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Medscape General Medicine
Original Article
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, Section of Child and Adolescent Psychiatry, Department of Psychiatry,
University of Chicago, Chicago, Ill.
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. [MedGenMed October 6,
1999. © 1999 Medscape, Inc.]
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.[4-6] Thus, the primary focus in clinical work has been on using
medications to treat specific target symptoms such as hyperactivity and aggression.[7-9]
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.
continued
ubjects 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). |
