A Double-Blind, Placebo-Controlled Trial of Secretin for the Treatment of Autistic Disorder

Thomas Owley, MD; Elisa Steele, MS; Christina Corsello, MA; Susan Risi, PhD; Kathryn McKaig, MS; Catherine Lord, PhD; Bennett L. Leventhal, MD; Edwin H. Cook Jr, MD

Disclosures
In This Article

Abstract and Introduction

Abstract

Objective: This study examines the efficacy of intravenous porcine secretin for the treatment of autism.
Methods: Using a randomized, double-blind, placebo-controlled crossover design, 20 subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Interview-Revised, the Autism Diagnostic Observation Schedule-Generic (ADOS-G), and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects.
Results: For the primary efficacy analysis, change of ADOS-G social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-1.0 ± 2.4) and secretin groups (-0.7 ± 1.4; t 0.34, df 18, P <.74). No significant differences were obtained for the other measures, including when all 20 subjects were compared by paired t-test from baseline to 4 weeks after secretin infusion.
Conclusion: There was no evidence for efficacy of secretin in this preliminary randomized controlled trial. These data were collected as part of a multicenter study with the University of California-Irvine and the University of Utah.

Introduction

Autism is a disorder characterized by impairments in reciprocal social interactions, verbal and nonverbal communication, and preoccupations with unusual activities or interests, particularly stereotyped or repetitive movements. This debilitating disorder is estimated to occur in 2-10/10,000 births. The prognosis of autistic disorder is frequently poor, with up to two thirds of autistic individuals not attaining independent social functioning.[1]

The deficits in social interaction include a failure to develop peer relationships appropriate for chronological age, marked impairment in the use of nonverbal behaviors such as gestures and eye-to-eye gaze, and a lack of spontaneous seeking to share enjoyment and interests with others. Among those individuals with autism who do express an interest in making friendships, the disorder continues to hamper their ability to understand many of the conventions of social interaction. The communication deficits manifest in both the semantic (understanding the meaning of words and phrases) and the pragmatic (the use of language in context) aspects of language. Language is usually significantly delayed, and up to 50% of autistic individuals remain without spoken language. Individuals with autistic disorder show restricted, repetitive, and stereotyped behaviors, interests, and activities. Their interests are often severely focused to the point of preoccupation. Changes in routines are often met with resistance and inflexibility. Often, there are stereotyped and repetitive motor mannerisms, especially hand flapping.[1]

The goals of treatment in autism are to reduce behavioral symptoms and to promote learning and development. Psychopharmacologically, there has been very little to offer the autistic individual with regard to the core social and communication symptoms described above. Early findings from open trials with medications such as naltrexone[2] and fenfluramine,[3] although promising, have subsequently not been confirmed in placebo-controlled trials.[4,5,6] Thus, the primary focus in clinical work has been on using medications to treat specific target symptoms such as hyperactivity and aggression.[7,8,9]

Because the core social and communication symptoms of the disorder have been so resistant to treatment, it was of great interest to those in the autistic community when a case series claimed that three patients had dramatic improvement in core symptoms after receiving the hormone secretin.[10] Secretin is an endogenous gastrointestinal polypeptide composed of 27 amino acids. It stimulates the secretion of digestive fluids from the pancreas, the production of pepsin from the stomach, and the production of bile from the liver. Physicians have primarily utilized porcine secretin in a provocation test to better characterize gastrointestinal complaints.[11] In the Horvath study, the effects of secretin in autistic disorder were discovered serendipitously following the administration of intravenous secretin (which was given as part of a diagnostic endoscopy test) in three autistic patients with gastrointestinal complaints, including persistent vomiting in one case. In that report, improvement was noted particularly in areas of eye contact, alertness, and language capacities.

The previous reports were uncontrolled case series.[10,12] In our current proposal, the effects of secretin were investigated in a double-blind, placebo-controlled, crossover design. Because of the debilitating nature of autistic disorder, the possibility of a relatively safe medication that might improve the core symptoms of the disorder deserved a thorough, controlled investigation. In addition, since the Horvath (1998) report, it is our understanding that hundreds, if not thousands, of children with autistic disorder have been exposed and continue to be exposed to this potential treatment under uncontrolled conditions. Therefore, an appropriately controlled assessment of the efficacy of secretin is very timely from a public health perspective.

The goal of the study was to evaluate the impact of secretin on the core symptoms of autism (social and communication deficits and stereotyped behaviors and interests). This protocol was designed to test the hypothesis that in 3- to 12-year-old children with autistic disorder, treatment with 2 clinical units per kilogram (CU/kg) of intravenous secretin would result in a significant change from baseline in core symptoms of autistic disorder relative to placebo.

Method

Subjects

Subjects were 20 children with autistic disorder, 3 to 12 years old (mean, 6.2 years; range, 3.4 to 9.2 years). The sample consisted of 14boys and six girls, including three black and 17 white children. All parents signed written informed consent for participation in the study. The study was approved by the Institutional Review Board.

The Autism Diagnostic Interview-Revised (ADI-R)[13] is a comprehensive, investigator-based interview that covers most developmental and behavioral aspects of autism. It was administered to the subject's primary caregiver. The Autism Diagnostic Observation Schedule-Generic (ADOS-G)[14,15] is a standardized observation of social and communicative behavior performed directly with the child over 20-40 minutes. It is organized in four overlapping modules according to the expressive language level of the subject. Both the ADI-R and the ADOS-G have a diagnostic algorithm keyed to DSM-IV criteria for the diagnosis of Autistic Disorder.

