Medical Policy

Policy Num:      05.001.040
Policy Name:    Repository Corticotropin Injection   
Policy ID:          [5.001.040]  [Ac / B / M+ / P+]  [5.01.17]

Last Review:       November 22, 2024
Next Review:      November 20, 2025

Related Policies: None 

Repository Corticotropin Injection

summary

Description

Repository corticotropin injection is a preparation of the natural form of adrenocorticotropic hormone (ACTH). The injection is used to treat corticosteroid-responsive conditions and as a diagnostic tool to test adrenal function.

Summary of Evidence

For individuals who have infantile spasms who receive repository corticotropin injection, the evidence includes systematic reviews/meta-analyses and a prospective study. A 2013 systematic review judged the overall quality of all included studies involving various medication for infantile spasms to be poor, with fewer than half reporting method of randomization and most assessing relatively few patients. There was heterogeneity across studies and either vigabatrin or prednisolone was used as comparators; however, the authors concluded that limited evidence from randomized controlled trials (RCTs) suggested that ACTH and prednisolone resolved infantile spasms more rapidly than vigabatrin. More recent meta-analyses also concluded that ACTH treatment was non-inferior to corticosteroid treatment with a similar adverse event profile and may be considered a safe and effective alternative treatment. A 2021 systematic review including 6 trials indirectly compared natural ACTH with synthetic ACTH therapies. Based on the limited evidence included, investigators suggested that repository corticotropin injection may be a better treatment option over synthetic ACTH therapies for improving cessation of spasms and other relevant symptoms. Multivariate analysis of a prospective cohort study found that children with infantile spasms who were treated with ACTH were more likely to respond than other children. However, the analysis might have been subject to residual confounding on unmeasured characteristics; further, the study did not differentiate between synthetic and natural ACTH. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have corticosteroid-responsive conditions (eg, rheumatoid arthritis, dermatomyositis, sarcoidosis, nephrotic syndrome, multiple sclerosis, serum sickness, systemic lupus erythematosus [SLE]) who receive repository corticotropin injection, the evidence includes RCTs and case series. Relevant outcomes are symptoms and change in disease status. One placebo-controlled trial supports the efficacy of repository corticotropin injection in patients with rheumatoid arthritis and an inadequate response to corticosteroids and disease-modifying therapies. Overall, more recent studies evaluating multiple sclerosis have demonstrated that intravenous corticosteroids are at least as effective, or more effective, than repository corticotropin injection. A recent RCT in patients with SLE found no difference in SLE Responder Index-4 responders in the repository corticotropin group compared to placebo. Most studies assessing nephrotic syndrome have been small retrospective case studies and the 1 RCT identified stopped early due to lack of efficacy of ACTH. Ongoing studies are being conducted. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have conditions not generally known to be responsive to corticosteroids (non-corticosteroid-responsive) such as tobacco cessation, childhood epilepsy, and acute gout who receive repository corticotropin injection, the evidence includes 3 head-to-head trials identified for use in gout. Relevant outcomes are symptoms and change in disease status. The quality of these studies was deemed very low to moderate because there were no direct placebo-controlled trials and no clinically relevant differences were detected between drugs studied. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who need diagnostic testing of adrenal function who receive repository corticotropin injection, the evidence does not include studies that compare the diagnostic accuracy of repository corticotropin injection with ACTH. Relevant outcomes are test validity and other test performance measures. The lack of published evidence precludes conclusions on the validity of using repository corticotropin injection as a diagnostic test for adrenal function. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

In response to requests, input was received from 3 physician specialty societies and 1 academic medical center while this policy was under review in 2010. In addition, unsolicited input was received from 1 Foundation and 3 physicians. There was strong support for the use of repository corticotropin injection in the treatment of infantile spasms (West syndrome).

OBJECTIVE

The objective of this evidence review is to evaluate whether the use of repository corticotropin injection to treat infantile spasms, corticosteroid-responsive conditions, and non-corticosteroid-responsive conditions improves the net health outcome. In addition, this review evaluates whether the use of repository corticotropin injection as a diagnostic test of adrenocortical function is an alternative to synthetic adrenocorticotropic hormone and improves the net health outcome.

POLICY STATEMENT

Repository corticotropin injection may be considered medically necessary for the treatment of infantile spasms (West syndrome).

Use of repository corticotropin injection is considered investigational as a treatment of corticosteroid-responsive conditions (see Policy Guidelines section).

Except as noted above, use of repository corticotropin injection is considered investigational for conditions that are not responsive to corticosteroid therapy including, but not limited to, use in tobacco cessation, acute gout, and childhood epilepsy.

