CAM 50117

Repository Corticotropin Injection

Category:Prescription Drug   Last Reviewed:January 2019
Department(s):Medical Affairs   Next Review:January 2020
Original Date:October 2013    

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 (eg, 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 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 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, St. Louis, MO) was approved by the U.S. Food and Drug Administration (FDA). 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.

A synthetic derivative of ACTH is commercially available outside of the United States (under the trade names Cortosyn® [Amphastar Pharmaceuticals, Rancho Cucamonga, CA] and Synacthen®) but it is not approved by FDA for any conditions currently on the label for H.P. Acthar Gel. In addition, a depot formulation of ACTH (Synacthen Depot) is available under a compassionate-use program through the specialty pharmacy Caligor Rx in New York. In June 2013, Questcor Pharmaceuticals (Anaheim, CA) announced that it had acquired the rights to market Synacthen in the United States, pending FDA approval.

Diagnostic testing of adrenocortical function, known as the ACTH test, is typically done with synthetic ACTH. Synthetic ACTH products have been approved by 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, 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 an elevated blood pressure, a decrease in bone density, new infections (or activation of a 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 INVESETIGATIONAL 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 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.

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 a technology improves the net health outcome. Broadly defined, health outcomes are 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 to 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 a technology, 2 domains are examined: the relevance and the 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. RCTs 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 Test Purpose 
The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with infantile spasms.

The question addressed in this evidence review is: Does the use of repository corticotropin injection to treat infantile spasms improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients 
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. 

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. 

Timing
Follow-up at 6, 12, and 24 months is of interest for repository corticotropin injection to monitor for changes in symptoms and disease status. 

Setting 
Patients with infantile spasms are actively managed by neurologists and pediatricians in an outpatient setting. 

Study Selection Criteria 
Evidence that repository corticotropin injection (ie, natural adrenocorticotropic hormone ACTH. injection) is a reasonable alternative to corticosteroid treatment requires controlled studies demonstrating superiority or noninferiority of repository corticotropin injection to corticosteroids as first-line treatment, or controlled studies showing comparable efficacy of with fewer adverse effects. RCTs are crucial to avoid noncomparability of treatment groups. Alternatively, for patients unable to tolerate corticosteroids, the most appropriate study design would be a controlled study comparing repository corticotropin injection with placebo.

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 longer 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. 

Systematic Reviews 
A Cochrane review by Hancock et al (2013) assessed medication treatment of infantile spasms, including ACTH.2. Reviewers identified 18 RCTs investigating 12 medications. The 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 (odds ratio, 0.38; 95% confidence interval, 0.15 to 0.99). The limited evidence from RCTs suggested that hormonal treatment (prednisolone, tetracosactide depot, ACTH) resolved infantile spasms faster than vigabatrin and resolved the condition in more children, but 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).3. 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<0.001). 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 
There is some evidence from several RCTs and a prospective database that natural and synthetic ACTH have greater short-term efficacy in resolving infantile spasms than other medications (e.g., vigabatrin, oral corticosteroids). However, most of the RCTs were small or of poor quality, and only a few evaluated natural ACTH. 

Corticosteroid-Responsive Conditions 
Clinical Context and Test Purpose 
The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with corticosteroid-responsive conditions.

The question addressed in this evidence review is: Does the use of repository corticotropin injection to treat corticosteroid-responsive conditions improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients 
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. 

Timing 
Treatment duration and follow-up of at least 6 months for repository corticotropin injection is necessary to monitor for changes in symptoms and disease status. 

Setting 
Patients with corticosteroid-responsive conditions are actively managed by dermatologists, rheumatologists, and primary care providers in an outpatient setting. 

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 longer 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. 

Randomized Controlled Trials 
Controlled studies were identified for treatment of multiple sclerosis with ACTH, but not treatment of other corticosteroid-responsive conditions. Several RCTs, published in the 1960s and early 1970s, compared ACTH with placebo for the treatment of acute exacerbations of multiple sclerosis. A trial described in recent review articles as the most rigorous of these RCTs was published by Rose et al (1969, 1970).4. 5. 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 multiple sclerosis. 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.6.

Use of ACTH for treating multiple sclerosis 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.8. The trialists did not find a statistically significant difference in the efficacy of the 2 treatments.

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, Gillis et al (2017) published a small case series of 8 adults with confirmed rheumatoid arthritis and American College of Radiology functional status between 1 and 3.9. Patients were refractory to prior therapies with at least 3 different modes of action. Repository corticotropin injection was administered for 12 weeks, with follow-up visits at weeks 14 and 16 (after cessation of repository corticotropin injection). Both physician and patient visual analog scale assessments of swollen and tender joints improved from baseline to 12 weeks: physician visual analog scale scores significantly decreased from median of 8.4 (range, 3.8-9.9) to 2.5 (range, 0.30-6.5; p<0.001); patient visual analog scale scores decreased from median of 28.5 (range, 8-97) to 17 (range, 0-40; p=0.022). The 28-item Disease Activity Score for rheumatoid arthritis was also used as an outcome measure. As an open-label, unblinded study, there was potential for sampling bias, and patients were permitted to continue a variety of concomitant medication during repository corticotropin injection treatment.

