Introduction
Clinical Value of Repository Corticotropin Injection
Citations | Objective, design, and endpoints | Key inclusion/exclusion criteria | Results |
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Clinical studies | |||
Infantile spasms | |||
Baram et al. [12] | Objective: To compare the efficacy of 2-week courses of high-dose ACTH vs. prednisone for IS treatment Study design: Randomized, single-blind trial Treatment groups: ACTH for 2 weeks (150 U/m2/day in 2 divided doses) or oral prednisone (2 mg/kg/day in 2 divided doses) Sample size: 29 Outcomes: Resolution of clinical signs and symptoms | Inclusion criteria: Infants with clinical IS Exclusion criteria: Previous steroid or ACTH treatment | Results favored ACTH; 86.6% of infants treated with ACTH and 28.6% of infants treated with prednisone had cessation of spasms and resolution of hypsarrhythmia (p = 0.002) |
Knupp et al. [13] | Objective: To evaluate early and sustained response to initial treatment of IS Study design: Prospective, observational, multisite study Treatment groups: ACTH, prednisolone, vigabatrin, and other (nonstandard) therapy (various dosing regimens) Sample size: 230 Outcomes: IS response rate; resolution of hypsarrhythmia on EEG at 2 weeks and 3 months | Inclusion criteria: Children with new onset IS between 2 months and 2 years of age Exclusion criteria: Early infantile epileptic encephalopathy; missing treatment, response, or follow-up data | At 2 weeks, 68% (66/97) of those who were receiving ACTH and 56% (30/54) of those who were receiving prednisolone had responded (p = 0.13); the ACTH response rate was significantly higher than in those receiving vigabatrin (49%, 23/47; p = 0.027) or nonstandard treatment (22%, 7/32; p < 0.001). At 3 months, 55% (53/97) of infants receiving ACTH had responded, compared with 39% (21/54) for prednisolone, 36% (17/47) for vigabatrin, and 9% (3/32) for other therapies (overall p < 0.001). The response rate in the ACTH group was significantly higher than in the vigabatrin group (p = 0.038) and marginally higher than in the prednisolone group (p = 0.06). Of children who received high-dose ACTH, 58% (46/80) responded, compared with 38% (6/16) of those who received low/intermediate-dose ACTH |
Multiple sclerosis relapse | |||
Rose et al. [20] | Objective: To investigate ACTH gel in the treatment of patients with acute MS relapses Study design: Randomized, double-blind, placebo-controlled, multisite trial Treatment groups: 40 U RCI or placebo gel IM twice daily for 7 days, 20 U twice daily for 4 days, and 20 U daily for 3 days Sample size: 197 patients Outcomes: Disability Status Scale administered weekly for 4 weeks | Inclusion criteria: Neurologic signs of disseminated CNS disease with clearly defined period of worsening (bout) within previous 8 weeks Exclusion criteria: Advanced CNS disease or complicating disease processes in their first bout, recent steroid or RCI therapy | Improvement in Disability Status Scale was seen in 65% of ACTH gel patients compared with 48% of patients in the placebo group (n = 94); between-group differences were significant at weeks 2 and 4. There was a 43% greater responder rate at week 1 with ACTH relative to placebo (70% vs. 49%; p < 0.01) and a 30% greater responder rate at week 3 (86% vs. 66%; p < 0.01). The average number of improved standard neurological examination items was greater for ACTH than placebo for each of the 4 weekly intervals (all p < 0.01) |
Proteinuria in nephrotic syndrome | |||
