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.

For individuals who have infantile spasms who receive repository corticotropin injection, the evidence includes randomized controlled trials, a systematic review, and a prospective cohort study. Relevant outcomes are symptoms and change in disease status. The systematic review judged the overall quality of the studies 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. 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 the effects of the technology on health outcomes.

Clinical input obtained in 2010 strongly supported the use of repository corticotropin injection for patients with infantile spasms; repository corticotropin is considered standard of care. Therefore, treatment of infantile spasms with repository corticotropin injection may be considered medically necessary.

For individuals who have corticosteroid-responsive conditions (e.g., rheumatoid arthritis, dermatomyositis, sarcoidosis, nephrotic syndrome, multiple sclerosis, serum sickness) who receive repository corticotropin injection, the evidence includes randomized controlled trials and small case series. Relevant outcomes are symptoms and change in disease status. Overall, more recent studies evaluating multiple sclerosis have demonstrated that intravenous corticosteroids are at least as effective, or more effective, than repository corticotropin. Most studies assessing nephrotic syndrome have been small retrospective case studies. Ongoing studies are being conducted. The evidence is insufficient to determine the effects of the technology on health outcomes.

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 three 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 the effects of the technology on health outcomes.

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 as a diagnostic test for adrenal function. The evidence is insufficient to determine the effects of the technology on health outcomes. 

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. 

REGULATORY STATUS
In 1952, H.P. Acthar^® Gel (Questcor Pharmaceuticals/Mallinckrodt Pharmaceuticals) was approved by the U.S. Food and Drug Administration. The original product label included at least 19 separate conditions, including infantile spasms. 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.

Indications
H.P. Acthar^® Gel was approved by the Food and Drug Administration before the requirement that companies provide evidence of clinical efficacy. Table 1 summarizes the current prescribing indications and usage for Acthar^® Gel.¹

Table 1. Indications for Repository Corticotropin Injection

Indication	Populations or Conditions
Infantile spasms	Monotherapy for infants and children < 2 years of age
Multiple sclerosisa	Acute exacerbations of multiple sclerosis in adults
Rheumatic disorders	Adjunctive therapy for short-term administration for acute episodes or exacerbations of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis
Collagen diseases	During an exacerbation or as maintenance therapy in select cases of systemic lupus erythematosus and systemic dermatomyositis
Dermatologic diseases	Severe erythema multiforme and Stevens-Johnson syndrome
Allergic states	Serum sickness
Ophthalmic diseasesb	Severe acute and chronic allergic and inflammatory processes
Respiratory diseases	Symptomatic sarcoidosis
Edematous statec	To induce a diuresis or a remission of proteinuria in the nephrotic syndrome

^aControlled 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 Food and Drug Administration 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, 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.

Related Policies:
None

Policy:
Repository corticotropin injection may be considered MEDICALLY NECESSARY for treatment of infantile spasms (West syndrome).

Repository corticotropin injection is considered INVESTIGATIONAL for use in diagnostic testing of adrenocortical function, because it has not been shown to be superior to cosyntropin for this purpose.

Use of repository corticotropin injection is considered INVESTIGATIONAL as treatment of corticosteroid-responsive conditions, because it has not been proven to be more effective than corticosteroids for these conditions.

Except as noted here, use of repository corticotropin injection is considered INVESTIGATIONAL AND UNPROVEN for all other indications, because its effectiveness for these indications has not been established.

Policy Guidelines:
There may be some patients who have medical contraindications or intolerance to corticosteroids that are not also expected to occur with use of repository corticotropin injection, and who, therefore, may benefit from repository corticotropin injections. This situation is not expected to occur commonly.

The product information material makes the following comments about 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 two weeks of treatment, dosing should be gradually tapered and discontinued over a two-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.

Acthar gel should never be used intravenously.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.