Repository corticotropin injection is considered investigational for use in diagnostic testing of adrenocortical function.

POLICY GUIDELINES

Some patients may have medical contraindications or intolerance to corticosteroids that are not expected to occur with use of repository corticotropin injection, and who therefore may benefit from repository corticotropin injections. This situation is not common.

Product information provides the following on dosage of H.P. Acthar® Gel for treatment of infantile spasms:

• In the treatment of infantile spasms, the recommended dose is 150 U/m² divided into twice daily intramuscular injections of 75 U/m². After 2 weeks of treatment, dosing should be gradually tapered and discontinued over a 2-week period.

• In the treatment of other disorders and diseases, dosing will need to be individualized, depending on the disease under treatment and the medical condition of the patient (it may be necessary to taper the dose).

H.P. Acthar Gel is used for intramuscular or subcutaneous injection and should never be used intravenously.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

According to the manufacturer’s website, beginning in 2007, H.P. Acthar Gel is only available through specialized pharmacy distribution (ie, it is no longer available from traditional pharmaceutical wholesalers or retail pharmacies).

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Repository Corticotropin Injection

Repository corticotropin injection (H.P. Acthar Gel) is a purified, sterile preparation of the natural form of adrenocorticotropic hormone (ACTH) in gelatin to provide a prolonged release after intramuscular or subcutaneous injection. ACTH is produced and secreted by the pituitary gland; H.P. Acthar Gel uses ACTH obtained from porcine pituitaries. ACTH works by stimulating the adrenal cortex to produce cortisol, corticosterone, and a number of other hormones.

Indications

H.P. Acthar Gel was approved by the FDA before the requirement that companies provide evidence of clinical efficacy. Table 1 summarizes the current prescribing indications and usage for Acthar Gel.^1, In 2006, a review of an efficacy supplement for the infantile spasms indication was initiated. The sponsor was requested to provide a dossier of safety and efficacy data from preexisting clinical trials and archival literature. In 2010, FDA finalized this review and determined there was sufficient scientific and clinical evidence to support its use for the infantile spasms indication.^2,

Table 1. Indications for Repository Corticotropin Injection

  a Controlled trials have shown H.P. Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease. b Keratitis; iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis; anterior segment inflammation. c Without uremia of the idiopathic type or due to lupus erythematosus.

Diagnostic testing of adrenocortical function, known as the ACTH test, is typically done with synthetic ACTH. Synthetic ACTH products have been approved by the FDA for this purpose.

Adverse Events

Contraindications for the use of this agent include scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, suspected congenital infection in infants, or sensitivity to proteins of porcine origin.

Repository corticotropin injection has potential adverse events similar to those that occur with other steroid medications such as elevated blood pressure, a decrease in bone density, new infections (or activation of previous infection), and overproduction of cortisol, which can cause symptoms of Cushing syndrome.

Regulatory Status

In 1952, H.P. Acthar Gel (Questcor Pharmaceuticals/Mallinckrodt Pharmaceuticals) was approved by the U.S. Food and Drug Administration (FDA). The original product label included at least 19 separate conditions, including infantile spasms. A 1979 efficacy supplement added the treatment of acute exacerbation of multiple sclerosis. At one time, this product was indicated as an injection for diagnostic testing of adrenocortical function. In 2010, this indication was removed with an update to the product label.

RATIONALE

This evidence review was created in February 2008 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 15, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Infantile Spasms

Clinical Context and Therapy Purpose

The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with infantile spasms.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with infantile spasms. This is a rare epileptic disorder of infancy (90% of cases are diagnosed in the first year of life). When infantile spasms are accompanied by neurodevelopmental regression and electroencephalogram findings of hypsarrhythmia, the condition is known as West syndrome.

Interventions

The therapy being considered is repository corticotropin injection. The product, marketed as Acthar Gel, is approved by the U.S. Food and Drug Administration (FDA) as monotherapy for infantile spasms in infants and children less than 2 years of age.

Comparators

The following therapies are currently being used to treat infantile spasms: prednisolone and vigabatrin oral solution. Treatment may also include anticonvulsant drugs.