Bomback et al. [27] | Objective: To collect prospective study data on ACTH treatment in resistant glomerular disease Study design: Prospective, nonblinded, open-label trial Treatment: ACTH gel (40 U SC twice weekly for 2 weeks, then 80 U twice weekly SC for 22 weeks) Sample size: 15 (5 with resistant MN, 5 with MCD or FSGS, and 5 with resistant IgA nephropathy) Outcomes: Proteinuria full or partial remission | Inclusion criteria: MN or MCD/FSGS with at least 2 previous immunosuppressive therapies or IgA nephropathy and receiving maximally tolerated renin–angiotensin–aldosterone system blockage Exclusion criteria: Age 18 years or younger, estimated glomerular filtration rate <30 mL/min/1.73 m2, use of a monoclonal antibody within previous 6 months, or cyclophosphamide within previous 3 months, and others | Proteinuria was reduced in 8 of 15 patients. Two MN, 1 MCD, and 1 FSGS patient achieved partial remission. Two patients achieved complete remission |
Bomback et al. [28] | Objective: To evaluate the initial use of RCI in patients with refractory nephrotic syndrome Study design: Retrospective case series Treatment: RCI Sample size: 21 Outcomes: Complete remission, partial remission, limited response, or no response | Inclusion criteria: Diagnosis of idiopathic nondiabetic nephrotic syndrome treated with RCI; at least 6 months of full data available Exclusion criteria: N/A | Of 21 patients who completed RCI treatment, 7 achieved partial remission and 4 achieved complete remission. Of 11 patients with idiopathic MN, 3 achieved complete remission and 6 achieved partial remission despite having previously failed a mean of 2.4 therapies. Of 10 patients with nephrotic syndrome of other etiologies, 1 with IgA nephropathy achieved complete remission, 1 with FSGS achieved partial remission, and 1 with MPGN had a limited response to therapy |
Hogan et al. [29] | Objective: To assess the use of ACTH in patients with proteinuria due to FSGS previously treated with other therapies Study design: Nonrandomized, two-site trial Treatment groups: (1) 40 U SC weekly for 2 weeks, 80 U SC twice weekly for 2 weeks, then 80 U SC twice weekly for 10 weeks (n = 12) or (2) 40 U SC twice weekly for 2 weeks, then 80 U SC twice weekly for a target duration of 24 weeks (n = 7) or (3) heterogeneous treatment regimens (n = 5) Sample size: 24 Outcomes: Complete remission of proteinuria | Inclusion criteria: Proteinuria due to biopsy-proven FSGS and evidence of nephrotic syndrome Exclusion criteria: Being of childbearing age and not using birth control, recent active immune therapy, pregnancy, decreased renal function, known contraindications to RCI therapy | Seven patients achieved remission (2 complete and 5 partial responses). Five patients had a sustained remission and 2 experienced proteinuria relapse (median follow-up of 90 weeks) |
Hladunewich et al. [30] | Objective: To assess the safety and efficacy of RCI in adults with biopsy-proven idiopathic MN and proteinuria due to nephrotic syndrome Study design: Randomized, nonblinded, dose-finding phase 1b/2 pilot study Treatment groups: 40 U or 80 U RCI once or twice a week for 12 weeks (1 dose per week for 4 weeks, then 2 doses per week) Sample size: 20 Primary outcomes: Changes in measures of nephrotic syndrome (improvements in proteinuria, serum albumin, and cholesterol profile), documented side effects, and toxicity Secondary outcomes: Complete remission (proteinuria <0.3 g/day), partial remission (reduction in proteinuria by >50% with a final urine protein <3.5 and >0.3 g/day), and no response (reduction in proteinuria by <50% or worsening of proteinuria) | Inclusion criteria: Biopsy-proven idiopathic MN, age >18 years Exclusion criteria: Documented resistance to immunosuppressive routines used in idiopathic MN; recent use of glucocorticoids, calcineurin inhibitors, mycophenolic mofetil or alkylating agents; active infection; secondary cause of membranous nephropathy, diabetes mellitus; acute thrombosis requiring anticoagulation therapy; pregnant or nursing | A >50% decrease in proteinuria was noted in 50% of patients at completion of treatment and in 65% of patients at 12 months. Proteinuria decreased from a mean (± SD) of 9.1 ± 3.4 g/day at baseline to 6.2 ± 4.8 g/day at treatment completion and 3.9 ± 4.2 g/day at 12 months (p < 0.001), with significant improvements in serum albumin and total and LDL cholesterol (all p < 0.001). Of 4 patients receiving 40 U RCI, 1 (25%) achieved partial remission. Of 16 patients receiving 80 U RCI, 2 (12.5%) achieved partial remission and 9 (56.3%) achieved full remission |