All subjects met criteria for autistic disorder by ADI-R and ADOS-G and had the diagnosis confirmed (using DSM-IV criteria[1]) by a child psychiatrist and child psychologist experienced in the diagnosis of autistic disorder. If any one of these diagnostic measures was not consistent with autistic disorder, the subject was excluded.

The Differential Abilities Scales (DAS)[16] was administered to all subjects at the first screening visit. If a nonverbal IQ of >35 was not established, the Mullen Scales of Early Learning[17] was administered to determine a ratio nonverbal IQ. If the Mullen Scales of Early Learning did not establish a nonverbal IQ >20, the subject was excluded. Subjects with a nonverbal IQ between 20 and 34 were also required to have overall age equivalents of 24 months or greater on the Vineland Adaptive Behavior Scales[18] in order to minimize the overinclusiveness of the diagnostic instruments for children at very low developmental levels.

Subjects were excluded if they were using any psychotropic medications with the exception of anticonvulsants and selective serotonin reuptake inhibitors (SSRIs). It was thought that improvement in communication or social development in the context of stable doses of anticonvulsants and SSRIs would not be difficult to interpret. No dosage changes in these medications were made in the 8 weeks before the baseline visit or at any point during the course of the 8-week study. Only one patient was taking medication during the study, and that dose was stable throughout the study (fluoxetine elixir, 40 mg per day). Patients were excluded if there was any history of allergy to porcine products.

All subjects lacked a significant medical history including nonfebrile seizures. A full physical and neurologic examination was performed on each subject. All subjects had blood drawn for laboratory tests (complete blood count and differential, metabolic panel, and thyroid function tests) at baseline and at week 4. Parents were asked to describe the emergence of any side effects throughout the study.

Assignment of Study Drug and Treatment Procedures

The study used a randomized, double-blind, placebo-controlled, crossover design with porcine secretin (Ferring Pharmaceuticals, Tarrytown, NY)(2 CU/kg) infused either at baseline (secretin-placebo group) or at the end of week 4 (placebo-secretin group). The placebo consisted of infused clear saline that was indistinguishable from drug.. Randomization was done by the Investigational Pharmacy at the University of Chicago. All patients, their parents, and all members of the assessment team were blind to drug assignments.

To reduce the risk of allergic reactions to secretin, an initial intravenous test dose of either one unit of secretin or saline in a fluid amount equal to one unit of secretin, was administered prior to infusion of the full dose. The subject was then observed for any signs of an acute hypersensitivity reaction (pruritis, urticaria, angioedema, respiratory distress, or hypotension). If no allergic reaction was noted after 1 minute, a secretin dose of 2 CU/ kg body weight (the same dose as in the Horvath (1998) study was injected slowly over 1 minute. The subject was then observed for 30 minutes for any evidence of allergic reaction before leaving.

Outcome Measures

Each patient took part in detailed assessment with the following instruments at baseline and at the end of weeks 4 and 8.

The ADOS-G,[14,15] is a standardized observation of social and communicative behavior performed directly with the child over 20-40 minutes. The Developmental Test of Visual Perception, Second Edition (DTVP-2)[19] was also administered to children 4 years of age or older or the fine motor (FM) scale of the Mullen Scales of Early learning was administered to determine a fine motor age equivalent estimate. The Peabody Picture Vocabulary Test (PPVT)[20](for children >5 years old) or the receptive language scale (RLS) of the Mullen Scales of Early Learning was also given to determine a receptive language age equivalent estimate.

The parents were interviewed about the child's development using the Vineland Adaptive Behavior Scales-Interview Edition at baseline and at the end of weeks 4 and 8.. Because of the possibility of a response at 2 weeks that would not be detected at 4 weeks after infusion, the parents completed the Gilliam Autism Rating Scale (GARS)[21] at baseline and at the end of weeks 2, 4, 6, and 8. The Aberrant Behavior Checklist, Community Version (ABC-C)[22] was also completed at baseline and at the end of weeks 2, 4, 6, and 8. It was specifically developed to assess the effects of medication and other treatment interventions in individuals with developmental disorders. It has been sensitive to drug effects in previous trials of autistic disorder.[23]

The Clinical Global Impression Scale[24] was completed at baseline and at the end of weeks 4 and 8.

Data Analysis

Twenty-one subjects were assessed for participation in the study. One subject was excluded for not reaching criteria on measures of nonverbal IQ. Each of the remaining 20 subjects completed the entire trial. One subject's parents did not complete the baseline GARS.

Baseline functioning was obtained from the initial testing at week 0. Independent t tests comparing the Secretin-Placebo and Placebo-Secretin groups for each measure revealed significant differences in baseline functioning for two ADOS-G measures.

The primary analysis was an independent t test of the difference in baseline and end-of-week 4 ADOS-G social communication total scores between the group infused with secretin at baseline and the group infused with placebo at baseline.

A repeated measures analysis of variance was performed to assess the effects of drug, order, and drug ´ order interactions for all subscales and total scores of all repeated measures (ADOS-G, ABC-C, GARS, Vineland, receptive language estimate, and fine motor estimate).

Data are reported as mean ± standard deviation, and results are considered significant when P <.05 (two-tailed).

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