Bomback et al (2011) published a retrospective case series in 21 patients with idiopathic, nondiabetic nephrotic syndrome who were treated with ACTH gel.10. ACTH gel was used as a 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 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 500-3500 mg/d). 

Section Summary: Corticosteroid-Responsive Conditions 
There is insufficient evidence that ACTH gel is at least as effective as IV corticosteroids for the treatment of multiple sclerosis. One RCT found that corticosteroids were more effective and another found no significant difference in efficacy. 

Non-Corticosteroid-Responsive Conditions 
Clinical Context and Test Purpose 
The purpose of repository corticotropin injection is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with non-corticosteroid- responsive conditions.

The question addressed in this evidence review is: Does the use of repository corticotropin injection to treat non-corticosteroid-responsive conditions improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients
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. 

Timing 
Treatment duration and follow-up of at least 6 months after repository corticotropin injection is necessary to monitor for changes in symptoms and disease status. 

Setting 
Patients with non-corticosteroid-responsive conditions are actively managed by primary care physicians and specialists in an outpatient setting. 

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 longer 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. 

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 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.11. Three head-to-head trials were identified; one 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 
There is a lack of controlled studies evaluating ACTH for treatment of non-corticosteroid- responsive conditions, with the exception of gout. A Cochrane review identified a single trial comparing ACTH and systemic corticosteroids; this trial did not report clinically relevant differences in outcomes. 

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 with suspected adrenocortical insufficiency is to inform a decision whether to proceed to treatment.

The question addressed in this evidence review is: Does the use of repository corticotropin injection for adrenocortical function testing improve the net health outcome?

The following PICOTS were used to select literature to inform this review. 

Patients 
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 the synthetic adrenocorticotropic hormone. 

Outcomes 
The general outcomes of interest are test validity and other test performance measures. 

Timing 
Laboratory testing of adrenocortical function is contemporaneous with the administration of the corticosteroid agent. 

Setting 
Patients requiring a diagnostic assessment of adrenal function are actively managed by endocrinologists and primary care providers in an outpatient setting. 

Study Selection Criteria 
For the evaluation of clinical validity of the repository corticotropin injection test, studies that met 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. 

Technically Reliable 
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility. 

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).

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.12.  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, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary 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 
No studies were identified that evaluated repository corticotropin injection, or compared natural with synthetic ACTH, for diagnostic assessment of adrenocortical function. 

Summary of Evidence 
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.

For individuals who have corticosteroid-responsive conditions (eg, 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 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 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.

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.

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 use of repository corticotropin injection in the treatment of infantile spasms (West syndrome). 

Practice Guidelines and Position Statements 
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.13. 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.14. 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.” 

American College of Rheumatology 
The American College of Rheumatology (2012) published guidelines on therapy and anti- inflammatory prophylaxis of acute gouty arthritis.15. The guidelines committee did not reach a consensus on the use of ACTH for patients with acute gout who are able to take medications orally. For patients unable to take oral medications, the committee agreed that subcutaneous synthetic ACTH was a reasonable alternative to oral prednisone or prednisolone therapy. 

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

Ongoing and Unpublished Clinical Trials 
Some currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date

Ongoing

NCT02290444

Effects of Adrenocorticotropic Hormone (ACTHAR Gel) on Recovery From Cognitive Relapses in Multiple Sclerosis

60 Dec 2017

NCT02132195a

Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome

60 Oct 2018

NCT02315872a

The Effect of ACTH (Acthar) on Measures of Chronic Fatigue in Patients With Relapsing Multiple Sclerosis

90 Dec 2019

NCT01950234a

Treatment of Progressive Forms of Multiple Sclerosis With Pulsed ACTH (Acthar Gel)

100 Dec 2020

Unpublished  

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)

NCT01601236a

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

40 Mar 2016 (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. 2018; http://www.acthar.com/pdf/Acthar- PI.pdf. Accessed September 12, 2018.
  2. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. Jun 05 2013;6(6):CD001770. PMID 23740534
  3. Knupp KG, Coryell J, Nickels KC, et al. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol. Mar 2016;79(3):475-484. PMID 26704170
  4. 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;94:126-133. PMID 4313957
  5. 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
  6. Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. Jan 2013;10(1):97-105. PMID 23229226
  7. 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):10-14. PMID 2540005
  8. 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):969-971. PMID 2544829
  9. Gillis T, Crane M, Hinkle C, et al. Repository corticotropin injection as adjunctive therapy in patients with rheumatoid arthritis who have failed previous therapies with at least three different modes of action. Open Access Rheumatol. Aug 2017;9:131-138. PMID 28790870
  10. Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. Mar 14 2011;5:147-153. PMID 21448451
  11. 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
  12. 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):4245-4253. PMID 18697868
  13. 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):1974-1980. PMID 22689735
  14. Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. Oct 2010;51(10):2175-2189. PMID 20608959
  15. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). Oct 2012;64(10):1447-1461. PMID 23024029 

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 and 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     

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

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