|5.01.17||Repository Corticotropin Injection|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/12:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Repository corticotropin injection (H.P. Acthar® gel, Questcor Pharmaceuticals, Union City, CA) 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.
H.P. Acthar gel was approved by the U.S. Food and Drug Administration (FDA) in 1952, before there was a requirement that companies provide clinical evidence of efficacy. The product label states that Acthar gel is indicted for a number of conditions, as follow:
According to the prescribing information (i.e. product label), repository corticotropin injection may be used in the treatment of the following conditions (1):
1.1 Infantile Spasms in infants and children younger than 2 years of age.
1.2 Multiple Sclerosis: Treatment of acute exacerbations of multiple sclerosis in adults. (indication added in 1978).
1.3 Rheumatic Disorders: Adjunctive therapy for patients with acute episodes or exacerbations of psoriatic arthritis, rheumatoid arthritis and ankylosing spondylitis.
1.4 Collagen Diseases: Treatment of selected cases of systemic lupus erythematous and systemic dermatomyositis.
1.5 Dermatologic Diseases: Treatment of severe erythema multiforme and Stevens-Johnson syndrome.
1.6 Allergic States: Treatment of serum sickness.
1.7 Ophthalmic Diseases: Treatment of severe acute and chronic allergic and inflammatory processes including optic neuritis, keratitis and iritis.
1.8 Respiratory Diseases: Treatment of symptomatic sarcoidosis)
1.9 Edematous State: Treatment of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or due to lupus erythematosus.
Among the above indications, repository cotricotropin injection is best known for the treatment of 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 (EEG) findings of hypsarrhythmia, the condition is known as West syndrome. Vigabatrin oral solution is another available treatment for infantile spasms.
A synthethic derivative of ACTH is commercially available outside of the United States (under the tradenames Cortosyn and Synacthen) but it is not approved by the FDA for any of the conditions currently included in the H.P. Acthar gel FDA-approved label. In addition, a depot formulation of ACTH (Synacthen Depot) is available through a compassionate-use program through the specialty pharmacy Caligor Rx in New York. In June 2013, Questcor Pharmaceuticals announced that they acquired the rights to market Synacthen in the United States, once FDA approval is obtained.
Diagnostic testing of adrenocortical function, known as the ACTH test, is typically done with synthetic ACTH. Synthetic ACTH products have been approved by the FDA for this purpose. Unlike previous versions of the H.P. Acthar product label, an updated label issued in 2010, did not mention the use of repository corticotropin injection for diagnostic testing of adrenocortical function.
Repository corticotropin injection has potential adverse effects similar to those that occur with steroid medication such as elevated blood pressure, decrease in bone density, new infections or activation of previous infection, and overproduction of cortisol, which can cause symptoms of Cushing’s syndrome.
H.P. Acthar gel (Questcor Pharmaceuticals) was approved by FDA in 1952. The product label states that Acthar gel is indicted for 19 conditions, including infantile spasms. Contraindications for 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. Unlike previous versions of the product label, an updated label issued in 2010, did not include the use of repository corticotropin injection for diagnostic testing of adrenocortical function
Repository corticotropin injection may be considered medicallynecessary for treatment of infantile spasms (West syndrome).
Use of repository corticotropin injection is considered not medically necessary as treatment of corticosteroid-responsive conditions (see Policy Guidelines).
Repository corticotropin injection is considered not medicallynecessary for use in diagnostic testing of adrenocortical function.
Except as noted above, use of repository corticotropin injection is considered investigational for conditions that are not responsive to corticosteroid therapy including, but not limited to, use in tobacco cessation, acute gout, and childhood epilepsy.
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/m 2 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.
BlueCard/National Account Issues
State or federal mandates (eg, 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 (ie, no longer available from traditional pharmaceutical wholesalers or retail pharmacies).
This policy was originally created in 2008 and was updated regularly with searches of the MEDLINE database. Most recently, the literature was reviewed through November 10, 2014. Following is a summary of the key literature to date.