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in disease status. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Duchowny et al (2021) indirectly compared the efficacy of repository corticotropin injection versus synthetic adrenocorticotropic hormone (ACTH) therapies (tetracosactide or corticotropin carboxymethyl-cellulose) in infantile spasms.^3, Reviewers identified 6 clinical trials to include in the meta-analysis. All included trials were found to be of moderate quality and had a low-to-moderate risk of bias. Two studies compared treatment with natural ACTH to oral corticosteroids. The remaining 4 trials compared synthetic ACTH to oral corticosteroids; 2 studies evaluating tetracosactide and 2 evaluating corticotropin carboxymethyl-cellulose. Based on the meta-analysis and indirect treatment comparison, repository corticotropin injection significantly improved cessation of spasms (odds ratio [OR], 8.39; 95% credible interval [CrI], 1.54 to 29.33) and resolution of hypsarrhythmia (OR, 5.42; 95% CrI, 1.08 to 17.72) compared to tetracosactide, reducing the risk of spasms and/or hypsarrhythmia by 10.2% to 13.7% (adjusted number needed to treat [NNT] for cessation of spasms, 4 patients; adjusted NNT for resolution of hypsarrhythmia, 5 patients). Repository corticotropin injection had 16.9 times higher odds of achieving the cessation of spasms compared to corticotropin carboxymethyl-cellulose and 14.5 times higher odds of resolution of hypsarrhythmia, reducing the risk of spasms and/or hypsarrhythmia by 39.9% to 50.2%, comparatively (adjusted NNT for cessation of symptoms/resolution of hypsarrhythmia, 2 patients). Based on the limited and indirect evidence included in the review, findings from the review suggest that repository corticotropin injection may be a better treatment option for improving cessation of spasms and other relevant symptoms compared to synthetic ACTH therapies. An analysis by Chang et al (2019) that included 5 RCTs (N=239), all of which were included in Duchowny et al (2021) review, compared effectiveness of oral corticosteroids to ACTH products, without differentiation of synthetic versus natural products.^4, Investigators found no difference in resolution of spasms at 13 or 14 days between ACTH products and corticosteroids, including high-dose corticosteroids.

Li et al (2020) completed a meta-analysis of 6 RCTs that found no difference between ACTH and prednisone/prednisolone in resolution of spasms at 14 and 42 days.^5, Adverse events were similar between treatments. The ACTH products in this meta-analysis did not differentiate between the naturally derived ACTH product which was used in 2 of the 6 studies and a synthetic product (tetracosactide) used in the remainder. There is significant overlap between the studies included in the analyses by Duchowny et al and Li et al ; however, the outcomes measured in each analysis differed.

A Cochrane review by Hancock et al (2013) assessed medication treatment of infantile spasms, including ACTH.^6, Reviewers identified 18 RCTs investigating 12 different medications. The included studies were deemed to be of poor quality, with more than half of them failing to report the method of randomization and nearly all of them consisting of fewer than 100 participants. Five studies compared treatment using ACTH with another medication. Three trials assessed natural ACTH and the others evaluated synthetic ACTH. Reviewers conducted several quantitative meta-analyses that did not differentiate between natural and synthetic ACTH. A pooled analysis of 3 studies found that symptom resolution occurred in 30 (67%) of 45 patients responding to vigabatrin and 40 (82%) of 49 patients responding to ACTH. The difference between groups was statistically significant (OR, 0.38; 95% confidence interval [CI], 0.15 to 0.99). The review concluded that the strongest evidence from the RCTs suggested that the hormonal treatment (prednisolone or tetracosactide depot) leads to resolution of spasms faster and in more infants than does vigabatrin. Long term developmental and epilepsy outcomes are unknown.

Prospective Studies

In addition to the RCTs evaluated in the Cochrane review, findings from a prospective national database of children with infantile spasms were published by Knupp et al (2016).^7, A total of 230 infants were included in the database, and 94 responded to initial treatment for infantile spasms. Response rates by type of treatment were 55 (55%) for ACTH, 21 (39%) for oral corticosteroids, 17 (36%) for vigabatrin, and 2 (9%) for “other” (p<.001). The type of ACTH, natural or synthetic, was not specified and the groups might have differed on characteristics that affect outcomes. Some significant differences between groups were identified (eg, length of time from diagnosis to the start of treatment, history of prior seizures). In logistic regression models controlling for some potential confounding factors, children on ACTH remained more likely to respond to treatment than other children. However, there might have been residual confounding on unmeasured characteristics.