Madan et al. [31] | Objective: To examine the efficacy and safety of RCI treatment in patients with nephrotic syndrome Study design: Retrospective multicenter case series Treatment: RCI Sample size: 44 Outcomes: Type of nephrotic syndrome, response to treatment | Inclusion criteria: Biopsy-confirmed nephrotic syndrome, 24-h proteinuria level or urine protein: creatinine ratio before and after ≥6 months of RCI treatment Exclusion criteria: N/A | Thirty-seven patients completed treatment. A proteinuria reduction ≥30% occurred in 81.1% (30/37) of patients. A proteinuria reduction ≥50% occurred in 62.2% (23/37). Mean reduction in proteinuria post-treatment was 3984.8 ± 4069.1 mg/day (p < 0.0001). Total cholesterol declined and serum albumin increased. Remission of proteinuria occurred in 56.8% (21/37) of patients, either partial (17/37, 45.9%) or complete (4/37, 10.8%) |
Rheumatoid arthritis | |||
Gaylis et al. [34] | Objective: To assess effects of RCI on clinical and structural endpoints in patients with early RA Study design: Prospective, observational, open-label trial Treatment: MTX 15 mg weekly plus RCI 80 U weekly or biweekly for 24 weeks Sample size: 10 Outcomes: Clinical response, remission | Inclusion criteria: At least 6 tender and swollen joints; a CDAI score >6.0; and osteitis, synovitis, or erosions on MRI Exclusion criteria: N/A | Eight of 10 patients showed a clinical response as measured by improvement in CDAI score. Two patients achieved clinical remission, 3 had low disease activity, 3 had moderate disease activity, 1 had high disease activity, and 1 patient terminated treatment early because of lack of efficacy. All 5 patients who received biweekly doses demonstrated a clinical response and showed a structural response of regression of synovitis and regression or nominal change in osteitis |
Gillis et al. [35] | Objective: To assess efficacy and safety of SC injections of RCI as adjunctive therapy in adults with active RA Study design: Prospective, nonrandomized, open-label, single-center trial Treatment: RCI 80 U SC every 72 h for 12 weeks Sample size: 6 Primary outcomes: Tender joint count, swollen joint count, change in 20-item Health Assessment Questionnaire Secondary outcomes: ESR level, CRP, and patient and physician global VAS, change in Disease Activity Score | Inclusion criteria: Active RA, not responding sufficiently to ≥2 biologic agents with different modes of action Exclusion criteria: N/A | At 12 weeks, all 6 patients had reduced tender and swollen joint counts. Three showed improvement in Health Assessment Questionnaire score and 6 showed improvement in Disease Activity Score. Improvements were seen in ESR (4/6), CRP level (4/6), and patient (5/6) and physician (6/6) global VAS. Improvements in all measures generally receded 4 weeks after treatment ended |
Dermatomyositis/polymyositis | |||
Levine [39] | Objective: To investigate efficacy and safety of ACTH in women with refractory DM or PM Study design: Retrospective observational case series Treatment: RCI 80 U SC once weekly or twice weekly for 12 weeks as short-term adjunctive treatment Sample size: 5 Outcomes: Muscle strength, pain, and function | Inclusion criteria: Female; refractory DM or PM; disease exacerbation; no response to or inability to tolerate side effects of corticosteroids, IV immunoglobulin, or steroid-sparing drugs for at least 60 days Exclusion criteria: N/A | Muscle strength, pain, and function improved in all 5 patients. Three patients with impaired ambulation before treatment returned to independent ambulation, and 1 was able to return to work |