In 2013, Hancock et al published an updated Cochrane review on medication treatment of infantile spasms.(2) The authors identified 18 randomized controlled trials (RCTs) investigating a total of 12 different medications. The overall quality of studies was deemed to be poor, ie, fewer than half the study reported the method of randomization, and only 2 studies had more than 100 participants. A total of 5 studies compared treatment with adrenocorticotropic hormone (ACTH) to another medication. The review authors did not differentiate between synthetic and natural forms of ACTH. Two studies compared ACTH to vigabatrin (total sample sizes 9 and 42, respectively), 2 compared ACTH to prednisone (n=29 and 24, respectively), and 1 study with 52 participants compared ACTH to nitrazepam. A 6th study compared vigabatrin and ACTH in a subset of patients. Dosages and treatment regimens varied. The authors conducted several quantitative meta-analyses. A pooled analysis of 3 studies found that symptom resolution occurred in 30 of 45 patients (67%) responding to vigabatrin and 40 of 49 patients (82%) responding to ACTH. The difference between groups was statistically significant (odds ratio, 0.38; 95% confidence interval, 0.15 to 0.99). The authors noted that the limited evidence from RCTs suggests that hormonal treatment (prednisolone, tetracosactide depot and ACTH) resolves infantile spasms faster than vigabatrin and resolves the condition in more children, but long-term developmental and epilepsy outcomes are unknown.
Since the Cochrane review, in 2014, an RCT was published that assigned children with previously untreated infantile spasms to treatment with 40 to 60 IU synthetic ACTH every other day or 40 to 60 mg/day of oral prednisolone.(3) The study was conducted in Sri Lanka and uses a form of ACTH that is not Food and Drug Administration‒approved for this indication. The primary outcome, assessed in a blinded fashion after a 14-day treatment period, was change in a hypsarrhythmia severity scale (possible score range, 0-16). Hypsarrhythmia is an abnormal interictal pattern seen on an electroencephalogram and can be considered an intermediate outcome; clinical outcomes such as symptom resolution were not assessed. Ninety-two children were randomized, and follow-up data were available on 80 (82%) of them. Mean improvement in the hypsarrhythmia score was 7.95 (SD=2.76) in the prednisolone arm and 6.00 (SD=2.61) in the ACTH arm. The between-group difference was significantly different (p<0.01), favoring treatment with prednisolone. Rates of adverse effects were similar in the 2 groups. This study suggests that prednisolone may at least as effective as synthetic ACTH for treatment of infantile spams. However, the study has methodologic limitations including a dropout rate of over 20%, lack of intention-to-treat analysis, short-term follow-up only, and use of intermediate outcomes.
There is some evidence from small, generally poor quality RCTs, that natural and synthetic ACTH has greater short-term efficacy in resolving infantile spasms than vigabatrin. A 2014 RCT suggests that prednisolone may be at least as effective in the short term as synthetic ACTH in the treatment of infantile spasms.
The product label for H.P. Acthar gel lists a number of corticosteroid-responsive conditions as indications for repository corticotropin injection, including rheumatoid arthritis, dermatomyositis, symptomatic sarcoidosis, nephrotic syndrome, multiple sclerosis (MS) exacerbations and serum sickness. Evidence that Acthar gel (ie, ACTH) is a reasonable alternative to corticosteroid treatment requires controlled studies demonstrating superiority or noninferiority of ACTH to corticosteroids as first-line treatment, or controlled studies showing comparable efficacy of ACTH with fewer adverse effects. Alternatively, for patients unable to tolerate corticosteroids, the most appropriate study design would be a controlled study comparing ACTH to placebo.
The only controlled studies were found for the treatment of MS (ie, not for other indications). Several RCTs published in the 1960s and early 1970s compared ACTH to placebo for the treatment of acute exacerbations of MS. A study described in recent review articles as the most rigorous of these RCTs was published by Rose et al.(4,5) This was a multicenter, double-blind study that included 197 patients. Patients were randomized to receive intramuscular injections of ACTH gel or placebo during a 2-week hospitalization for acute exacerbations of MS. The study used Depo-ACTH and placebo, both prepared by the Upjohn Company. Review articles report that the study found that ACTH hastened improvement in symptoms but that the differences between the ACTH and placebo-treated patients was less marked as the dosage of ACTH was reduced during the second week of treatment.(6)
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 to IV corticosteroids. A study by Milanese et al with 30 patients found that dexamethasone was more effective than ACTH in shortening the length of the exacerbation.(7) Thompson et al published a study that included 61 patients and compared ACTH and high-dose IV methylprednisolone.(8) The authors did not find a statistically significant difference in the efficacy of the 2 treatments. The study was powered to detect a 1-point difference between the 2 groups on Kurtzke’s function and disability scales. The scores before and after treatment were not reported.
There are also a limited number of small case series reporting on use of ACTH for other corticosteroid-responsive conditions. For example, in 2011, Bomback et al published a retrospective case series in 21 patients with idiopathic, nondiabetic nephritic syndrome who were treated with ACTH gel. 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.(9) An additional 5 patients were identified who were treated for less than 6 months and were taken off therapy for lack of response; these patients were not included in the analysis. Four of the 21 (19%) patients were in complete remission, defined as stable or improved renal function with final proteinuria falling to less than 500 mg/day. An additional 7 of 21 (33%) patients had a partial remission (at least a 50% reduction in proteinuria and final proteinuria 500-3500 mg/day).
