
| Serious AE, n (%) | 3 (1.2) |
| Serious infectious event, n (%) | 1 (0.4) |
| Opportunistic infections, herpes zoster, n (%) | 1 (0.4) |
| Part 2 (Double-blind period) | ||
| AE | Acthar Gel (n=77) | Placebo (n=77) |
| Any AE,†††† n (%) | 25 (32.5) | 31 (40.3) |
| Anemia, n (%) | 2 (2.6) | 2 (2.6) |
| Back pain, n (%) | 2 (2.6) | 0 |
| Diarrhea, n (%) | 1 (1.3) | 3 (3.9) |
| Dizziness, n (%) | 1 (1.3) | 1 (1.3) |
| Gastritis, n (%) | 1 (1.3) | 2 (2.6) |
| Glycosylated hemoglobin increased,‡‡‡‡ n (%) |
1 (1.3) | 2 (2.6) |
| Headache, n (%) | 5 (6.5) | 5 (6.5) |
| Hyperglycemia, n (%) | 3 (3.9) | 2 (2.6) |
| Hypertension, n (%) | 3 (3.9) | 0 |
| Influenza, n (%) | 1 (1.3) | 1 (1.3) |
| Nasopharyngitis, n (%) | 2 (2.6) | 2 (2.6) |
| Rhinitis, n (%) | 0 | 2 (2.6) |
| Upper respiratory tract infection, n (%) | 0 | 3 (3.9) |
| Urinary tract infection, n (%) | 2 (2.6) | 3 (3.9) |
| AE resulting in study drug withdrawal, n (%) |
0 | 1 (1.3) |
AE=adverse event.
††††AEs reported in ≥1.5% of patients in part 1 or in either group in part 2.
‡‡‡‡Refers to glycosylated hemoglobin values >6.5%.
- AEs that are typically associated with glucocorticoid use (eg, hypertension, hyperglycemia, weight gain, and edema) occurred at less than 5%
- A greater incidence of common AEs associated with glucocorticoid use may occur if Acthar Gel therapy is continued indefinitely. Further studies are needed to evaluate the safety of long-term Acthar Gel therapy
- Three patients reported serious AEs (chest pain, pneumonia, and craniocerebral injury) during the open-label period. No serious AEs were reported during the double-blind period
- No deaths were reported in the overall study