Because repository corticotropin is generally more costly than alternative agents but has not been shown to lead to improved outcomes compared to those obtained with alternatives, it is considered not medically necessary for some indications using the Medical Policy Reference Manual (MPRM) medical necessity definition. For contracts that do not use this definition of medical necessity, other contract provisions may be applied; benefit or contract language describing the "least costly alternative" may also be applicable for this choice of treatment.

According to the manufacturer’s website, beginning in August 2007, H.P. Acthar Gel is only available through specialized pharmacy distribution (i.e., no longer available from traditional pharmaceutical wholesalers or retail pharmacies). As of August 2009, the specialty pharmacy exclusive distribution is unchanged.

 

Rationale:  
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, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses 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.

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 patients with infantile spasms.

he question addressed in this evidence review is: Does the use of repository corticotropin injection improve the net health outcome in patients 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 as monotherapy for infantile spasms in infants and children less than two 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 days⁵. 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 (e.g., 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 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.

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 patients with corticosteroid-responsive conditions.

The question addressed in this evidence review is: Does the use of repository corticotropin injection improve the net health outcome in patients 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, 9 to 32), compared with 15 out of 16 (94%) participants at a median of 21 days (interquartile range, 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, 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.

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  

Study	Type	Partial Remission in Proteinuria	Complete Remission in Proteinuria	Serious AEs	Percent Change in eGFR LSM (SE)	Relapse of Nephrotic Syndrome
NCT013865541	RCT, double blind, parallel-group
Acthar 40U		1 (25%)	0 (0%)	1 (25%)
Acthar 80U		5 (14.3%)	0 (0%)	7 (20%)
Placebo		2 (9.5%)	0 (0%)	2 (14.3%)
NCT016012362	RCT, double blind, parallel-group
Acthar 8U		0 (0%)	0 (0%)	1 (14.3%)	-20.563 (6.8126)
Acthar 16U		0 (0%)	1 (12.5%)	2 (11.8%)	-17.447 (4.3473)
Placebo		0 (0%)	0 (0%)	0 (0%)	-24.927 (5.4198)

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.¹⁶ 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 (e.g., 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 intravenous 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.

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 patients with non-corticosteroid-responsive conditions.

The question addressed in this evidence review is: Does the use of repository corticotropin injection improve the net health outcome in patients 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.¹⁷ 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, “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.

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 patients who have suspected adrenocortical insufficiency is to inform a decision whether to proceed to treatment.

The question addressed in this evidence review is: Does testing for adrenocortical function with repository corticotropin injection improve the net health outcome in individuals with suspected adrenocortical insufficiency?

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.¹⁸ A comparable literature base was not identified for the use of natural ACTH (i.e., 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 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.

For individuals who have corticosteroid-responsive conditions (e.g., 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.

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.

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.

American Academy of Neurology and Child Neurology Society
The American Academy of Neurology and the Child Neurology Society (2012) updated their evidence-based guidelines on the treatment of infantile spasms.¹⁹ The guidelines included the following recommendations on the use of adrenocorticotropic hormone (ACTH):  

• “ACTH (Level B) or VGB [vigabatrin] (Level C) may be offered for short-term treatment of infantile spasms.”

• “Hormonal therapy (ACTH or prednisolone) may be considered for use in preference to VGB in infants with cryptogenic infantile spasms….”

Infantile Spasms Working Group
An industry-sponsored Infantile Spasms Working Group (2010) published a consensus report on the diagnosis and treatment of infantile spasms.²⁰ 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))²¹. The recommendations for the management of infantile seizures was based on an international survey due to the lack of evidence-based data.

American College of Rheumatology
The American College of Rheumatology (2020) published a guideline on the management of gout.²² 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.²³ 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.

U.S. Preventive Services Task Force Recommendations
Not applicable.