There is insufficient evidence that ACTH gel is at least as effective as IV corticosteroids for treatment of multiple sclerosis. One of 2 RCTs found that corticosteroids were more effective and the other found no significant difference in efficacy. There is a lack of evidence from controlled trials that ACTH is an effective treatment of other corticosteroid-responsive conditions.
Diagnostic testing of adrenocortical function
Diagnostic testing of adrenocortical function is typically done with synthetic ACTH. Studies have evaluated the value of synthetic ACTH for diagnosing adrenal insufficiency. For example, a 2008 meta-analysis identified 13 studies comparing low- and high-dose corticotropin tests for diagnosing adrenal insufficiency.(10) A comparable literature base was not identified for use of H.P. Acthar gel used in the diagnostic testing of adrenocortical function, and no studies were found that compared synthetic ACTH and Acthar gel for this purpose.
Repository corticotropin injection has also been proposed for several off-label non-steroid-responsive conditions including tobacco cessation, acute gout, and childhood epilepsy. Controlled studies were identified only for treatment of acute gout. In 2008, Janssens et al published a Cochrane review that examined the efficacy and safety of systemic corticosteroids in the treatment of acute gout in comparison with placebo, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, other active drugs, other therapies including repository corticotropin injection, or no therapy.(11) Three head-to-head trials were identified; 1 of these compared systemic corticosteroids to oral indomethacine and intramuscular ACTH. The quality of the 3 studies identified was graded as very low to moderate. None of the studies found clinically relevant differences between the studied systemic corticosteroids and the comparator drugs and important safety problems attributable to the used corticosteroids were not reported. The authors concluded that “There is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout.”
There is insufficient evidence from controlled trials that ACTH is a safe and effective treatment of non-corticosteroid-responsive treatments.
Ongoing and Unpublished Clinical Trials
The following RCTs were identified in a search of online Clinicaltrials.gov on October 22, 2014. Questor Pharmaceuticals is either the primary sponsor or a collaborator of all of these ongoing trials.
Safety and Efficacy Study of Acthar in Subjects With ARDS (cute Respiratory Distress Syndrome) (NCT02113735): The RCT will be recruiting adult patients with ARDS and will randomize them to treatment with 1 of 3 doses of Acthar gel or placebo. The primary outcome is the number of ventilator-free days at the 1-month follow-up. The study aims to enroll 210 patients and the estimated study completion date is March 2016.
Acthar for treatment of proteinuria in diabetic nephropathy patients (NCT01601236): This is a pilot study randomizing patients to 1 of 3 doses of Acthar gel or equivalent volumes of placebo for 36 weeks with a 4-week dose taper. The primary study outcome is percent change in estimated glomerular filtration rate (eGFR) at week 36. The total sample size will be approximately 40 patients and the estimated completion date is June 2014.
Acthar for treatment of proteinuria in membranous nephropathy patients (NCT01386554): The study includes patients with treatment-resistant idiopathic membranous nephropathy. Patients will be randomized to an active treatment or placebo group and will be treated for 24 weeks. The primary outcome is the proportion of patients who have a complete or partial remission in proteinuria at week 28. The total sample size will be approximately 60 patients and the estimated completion date is June 2014.
Acthar for the treatment of systemic lupus erythematosus (SLE) in patients with a history of persistently active disease (NCT01753401): This study includes patients with steroid-dependent, persistently active SLE with arthritic and/or cutaneous involvement. Patients will be randomized to an active treatment or a placebo group. The primary outcome is the proportion of patients who are considered responders at week 4. The total sample size will be approximately 36 patients and the estimated completion date is December 2014.
ACTH in progressive forms of multiple sclerosis (MS) (NCT01950234): The study will compare Acthar gel given to MS patients using a pulsed regimen (i.e. injections on 3 consecutive days per month) and placebo. The primary outcome is the proportion of patients with a 20% worsening in the timed 25-foot walk test (T25FW) at 36 months. The study will include approximately 100 patients and the estimated completion dates is December 2017.
A Phase IV trial of neuroprotection with ACTH in acute optic neuritis (NCT01838174): The study includes patients with a diagnosis of clinically unilateral acute demyelinating optic neuritis and clinical signs and symptoms within the previous 14 days. Patients will be randomized to receive 15 days of daily injections of Acthar gel or 3 days of intravenous steroid injection followed by 11 days of oral steroid taper. The primary outcome is the average retinal nerve fiber layer (RNFL) thickness at 6 months. The study will include approximately 60 patients and the estimated completion dates is April 2015.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received from 3 physician specialty societies and 1 academic medical center while this policy was under review for April 2010. In addition, unsolicited input was received from 1 foundation and 3 physicians. 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. There was strong support for use of repository corticotropin in treatment of infantile spasms (West syndrome).