Section Summary: Infantile Spasms

For individuals who have infantile spasms who receive repository corticotropin injection, the evidence includes systematic reviews/meta-analyses and a prospective study. A 2013 systematic review judged the overall quality of all included studies involving various medications for infantile spasms to be poor, with fewer than half reporting method of randomization and most assessing relatively few patients. There was heterogeneity across studies and either vigabatrin or prednisolone was used as comparators; however, the authors concluded that limited evidence from RCTs suggested that ACTH and prednisolone resolved infantile spasms more rapidly than vigabatrin. More recent meta-analyses also concluded that ACTH treatment was non-inferior to corticosteroid treatment with a similar adverse event profile and may be considered a safe and effective alternative treatment. A 2021 systematic review including 6 trials indirectly compared natural ACTH with synthetic ACTH therapies. Based on the limited evidence included, investigators suggested that repository corticotropin injection may be a better treatment option over synthetic ACTH therapies for improving cessation of spasms and other relevant symptoms. Multivariate analysis of a prospective cohort study found that children with infantile spasms who were treated with ACTH were more likely to respond than other children. However, the analysis might have been subject to residual confounding on unmeasured characteristics; further, the study did not differentiate between synthetic and natural ACTH.

Summary of Evidence

For individuals who have infantile spasms who receive repository corticotropin injection, the evidence includes systematic reviews/meta-analyses and a prospective study. A 2013 systematic review judged the overall quality of all included studies involving various medication for infantile spasms to be poor, with fewer than half reporting method of randomization and most assessing relatively few patients. There was heterogeneity across studies and either vigabatrin or prednisolone was used as comparators; however, the authors concluded that limited evidence from RCTs suggested that ACTH and prednisolone resolved infantile spasms more rapidly than vigabatrin. More recent meta-analyses also concluded that ACTH treatment was non-inferior to corticosteroid treatment with a similar adverse event profile and may be considered a safe and effective alternative treatment. A 2021 systematic review including 6 trials indirectly compared natural ACTH with synthetic ACTH therapies. Based on the limited evidence included, investigators suggested that repository corticotropin injection may be a better treatment option over synthetic ACTH therapies for improving cessation of spasms and other relevant symptoms. Multivariate analysis of a prospective cohort study found that children with infantile spasms who were treated with ACTH were more likely to respond than other children. However, the analysis might have been subject to residual confounding on unmeasured characteristics; further, the study did not differentiate between synthetic and natural ACTH. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

In response to requests, input was received from 3 physician specialty societies and 1 academic medical center while this policy was under review in 2010. In addition, unsolicited input was received from one Foundation and three physicians. There was strong support for the use of repository corticotropin injection in the treatment of infantile spasms (West syndrome).

Population Reference No. 2 

Corticosteroid-Responsive Conditions

Clinical Context and Therapy Purpose

The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with corticosteroid-responsive conditions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with corticosteroid-responsive conditions. Corticosteroid therapy is common in therapeutic regimens treating autoimmune and rheumatologic disorders.

Interventions

The therapy being considered is repository corticotropin injection.

Comparators

The following therapies are currently being used to treat corticosteroid-responsive conditions: synthetic corticosteroids.

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in disease status. Treatment duration and follow-up of at least 6 months are of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Fleischmann et al (2020) conducted a placebo-controlled, randomized, multicenter study evaluating the efficacy of ACTH in patients with rheumatoid arthritis with an inadequate response to prednisone or 1 to 2 disease-modifying therapies (including biologics).^8, Open-label ACTH was given for 12 weeks, then patients who achieved low disease activity were randomized to double-blind treatment with ACTH or placebo. At 12 weeks, 62.9% of patients achieved the prespecified criteria for low disease activity (the primary endpoint). At week 24, low disease activity was maintained in significantly more patients in the ACTH group than the placebo group (61.0% vs. 42.1% ; p=.019). Adverse events were similar between groups.

Askanase et al (2020) reported an RCT assessing the safety and efficacy of repository corticotropin injection in patients with persistently active systemic lupus erythematosus (SLE) despite use of moderate-dose glucocorticoids.^9, Adults with active SLE and moderate to severe rash and/or arthritis despite stable glucocorticoid doses were included in the study. Patients were randomized 1:1 to repository corticotropin injection (n=84) or placebo (n=85). At week 16, the proportion of SLE Responder Index-4 responders was not significantly different between groups (repository corticotropin injection, 47.6%; placebo, 43.5%; OR, 1.2; 95% CI, 0.6 to 2.2; p=.5762). There were numerically more SLE Responder Index-4 responders at all time points through week 24 of the trial in the repository corticotropin injection group than in placebo; however, there were no statistically significant differences observed between groups at any time point.