Aggarwal et al. [40] | Objective: To evaluate the efficacy, safety, tolerability, and steroid-sparing effect of RCI in refractory adult DM/PM Study design: Prospective, uncontrolled, open-label trial Treatment: 80 U RCI twice weekly for 6 months Sample size: 12 Outcomes: Improvement in myositis as defined by the International Myositis Assessment and Clinical Studies Group (IMACS); safety; tolerability; steroid-sparing effect; myositis response criteria | Inclusion criteria: N/A Exclusion criteria: N/A | 10 of 11 patients (91%) completing the study experienced improvement in myositis at 2–3 months; sustained improvement occurred in 8 patients (73%). One patient stopped treatment because of heart block. Steroid dose decreased from a median (IQR) of 15 mg at baseline to 1.25 mg at last visit |
Systemic lupus erythematosus | |||
Fiechtner and Montroy [44] | Objective: To assess the efficacy and safety of RCI in reducing the intensity of flares in patients with SLE Study design: Prospective open-label trial Treatment groups: RCI (80 U/mL by SC injection for 10 days, with an optional 5 additional days) Sample size: 10 Primary outcomes: Reduction in flare intensity based on SLEDAI-2 K scores Secondary outcomes: Physician Global Assessment; Patient Global Assessment; Lupus Quality of Life scale; Functional Assessment of Chronic Illness Therapy-Fatigue scale; British Isles Lupus Assessment Group Index scores; and markers of inflammation, including ESR and CRP | Inclusion criteria: Diagnosis of SLE with chronic disease activity requiring ongoing treatment or observation for ≥8 weeks, moderately to severely active disease, meet ACR criteria for SLE flare, receipt of prednisone ≤20 mg/day or equivalent for ≥4 weeks or immunosuppressive or antimalarial treatment for SLE for ≥8 weeks Exclusion criteria: Any new prednisone therapy or change in current oral prednisone therapy, receipt of ≥1 prescribed NSAID, or surgery within past 4 weeks; history of allergy or reaction to any component of RCI or live or attenuated vaccine; and others | At day 28 there were statistically significant reductions in SLEDAI-2 K scores and improvements in Physician Global Assessment, Patient Global Assessment, Functional Assessment of Chronic Illness Therapy-Fatigue, and erythrocyte sedimentation rate (all p ≤ 0.5) |
Furie et al. [45] | Objective: To evaluate the efficacy of RCI added to standard of care in patients requiring moderate-dose corticosteroids for symptomatic SLE Study design: Prospective, randomized, double-blind, placebo-controlled, phase 4 pilot study Sample size: 38 Treatment: RCI 40 U daily or 80 U every other day or volume-matched placebo gel for 4 weeks, then RCI tapered to twice weekly for 4 weeks Outcomes: Change in composite measure of hybrid SLEDAI (hSLEDAI), BILAG, and CLASI scores, and tender and swollen joint count | Inclusion criteria: Persistently active SLE and/or cutaneous involvement (hSLEDAI score >2), moderate to severe rash with arthritis and/or skin involvement and BILAG score of A or B in mucocutaneous and/or musculoskeletal systems despite a stable dose of prednisone for ≥4 weeks Exclusion criteria: Initiation of corticosteroid treatment within previous 2 months; active nephritis or active CNS lupus requiring treatment within previous 3 months, and other criteria | At week 8, the proportion of responders was higher in RCI groups (RCI 40 U, 53.8%; RCI 80 U, 33.3%), but difference from placebo (27.3%) was not statistically significant. Statistically significant improvements were seen in the RCI groups for hSLEDAI, BILAG, and CLASI scores |
Symptomatic sarcoidosis | |||
Salomon et al. [51] | Objective: To record observations on effects of RCI and cortisone therapy in patients with systemic sarcoidosis of the lungs Study design: Case series Treatment: RCI 80 U IM each day, with a gradual taper, for a total dose of 1500–2000 U, or oral cortisone for 35–45 days (300 mg daily for 3 days, 200 mg daily for 5 days, and 100 mg daily for the remaining 34 days, for a total dose of 5300 mg) Sample size: 5 Outcomes: Lesions, lung volume, vital capacity, residual volume, ratio of residual volume to total lung capacity, dyspnea, cough, and general well-being | Inclusion criteria: Active confirmed systemic sarcoidosis of the lungs Exclusion criteria: N/A | RCI and cortisone markedly suppressed sarcoidosis lesions in all 5 patients. However, no patients experienced full remission |