Summary of Evidence
Repository corticotropin injection is a preparation of the natural form of adrenocorticotropic hormone (ACTH). It is intended to be used as an alternative to corticosteroids in steroid-responsive conditions.
For the treatment of infantile spasms, there is uncertainty about the efficacy of repository corticotropin injection compared with alternatives. However, this use has been accepted as standard of care treatment, and there is strong clinical support. Thus, this use may be considered medically necessary.
There is insufficient evidence from controlled studies that repository corticotropin injection is at least as safe and effective as corticosteroid treatment for treating other corticosteroid-responsive conditions, or is at least as safe and effective as synthetic ACTH for diagnostic testing of adrenocortical function. Because repository corticosteroid injection has not been found to be at least as beneficial as other approaches in
these situations, and because it is generally more costly than alternatives, it is considered not medically necessary for routine use. (See Benefit Application section for contractual items that may impact use in these situations.)
There is a lack of evidence that repository corticotropin injection is at least as safe and effective as synthetic ACTH for diagnostic testing of adrenocortical function and thus, this is considered not medically necessary. The evidence is insufficient to support the use of repository corticotropin injection in conditions not responsive to corticosteroid therapy, such as tobacco cessation, acute gout, childhood epilepsy, and thus these indications are considered investigational.
Practice Guidelines and Position Statements
In 2012, the American Academy of Neurology and the Practice Committee of the Child Neurology Society published an updated evidence-based guideline on treatment of infantile spasms. (12) The guideline included the following recommendations regarding use of ACTH:
- ACTH or vigabatrin may be useful for the short-term treatment of infantile spasms
- ACTH should be preferred over vigabatrin
- Hormonal therapy (ACTH or prednisolone) may be considered for treatment of infants with cryptogenic infantile spasms
In 2012, the American College of Rheumatology published guidelines on therapy and anti-inflammatory prophylaxis of acute gouty arthritis.(13) The guideline committee did not reach a consensus on 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.
In 2010, an industry-sponsored Infantile Spasms Working Group published a consensus report on 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 hyparrhythmic EEG in a randomized clinical trial setting (Mackay et al., 2004) and thus remain first-line treatment.”
US Preventive Services Task Force Recommendations
NO US Preventive Services Task Force recommendations on repository corticotropin injection have been identified.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- H.P. Actar Gel Product Label. http://www.acthar.com/pdf/Acthar-PI.pdf. Accessed November 10, 2014.
- Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2013;6:CD001770. PMID 3740534
- Wanigasinghe J, Arambepola C, Sri Ranganathan S, et al. The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial. Pediatr Neurol. Jul 2014;51(1):24-30. PMID 24938136
- 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
- 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
- Berkovich R. Treatment of acute relapses in multiple sclerosis. Neurotherapeutics. Jan 2013;10(1):97-105. PMID 23229226
- 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
- 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
- Bomback AS, Tumlin JA, Baranski J, et al. Treatment of nephrotic syndrome with adrenocorticotropic hormone (ACTH) gel. Drug Des Devel Ther. 2011;5:147-153. PMID 21448451
- 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
- Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. 2008(2):CD005521. PMID 18425920
- 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
- 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
- Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. Oct 2010;51(10):2175-2189. PMID 20608959
Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscluar
Infantile spasms, code range
|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|
Adrenocorticotropin hormone (ACTH)
HP Acthar Gel
|02/14/08||Add to Prescription Drug section||New policy|
|10/06/09||Replace policy||Policy updated with literature search January 2008 to August 2009;title “repository corticotrophin injection” replacing “ACTH gel”; acute gout and childhood epilepsy added as investigational conditions; other policy statements unchanged; reference numbers 7-11 added.|
|05/13/10||Replace policy||Policy updated with literature review, reference 12 added. Clinical input reviewed. Policy statements for use in diagnosis of adrenocortical function changed to not medically necessary.|
|5/12/11||Replace policy||Policy updated with literature review. Rationale extensively rewritten. References 1, 10 and 11 added; other references renumbered or removed. Policy statements unchanged.|
|12/12/13||Replace policy||Policy returned to active review. Literature search through October 29, 2013. Statement on corticosteroid-responsive conditions remains not medically necessary; caveats about this statement edited and moved to Policy Guidelines. References 2-7, 9, and 11 added; other references renumbered or removed.|
|12/11/14||Replace policy||Policy updated with literature review through November 10, 2014. No change to policy statement. Reference 3 added.|