Wang et al (2018) performed an RCT evaluating efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome.^10, Patients aged 2 to 20 years (N=31) with frequently relapsing or steroid-dependent nephrotic syndrome were randomized 1:1 to ACTH or no relapse-preventing treatment. The trial was stopped at interim analysis due to lack of efficacy of ACTH. Of the patients included in the ACTH treatment arm, 14 out of 15 (93%) experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range [IQR], 9 to 32), compared with 15 out of 16 (94%) participants at a median of 21 days ( IQR, 14 to 51) in the control group. There was no difference in the proportion of relapsed patients (OR, 0.93; 95% CI, 0.05 to 16.40; p>.99) or time to first relapse (hazard ratio [HR], 1.03; 95% CI, 0.50 to 2.15; p=.93). Side effects were similar between groups.

Several RCTs, published in the 1960s and early 1970s, compared ACTH with placebo for the treatment of acute exacerbations of multiple sclerosis (MS). A trial described in recent review articles as the most rigorous of these RCTs was published by Rose et al (1969, 1970).^11,12, This multicenter, double-blind study included 197 patients. Patients were randomized to intramuscular injections of ACTH gel or placebo during a 2-week hospitalization for acute exacerbations of MS. The trial used Depo-ACTH and placebo, both prepared by Upjohn. A review article by Berkovich (2013) found that ACTH hastened improvement in symptoms but the differences between the ACTH and placebo-treated patients were less marked as the dosage of ACTH was reduced during the second week of treatment.^13,

Use of ACTH for treating MS exacerbations decreased in the 1980s as intravenous (IV) corticosteroid treatment became more common. Two RCTs published in the late 1980s compared ACTH with IV corticosteroids. A trial by Milanese et al (1989), which assessed 30 patients, found that dexamethasone was more effective than ACTH in shortening the length of the exacerbation.^14, Thompson et al (1989) conducted a study that evaluated 61 patients and compared ACTH with high-dose IV methylprednisolone.^15, The trialists did not find a statistically significant difference in the efficacy of the 2 treatments. A 2022 RCT by Wynn et al evaluated repository corticotropin injection in 35 patients with MS relapse that did not adequately respond to corticosteroids.^16, More patients in the repository corticotropin injection group were Expanded Disability Status Scale (EDSS) responders compared to the placebo group (61.1%; 90% CI, 42.0 to 77.3 vs. 11.8%; 90% CI, 4.0 to 30.1, respectively). Qualitative Clinical Global Impression of Improvement (CGI-I) results showed more patients as being much improved or very much improved compared to placebo; however, there was no significant difference in the mean CGI-I scores between treatment groups.

Additional Clinical Trials

A summary of the results of completed but unpublished clinical trials is shown in Table 2.

Table 2. Summary of Unpublished Clinical Trial Results

  ACTH: adrenocorticotropic hormone; AE: adverse event; eGFR: estimated glomerular filtration rate; LSM: least squares mean; SE: standard error; RCT: randomized controlled trial; U: units.  1 A Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Study of H.P. Acthar Gel (Acthar) in Treatment-Resistant Subjects with Persistent Proteinuria and Nephrotic Syndrome Due to Idiopathic Membranous Nephropathy (iMN) 2 A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Adaptive Design Pilot Safety and Efficacy Study of H.P. Acthar Gel (Acthar) in Patients with Diabetic Nephropathy and Proteinuria

Case Series

There are also a limited number of small case series reporting on the use of ACTH for other corticosteroid-responsive conditions.

For example, Bomback et al (2011) published a retrospective case series in 21 patients with idiopathic, nondiabetic nephrotic syndrome who were treated with ACTH gel.^17, ACTH gel was used as primary therapy in 3 patients; the other 18 patients had failed a mean of 2.3 immunosuppressive regimens before using ACTH gel. An additional 5 patients who were treated for less than 6 months and were taken off therapy for lack of response were not included in the analysis. Four (19%) of the 21 patients were in complete remission, defined as a stable or improved renal function with final proteinuria falling to less than 500 mg/d. An additional 7 (33%) of 21 patients had a partial remission (at least a 50% reduction in proteinuria and final proteinuria 500 to 3500 mg/d).

Section Summary: Corticosteroid-Responsive Conditions

For individuals who have corticosteroid-responsive conditions (eg, rheumatoid arthritis, dermatomyositis, sarcoidosis, nephrotic syndrome, MS, serum sickness, SLE) who receive repository corticotropin injection, the evidence includes RCTs and case series. One placebo-controlled trial supports the efficacy of repository corticotropin injection in patients with rheumatoid arthritis and an inadequate response to corticosteroids and disease-modifying therapies. Overall, more recent studies evaluating MS have demonstrated that IV corticosteroids are at least as effective, or more effective, than repository corticotropin. A recent RCT in patients with SLE found no difference in SLE Responder Index-4 responders in the repository corticotropin group compared to placebo. Most studies assessing nephrotic syndrome have been small retrospective case studies and the one RCT identified stopped early due to lack of efficacy of ACTH. Ongoing studies are being conducted.

