BY JAMIE TALAN
In a single randomized trial of 97 infants with West syndrome — a disorder characterized by epileptic/infantile spasms, hypsarrhythmia, and intellectual disability — synthetic adrenocorticotropic hormone (ACTH) and prednisolone were found to be equally effective at controlling seizures at one year, a team of investigators at the University of Colombo in Sri Lanka reported in the August 14 online edition of Pediatric Neurology.
The findings come on the heels of a longstanding debate among pediatric neurologists about which therapy is most cost effective. The question, they say, is this: If the two drugs are similarly effective in controlling seizures, why use the much more expensive treatment?
"The whole issue of infantile spasms therapy is controversial," said E. Steven Roach, FAAN, chief of neurology at Nationwide Children's Hospital in Columbus, OH, and editor-in-chief of Pediatric Neurology, who was not involved with the study. "This is partly because of the shifting science and partly because Questcor bought the rights to ACTH and dramatically increased its price. We have traditionally recommended ACTH injections in the US, but it is extremely costly, and outside of the US people tend to use the cheaper prednisolone alternative. We are talking something on the order of $150,000 per treatment course [for ACTH] versus $200 [for prednisolone]."
"The Sri Lanka study is something we could not easily do here," Dr. Roach acknowledged. "It would be too expensive to purchase natural ACTH for a study."
But it was not always so expensive. The ACTH agent, Acthar, cost $40 a vial when it was first licensed by Questcor Pharmaceuticals in 2001, and over the years, the price hiked, in large part, according to the Federal Trade Commission (FTC), because the company bought the rights to competitive products, monopolizing the market, stifling competition, and keeping prices high.
In January, Mallinckrodt Pharmaceuticals, which acquired Questcor in 2014, agreed to pay $100 million to settle the lawsuit by the FTC and several state attorneys general, alleging that the company had violated antitrust laws in regard to Acthar. (For more on this story, see the sidebar, "The High Price of Acthar: The Back Story.")
Acthar, after several attempts by Questcor, was approved by the Food and Drug Administration (FDA) for infantile spasms in 2010.
STUDY METHODS, FINDINGS
Sri Lanka, where the trial was conducted, has limited access to ACTH, the study author Jithangi Wanigasinghe, MD, a pediatric neurologist at the University of Colombo told Neurology Today. Dr. Wanigasinghe said she assesses and treats two children a month with infantile spasms and has always treated them with prednisolone. But she wants to compare synthetic ACTH and prednisolone. The study was partly funded by the Sri Lanka Medical Association.
“We were not trying to find that one was superior to the other but whether they were similar in efficacy,” said Dr. Wanigasinghe.
The investigators randomized half of the 97 infants with untreated West syndrome to intramuscular long-acting synthetic ACTH (40 to 60 IU every other day) and half to 14 days of oral prednisolone (40 to 60 mg/day). Both groups received a subsequent three-week taper with prednisolone. The children were evaluated at three, six, and 12 months. Everyone completed the protocol but some were lost to follow-up. They examined 85 children at three months; 82 at six months, and 76 at one year.
The children were always evaluated by the same pediatric neurologist who was blinded to the treatment arm. A spasm-free period was determined by parental reports over the preceding week at each testing period, which the scientists said was a limitation of the study. They also did not have extensive electroencephalogram (EEG) data for every visit.
The investigators reported that 64.6 percent of those on prednisolone were seizure-free at three months compared to 39 percent of patients who had received ACTH (p=0.01). By six months and at one year, there was no statistical difference between the control of spasms in either treatment arm: 58.3 percent were seizure-free on prednisolone versus 44.9 percent for ACTH at six months (p=0.19) and 56.2 percent versus 40.8 percent with ACTH, respectively, at twelve months (p=0.13).
Also, the rate of relapse during the year was equivalent in both groups. Dr. Wanigasinghe said that there were 28 in the prednisolone group who went into remission by day 14 of the treatment and 18 in the ACTH group. The total number who relapsed at least one time during the 12-month follow up period was 14 (30 percent) – six from the prednisolone group and eight from ACTH group.
Children who relapsed were re-treated with the same hormonal therapy if it was two months after the first treatment ended. Other alternative oral anticonvulsants were used if the child relapsed earlier. Thirty percent of the children who had gone into remission by day 14 would go on to have at least one relapse by the one-year assessment.
There were eleven deaths during the 12 months follow up, all occurring after the completion of the initial treatment and related to other systemic diseases, Dr. Wanigasinghe said.
“Our clinical trial provided additional evidence that first-line high-dose oral prednisolone may be superior to ACTH for short-term spasm control,” she said.
The current follow-up data show that the long-term control of spasms is similar for the two treatments, with a statistically insignificant trend favoring prednisolone therapy,” the authors wrote in the paper. “Given the substantially higher cost of ACTH versus prednisolone, even similar efficacy between the two drugs would seemingly favor the use of prednisolone.”
In a phone interview, the investigator added that it is frustrating "that the field has not reached a consensus on the optimal therapy." Among the reasons, she contends, are that different types of ACTH have been used in the various studies. Clinicians outside of the United States use a synthetic version that contains 24 amino-acids in the ACTH peptide.
Synthetic ACTH is not approved by the US Food and Drug Administration (FDA) and is rarely used in the US. Mallinckrodt's H.P. Acthar Gel is the only natural ACTH substance available in the US. It contains the full 39 amino acid peptide.
The current study did not use the H.P. Acthar Gel, which is used in the US. Dr. Wanigasinghe noted that it is difficult to make sense of the conflicting results because of varying types, doses, and treatment durations of ACTH and the oral steroids. Most of the studies have had very small numbers of patients, she pointed out.
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