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 No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02030028	Open Label Study to Evaluate Efficacy and Safety of Short-Term, Adjunctive Adrenocorticotropic Hormone (ACTH) Gel in Rheumatoid Arthritis	20	Dec 2021
NCT02245841	Efficacy and Safety of H.P. Acthar Gel for the Treatment of Refractory Cutaneous Manifestations of Dermatomyositis	15	July 2021
NCT03320070a	A Phase 4, Multicenter, Randomized, Double Blind, Placebo Controlled Pilot Study to Assess the Efficacy and Safety of Acthar Gel in Subjects With Pulmonary Sarcoidosis	100	Jan 2022
NCT02541955	Use of Acthar in Rheumatoid Arthritis Related Flares	40	June 2021
NCT03644771	Experience With H.P. Acthar Gel Treatment of Patients With Nephrotic Syndrome/Proteinuria Due to Various Etiologies and Its Effect on Podocyte Function	40	Dec 2021
NCT03414086	Predictor of Clinical Response to Acthar in Myositis: Phase II of Acthar Clinical Trial	20	July 2021
NCT01950234a	Treatment of Progressive Forms of Multiple Sclerosis With Pulsed ACTH (Acthar Gel)	100	Dec 2022
NCT02725177	Ocular Sarcoidosis Open Label Trial of ACTHAR Gel	20	Dec 2022
NCT03511625	The Effects of Acthar on Synovial Inflammation in Rheumatoid Arthritis	6	Dec 2021
Unpublished
NCT02298491	Clinical Biomarkers of Disease Activity and Treatment Responses in Patients With CNS Sarcoidosis Treated With H.P. Acthar Gel	4	Nov 2020 (completed)
NCT02315872a	The Effect of ACTH (Acthar) on Measures of Chronic Fatigue in Patients With Relapsing Multiple Sclerosis	8	Dec 2018 (completed)
NCT01367964	Early Treatment of Infants at High Risk of Developing West Syndrome With Low-dose Adrenocorticotropin Hormone (ACTH)	28	Dec 2018
NCT01386554a	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)	60	May 2017 (completed)

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. 2021; http://www.acthar.com/pdf/Acthar-PI.pdf. Accessed August 30, 2021.
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 30, 2021.
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; (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. 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
9. 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
10. 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
11. 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
12. 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
13. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. Jan 2013; 10(1): 97-105. PMID 23229226
14. 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
15. 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
16. 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
17. Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. Apr 16 2008; (2): CD005521. PMID 18425920
18. 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
19. Go CY, Mackay MT, Weiss SK, et al. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. Jun 12 2012; 78(24): 1974-80. PMID 22689735
20. Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. Oct 2010; 51(10): 2175-89. PMID 20608959
21. 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
22. 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
23. 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

Coding Section

Codes	Number	Description
CPT	96372	Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
ICD-9-Diagnosis	345.60 – 345.61	Infantile spasms, code range
HCPCS	J0800	Injection, corticotropin, up to 40 units
ICD-10-CM (effective 10/1/15)	G40.401 – G40.409	Other generalized epilepsy and epileptic syndromes, not intractable code range
ICD-10-PCS (effective 10/1/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific code for this procedure.
	3E013VJ	Administration, physiological systems and anatomical regions, introduction, subcutaneous tissue, percutaneous, hormone
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward

02/15/2023	Annual review, no change to policy intent.
01/18/2023	Updated annual review to 02/06/2023. No changes made to policy.
01/24/2022	Annual review, no change to policy intent. Updating rationale and references.
01/19/2021	Annual review, no change to policy intent.
01/13/2020	Annual review, no change to policy intent. Updating regulatory status, rationale and references.
01/17/2019	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/31/2018	Interim review, updating indications section of policy. No change to policy verbiage.
02/12/2018	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
01/03/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
01/27/2016	Annual review, no change to policy intent, however, use of repository corticotropin for treatment of corticosteroid responsive conditions and for use in diagnostic testing of adrenocortical function has been updated to indicate investigational status rather than not medically necessary status. Updated background, description, rationale and references.
10/01/2015	Annual review, no change to policy intent. Updated background, description, rationale, references and cpt coding.
10/07/2014	Annual review. No change to policy intent. Updated background/description, regulatory status, guidelines, rationale and references. Added coding section.
10/21/2013	NEW POLICY