Summary of Evidence

For individuals who have corticosteroid-responsive conditions (eg, rheumatoid arthritis, dermatomyositis, sarcoidosis, nephrotic syndrome, MS , serum sickness, SLE) who receive repository corticotropin injection, the evidence includes RCTs and case series. Relevant outcomes are symptoms and change in disease status. One placebo-controlled trial supports the efficacy of repository corticotropin injection in patients with rheumatoid arthritis and an inadequate response to corticosteroids and disease-modifying therapies. Overall, more recent studies evaluating MS have demonstrated that intravenous corticosteroids are at least as effective, or more effective, than repository corticotropin injection. A recent RCT in patients with SLE found no difference in SLE Responder Index-4 responders in the repository corticotropin group compared to placebo. Most studies assessing nephrotic syndrome have been small retrospective case studies and the 1 RCT identified stopped early due to lack of efficacy of ACTH. Most studies assessing nephrotic syndrome have been small retrospective case studies and the 1 RCT identified stopped early due to lack of efficacy of ACTH. Ongoing studies are being conducted. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

Non-Corticosteroid-Responsive Conditions

Clinical Context and Therapy Purpose

The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies for individuals with non-corticosteroid-responsive conditions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with non-corticosteroid-responsive conditions. Proposed examples include tobacco cessation therapy, acute gout, and childhood epilepsy.

Interventions

The therapy being considered is repository corticotropin injection.

Comparators

The following therapy is currently being used to treat non-corticosteroid-responsive conditions: standard of care.

Outcomes

The general outcomes of interest are reductions in symptoms and improvements in disease status. Treatment duration and follow-up of at least 6 months are of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Repository corticotropin injection has been proposed for several off-label non-corticosteroid-responsive conditions, including tobacco cessation, acute gout, and childhood epilepsy. Controlled studies were identified only for the treatment of acute gout. Janssens et al (2008) published a Cochrane review that compared the efficacy and safety of systemic corticosteroids in the treatment of acute gout with placebo, nonsteroidal anti-inflammatory drugs, colchicine, other active drugs, other therapies including repository corticotropin injection, or no therapy.^18, Three head-to-head trials were identified; 1 compared systemic corticosteroids with oral indomethacin and intramuscular ACTH. The quality of the 3 studies identified was graded as very low to moderate. None found clinically relevant differences between the systemic corticosteroids and the comparator drugs, and important safety problems attributable to the used corticosteroids were not reported. Reviewers concluded that “There is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout.”

Section Summary: Non-Corticosteroid-Responsive Conditions

For individuals who have conditions not generally known to be responsive to corticosteroids (non-corticosteroid-responsive) such as tobacco cessation, childhood epilepsy, and acute gout who receive repository corticotropin injection, the evidence includes 3 head-to-head trials identified for use in gout. The quality of these studies was deemed very low to moderate because there were no direct placebo-controlled trials and no clinically relevant differences were detected between drugs studied.

Summary of Evidence

For individuals who have conditions not generally known to be responsive to corticosteroids (non-corticosteroid-responsive) such as tobacco cessation, childhood epilepsy, and acute gout who receive repository corticotropin injection, the evidence includes 3 head-to-head trials identified for use in gout. Relevant outcomes are symptoms and change in disease status. The quality of these studies was deemed very low to moderate because there were no direct placebo-controlled trials and no clinically relevant differences were detected between drugs studied. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Diagnostic Testing of Adrenocortical Function

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Clinical Context and Test Purpose

The purpose of repository corticotropin injection in individuals who have suspected adrenocortical insufficiency is to inform a decision whether to proceed to treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who need a diagnostic assessment of adrenal function.

Interventions

The test being considered is repository corticotropin injection.

Comparators

The following test is currently being used to make decisions about diagnosing adrenal insufficiency: testing with synthetic ACTH.

Outcomes

The general outcomes of interest are test validity and other test performance measures. Laboratory testing of adrenocortical function is contemporaneous with the administration of the corticosteroid agent.