Baughman et al. [52] | Objective: To present experience with RCI to treat sarcoidosis Study design: Retrospective observational study Treatment: RCI Sample size: 47 Outcomes: Response to treatment, based on the response of the target organ, as improved disease, stable disease, or no response to treatment | Inclusion criteria: All patients with sarcoidosis treated with RCI at two centers and with at least 6 months of follow-up data Exclusion criteria: N/A | All patients were initially treated with RCI 80 IU (IM or SC) twice a week. Of 47 cases reviewed, 18 discontinued drug use within 6 months because of cost, death, drug toxicity, or noncompliance. Of the remaining 29 patients, 11 (38%) had objective improvement in one or more organs after ≥3 months of RCI treatment. Of 21 patients treated for ≥6 months, 11 had improvements in ≥1 organ and 10 had stable disease; 2 had a relapse. Of 19 patients receiving prednisone at baseline, 17 were able to reduce prednisone reduce by >50% |
Healthcare resource utilization studies | |||
Infantile spasms | |||
Gold et al. [53] | Objective: To describe healthcare resource utilization and costs resulting from early (within 30 days of diagnosis) versus late (30 days after diagnosis) treatment with RCI to manage IS Study design: Retrospective observational study of healthcare claims data Treatment: RCI Sample size: 252 Outcomes: Adjusted 12-month mean number of outpatient and inpatient services, medications, and costs | Inclusion criteria: Age <2 years at time of IS diagnosis Exclusion criteria: Not continuously enrolled in health plan for ≥3 months before and ≥12 months after index date; subsequent diagnosis of tuberous sclerosis complex | Of 252 patients, 191 (76%) had early RCI treatment and 61 (24%) had late treatment. Early RCI treatment was associated with 3.8 fewer outpatient services (99% CI, −6.7 to −0.7) |
Multiple sclerosis relapse | |||
Gold et al. [54] | Objective: To describe healthcare resource utilization and costs in patients with MS relapse treated with RCI vs. PMP or IVIG Study design: Retrospective observational study of healthcare claims data Treatment: RCI vs. PMP or IVIG Sample size: 439 (12-month analysis); 228 (24-month analysis) Outcomes: 12-month and 24-month mean number and cost of hospitalizations, outpatient services, and prescription medications | Inclusion criteria: Diagnosis of MS; ≥2 relapses with first relapse treated with IVMP and second relapse treated with RCI, PMP, or IVIG within 30 days of exacerbation Exclusion criteria: Not continuously enrolled in health plan for ≥6 months before and ≥12 months (for 12-month analysis) or ≥24 months (for 24-month analysis) after index date | In the 12-month adjusted analysis, compared with the PMP/IVIG group (n = 226), the RCI group (n = 213) had fewer hospitalizations (0.2 vs. 0.4; p = 0.01) and outpatient services (29 vs. 43; p = 0.0001), more prescription medications (36 vs. 30; p = 0.0001), lower inpatient costs (US$15,000 lower; p = 0.001) and lower outpatient costs (US$54,000 lower; p = 0.0001), and similar total costs. Results were similar for the 24-month analysis |
Rheumatoid arthritis | |||