Study Selection Criteria

For the evaluation of clinical validity of the repository corticotropin injection test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Studies have evaluated the value of synthetic ACTH for diagnosing adrenal insufficiency. For example, a meta-analysis by Kazlauskaite et al (2008) identified 13 studies comparing low- with high-dose corticotropin tests for diagnosing adrenal insufficiency.^19, A comparable literature base was not identified for the use of natural ACTH (ie, H.P. Acthar Gel used in the diagnostic testing of adrenocortical function), and no studies were found that compared synthetic with natural ACTH for this purpose.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified assessing the clinical utility of the use of repository corticotropin injection in diagnosing adrenal insufficiency.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical validity of repository corticotropin injection testing in the diagnosis of adrenal insufficiency has not been established, a chain of evidence cannot be constructed.

Section Summary: Diagnostic Testing of Adrenocortical Function

For individuals who need diagnostic testing of adrenal function who receive repository corticotropin injection, the evidence does not include studies that compare the diagnostic accuracy of repository corticotropin injection with ACTH. The lack of published evidence precludes conclusions on the validity of using repository corticotropin injection as a diagnostic test for adrenal function.

Summary of Evidence

For individuals who need diagnostic testing of adrenal function who receive repository corticotropin injection, the evidence does not include studies that compare the diagnostic accuracy of repository corticotropin injection with ACTH. Relevant outcomes are test validity and other test performance measures. The lack of published evidence precludes conclusions on the validity of using repository corticotropin injection as a diagnostic test for adrenal function. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2010 Input

In response to requests, input was received from 3 physician specialty societies and 1 academic medical center while this policy was under review in 2010. In addition, unsolicited input was received from 1 Foundation and 3 physicians. There was strong support for the use of repository corticotropin injection in the treatment of infantile spasms (West syndrome).

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

Infantile Spasms Working Group

An industry-sponsored Infantile Spasms Working Group (2010) published a consensus report on the diagnosis and treatment of infantile spasms.^23, Regarding treatment, the report concluded: “At this time, ACTH and VGB [vigabatrin] are the only drugs with proven efficacy to suppress clinical spasms and abolish the hypsarrhythmic EEG [electroencephalogram] in a randomized clinical trial setting (Mackay et al., 2004) and thus remain first-line treatment.”

International League Against Epilepsy

The International League Against Epilepsy Commission of Pediatrics (2015) recommendations on management of infantile seizures states that ACTH (either low or high doses) is a preferred treatment for short-term control of infantile spasms (evidence level B [probably effective]).^24, The recommendations for the management of infantile seizures was based on an international survey due to the lack of evidence-based data.

National Institute for Health and Care Excellence

The NICE (2022) published a guideline on epilepsies in children, young people, and adults that addresses infantile spasm.^25, For first-line treatment, NICE recommends combining steroids with vigabatrin which has been shown to be more effective than either steroids or vigabatrin alone in stopping spasms. Based on NICE committee consensus opinion, the committee agreed that "steroids may not be suitable for all children under 2 years and that vigabatrin alone should be considered for those at high risk from the side effects of steroid treatment, such as those with neurological impairments and other comorbidities". There was no specific mention of repository corticotropin injection or ACTH.

American College of Rheumatology

The American College of Rheumatology (2020) published a guideline on the management of gout.^26, The guideline recommends that other agents be used first-line for the treatment of a gout flare rather than ACTH. For patients who are unable to take oral medications, parenteral corticosteroids are preferred over ACTH.

American College of Physicians

A practice guideline on acute and recurrent gout from the American College of Physicians (2017) does not provide a formal recommendation about use of ACTH.^27, However, the guideline authors state that ACTH may reduce pain in patients with acute gout (based on moderate quality evidence). Comparative evidence suggests greater efficacy compared to corticosteroids and nonsteroidal anti-inflammatory drugs, with a potential for harm similar to corticosteroids.

European Respiratory Society

A European Respiratory Society (2021) guideline includes repository corticotropin injection (40 to 80 units twice a week) among immunosuppressive options for sarcoidosis in patients who have failed prior treatments with steroids and/or anti-metabolites.^28, However, the guideline also notes the following: “Additional studies are needed to evaluate the efficacy, safety and cost efficiency of rituximab, repository corticotropin injection, anti-TNF biosimilars and other agents.”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

  NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

1. Mallinckrodt Pharmaceuticals. H.P. Acthar Gel (repository corticotropin injection) INJECTION, GEL for INTRAMUSCULAR | SUBCUTANEOUS use. 2024; http://www.acthar.com/pdf/Acthar-PI.pdf. Accessed August 15, 2024.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Summary review. Action memo for NDA 22-432, for the use of H.P. Acthar Gel (repository corticotropin injection) in the treatment of infantile spasms (IS). April 5, 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022432Orig1s0900SumR.pdf. Accessed August 14, 2024.
3. Duchowny MS, Chopra I, Niewoehner J, et al. A Systematic Literature Review and Indirect Treatment Comparison of Efficacy of Repository Corticotropin Injection versus Synthetic Adrenocorticotropic Hormone for Infantile Spasms. J Health Econ Outcomes Res. Jan 27 2021; 8(1): 1-9. PMID 33521161
4. Chang YH, Chen C, Chen SH, et al. Effectiveness of corticosteroids versus adrenocorticotropic hormone for infantile spasms: a systematic review and meta-analysis. Ann Clin Transl Neurol. Nov 2019; 6(11): 2270-2281. PMID 31657133
5. Li S, Zhong X, Hong S, et al. Prednisolone/prednisone as adrenocorticotropic hormone alternative for infantile spasms: a meta-analysis of randomized controlled trials. Dev Med Child Neurol. May 2020; 62(5): 575-580. PMID 31903560
6. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. Jun 05 2013; 2013(6): CD001770. PMID 23740534
7. Knupp KG, Coryell J, Nickels KC, et al. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol. Mar 2016; 79(3): 475-84. PMID 26704170
8. Mirsaeidi M, Baughman RP, Sahoo D, et al. Results From a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Repository Corticotropin Injection for the Treatment of Pulmonary Sarcoidosis. Pulm Ther. Jun 2023; 9(2): 237-253. PMID 37072607
9. Fleischmann R, Furst DE, Connolly-Strong E, et al. Repository Corticotropin Injection for Active Rheumatoid Arthritis Despite Aggressive Treatment: A Randomized Controlled Withdrawal Trial. Rheumatol Ther. Jun 2020; 7(2): 327-344. PMID 32185745
10. Askanase AD, Zhao E, Zhu J, et al. Repository Corticotropin Injection for Persistently Active Systemic Lupus Erythematosus: Results from a Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Rheumatol Ther. Dec 2020; 7(4): 893-908. PMID 32996096
11. Wang CS, Travers C, McCracken C, et al. Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial. Clin J Am Soc Nephrol. Dec 07 2018; 13(12): 1859-1865. PMID 30442868
12. Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbation. Trans Am Neurol Assoc. 1969; 94: 126-33. PMID 4313957
13. Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report. Neurology. May 1970; 20(5): 1-59. PMID 4314823
14. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. Jan 2013; 10(1): 97-105. PMID 23229226
15. Milanese C, La Mantia L, Salmaggi A, et al. Double-blind randomized trial of ACTH versus dexamethasone versus methylprednisolone in multiple sclerosis bouts. Clinical, cerebrospinal fluid and neurophysiological results. Eur Neurol. 1989; 29(1): 10-4. PMID 2540005
16. Thompson AJ, Kennard C, Swash M, et al. Relative efficacy of intravenous methylprednisolone and ACTH in the treatment of acute relapse in MS. Neurology. Jul 1989; 39(7): 969-71. PMID 2544829
17. Wynn D, Goldstick L, Bauer W, et al. Results from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection for multiple sclerosis relapse that did not adequately respond to corticosteroids. CNS Neurosci Ther. Mar 2022; 28(3): 364-371. PMID 34984839
18. Fernandez AP, Gallop J, Polly S, et al. Efficacy and safety of repository corticotropin injection for refractory cutaneous dermatomyositis: a prospective, open-label study. Rheumatology (Oxford). Nov 06 2023. PMID 37941470
19. Hayes K, Niewoehner J, Rice JB, et al. Corticosteroid Use and Adherence in Patients Treated with Acthar Gel for Advanced Sarcoidosis. Adv Ther. Nov 2023; 40(11): 4999-5015. PMID 37728695
20. Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. Mar 14 2011; 5: 147-53. PMID 21448451
21. Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. Apr 16 2008; 2008(2): CD005521. PMID 18425920
22. Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. Nov 2008; 93(11): 4245-53. PMID 18697868
23. Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. Oct 2010; 51(10): 2175-89. PMID 20608959
24. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia. Aug 2015; 56(8): 1185-97. PMID 26122601
25. National Institute for Health and Care Excellence (NICE). Epilepsies in children, young people and adults [NICE Guideline NG217]. https://www.nice.org.uk/guidance/ng217. 2022. Accessed August 15, 2024.
26. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Rheumatol. Jun 2020; 72(6): 879-895. PMID 32390306
27. Qaseem A, Harris RP, Forciea MA, et al. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. Jan 03 2017; 166(1): 58-68. PMID 27802508
28. Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J. Dec 2021; 58(6). PMID 34140301

Codes

Policy History