Wu et al. [55] | Objective: To describe healthcare resource utilization and costs for management of RA before and after treatment with RCI Study design: Retrospective observational study of healthcare claims data Treatment: RCI Sample size: 180 Outcomes: Healthcare utilization rates and costs for hospitalizations, ED visits, outpatient services, and drugs before and after initiation of treatment with RCI | Inclusion criteria: Age ≥18 years with RA Exclusion criteria: N/A | Healthcare utilization before vs. after treatment: Hospitalizations: All-cause, 42 vs. 25 per 1000 patient-years, p < 0.01; RA-related, 13 vs. 4 per 1000 patient-years, p < 0.01 ED visits: All-cause, 43 vs. 23 per 1000 patient-years, p = 0.04; RA-related, 8 vs. 1 per 1000 patient-years, p < 0.01 Outpatient services: All-cause, 56 vs. 47 per patient-year, p < 0.01; RA-related, 10 vs. 5 per patient-year, p < 0.01 Costs before vs. after treatment: Drugs: US$273 vs. US$4379 PPPM, p < 0.01 Medical: US$658 vs. US$93 PPPM, p < 0.01 |
Dermatomyositis/polymyositis | |||
Knight et al. [56] | Objective: To compare real-world healthcare resource utilization and costs in patients with DM/PM treated with RCI vs. IVIG and/or rituximab Study design: Retrospective observational study of commercial healthcare claims data; propensity score matching Treatment: RCI vs. IVIG and/or rituximab Sample size: 1134 Outcomes: Mean number and costs of hospitalizations and outpatient visits, mean hospital length of stay, mean medication costs, mean total nonmedical costs | Inclusion criteria: Diagnosis of DM/PM, treatment with RCI, IVIG and/or rituximab Exclusion criteria: N/A | Compared with IVIG, RCI had fewer hospitalizations (0.09 vs. 0.17 PPPM; p = 0.049), hospital outpatient department (HOPD) visits (0.60 vs. 1.39 PPPM; p < 0.001), and physician office visits (2.01 vs. 2.33 PPPM; p = 0.035) and shorter mean length of stay (3.24 days vs. 4.55 days; p = 0.004). Compared with rituximab, RCI had fewer HOPD visits (0.56 vs. 0.92; p < 0.001). Compared with IVIG + rituximab, RCI had shorter length of stay (2.18 days vs. 5.15; p < 0.001) and fewer HOPD visits (0.53 vs. 1.26; p < 0.001). Total mean nonmedication PPPM costs were lower for RCI compared with IVIG (US$2126 vs. US$3964; p < 0.001), rituximab (US$2008 vs. US$2607; P = 0.018), and IVIG + rituximab (US$1234 vs. US$4858; p < 0.001) |
Systemic lupus erythematosus | |||
Wu et al. [57] | Objective: To describe the profile of patients with SLE initiating RCI treatment Study design: Retrospective observational study of healthcare claims data Treatment: RCI Sample size: 29 Outcomes: Hospitalization and outpatient visit rates and costs before and after RCI treatment | Inclusion criteria: Age ≥18 years with ≥2 diagnoses of SLE and RCI treatment | Compared with the preindex period, the postindex period had fewer hospitalizations PPPM (0.075 vs. 0.061) and ED visits (0.081 vs. 0.046) visits postindex compared with preindex. Total medical costs were lower postindex (US$5869 vs. US$3724) as were inpatient costs (US$3192 vs. US$799) and ED costs (US$163 vs. US$84). Total postindex costs were higher (US$6774 vs. US$11,167 PPPM), largely driven by higher pharmacy costs (US$905 vs. US$7443) |
Multiple rheumatic conditions | |||
Myung et al. [58] | Objective: To describe the profile of patients with RA, DM/PM, or SLE initiating RCI treatment Study design: Retrospective observational study of healthcare claims data Treatment: RCI Sample size: 2749 Outcomes: Demographic characteristics, patterns of RCI, and concomitant medication use | Inclusion criteria: ≥1 claim with diagnosis code for RA, DM/PM, or SLE and any use of RCI Exclusion criteria: Claim for nonrheumatologic condition associated with RCI use (multiple sclerosis, proteinuria) | Most patients received 80 U of RCI twice weekly. The proportions of patients who used a corticosteroid were lower after RCI initiation than before (RA, 67% preindex and 54% postindex; SLE, 73% preindex and 58% postindex; DM/PM, 76% preindex and 58% postindex; all p < 0.05). In RA patients who had consistently taken corticosteroids for 24 weeks before RCI initiation, the postindex mean corticosteroid dose (11.47 ± 1.63 mg/day supply) was 28% lower than in the preindex period (15.86 ± 1.71 mg/day supply). The proportions of RA and SLE patients receiving biologics and of RA, SLE, and DM/PM patients receiving DMARDs were lower after RCI initiation (all p < 0.05) |