Autism, Autistic Disorder
Conditions
Keywords
Irritability, Risperidone, Antipsychotic agent, Autism, Adolescents, Children
Brief summary
The purpose of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) and safety and tolerability of the administration of 2 different fixed dose levels of risperidone (an atypical antipsychotic drug) compared with placebo in children or adolescents who have autism, and to evaluate the safety and tolerability of the drug for additional 26 weeks after the initial 6-week study period.
Detailed description
Autistic Disorder is a condition that develops early in childhood and persists throughout life. Seventy-five percent of children and adolescents with autistic disorder have irritability symptoms such as aggression towards others, deliberate self-injurious behavior, temper tantrums, and quickly changing moods. These symptoms affect their daily functioning such as school performance, interactions with family members and compliance to treatment. Risperidone is an atypical antipsychotic agent that has been recently approved for the treatment of irritability associated with Autistic Disorder in children and adolescents aged 5 to 16 years. The approved dose range is 0.5-3 mg per day. The aim of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) of a lower dose (0.125 mg or 0.175 mg risperidone per day depending on body weight). The study will include three treatment groups. A placebo group, a low dose risperidone group and a higher dose risperidone group (1.25 mg or 1.75mg per day depending on body weight). This phase of the study will be 6 weeks. During the study, neither investigators nor the patients will be told which treatment the patient received. This is called double blind. The placebo treatment is not expected to be effective. The higher dose group is expected to be effective. At the end of the study, data from the lower dose group will be compared to the placebo group to see if it is effective. Another aim of this study is to evaluate the safety and tolerability of risperidone. At the end of the 6-week double-blind period, patients may enter a 6-month open-label period during which all patients will receive risperidone. During this phase of the study, the doses can be adjusted to a maximum of 1.25 mg or 1.75mg per day depending on body weight. Both investigator and the patient will know what dose the patient is taking. About 93 patients will be randomized. The study will be conducted by investigators from about 15 clinics. Assessments of effectiveness include the Aberrant Behavior Checklist (ABC) subscales including the irritability subscale (ABC-I), the Clinical Global Impression of Change (CGI C); the Clinical Global Impression of Severity (CGI-S); the response rate, and the Compulsions Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY BOCS). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests, nighttime sleep quality and daytime drowsiness, and extrapyramidal symptoms (EPS) as assessed using the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS) and the Simpson-Angus Scale (SAS). Venous blood samples will be collected for the determination of plasma concentrations of risperidone and 9-hydroxyrisperidone. The study hypotheses are that the higher dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal) and that the lower dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal). Double-blind phase: Risperidone oral solutions taken once daily. Depending on body weight patients take 1.25 mL or 1.75 mL of either a 0.1 mg/mL or a 1.0 mg/mL risperidone solution or matching placebo, for 6 weeks. Open-label phase: Medication can be taken once or twice a day. Starting from 0.125mg or 0.175mg per day, drug levels are titrated over 2 weeks to a maximum dose level of 1.25 mg risperidone/day or 1.75 mg /day depending on body weight, for 26 weeks.
Interventions
DRUGPlacebo
Oral solution qd or bid for 6 weeks
DRUGRisperidone high dose
Risperidone oral solution 1.25 mg (if \<45 kg) or 1.75 mg (if \>=45 kg) qd or bid for 6 weeks
DRUGRisperidone low dose
Risperidone oral solution 0.125 mg (if \<45 kg) or 0.175 mg (if \>=45 kg) qd or bid for 6 weeks
Sponsors
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* DSM-IV diagnosis of Autistic Disorder (299.00) * ABC-I Subscale score of greater than or equal to 18 * CGI-S of greater than or equal to 4 * mental age \>18 months, body weight of at least 20 kg, seizure-free for at least 6 consecutive months and if on anticonvulsants must be on a dosage that has been stable for at least 4 weeks * Medication free for 1 week before the start of the study for all psychotropic drugs, except 4 weeks for fluoxetine and at least 8 weeks for injectable medications * Female patients must be premenarchal or sexually abstinent or, if heterosexually active, must practice an effective method of birth control.
Exclusion criteria
* History of prior or current DSM-IV psychotic disorder (e.g., schizophrenia, bipolar disorder, other psychosis), Pervasive Developmental Disorder not otherwise specified (PDD NOS), Asperger's, or Rett's * Any history of hypersensitivity to risperidone, or its excipients in formulation, or other known drug allergy * Patients who received risperidone within 3 months before screening (except p.r.n. use) * Patients who did not demonstrate sufficient clinical response to an adequate trial of risperidone treatment in the past (an adequate trial is defined as a period of at least 4 weeks at an adequate dose) * Neurologic disorder (e.g., Neuroleptic Malignant Syndrome, seizure disorders that are unstable, seizure activity within the past 6 months) * History of alcohol or substance dependence within 3 months of screening * Female subject who is pregnant (positive beta-HCG) or breast feeding * Patients with existing moderate or severe EPS or history of tardive dyskinesia * Patients who have received an experimental drug or used an experimental medical device within 3 months before the planned start of treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale | Baseline and 6 weeks | Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Global Impression Severity (CGI-S) | Baseline and 6 weeks | Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1=not ill, 2=very mild, 3=mild, 4=moderate, 5=marked, 6=severe, 7=extremely severe). |
| Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. | 6 weeks | Investigator impression of change over time from double-blind baseline on a 7-point scale (1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse). |
| Change in Fasting Glucose (mg/dL) at 6 Weeks | Baseline and 6 weeks | — |
| Number of Participants Who Had at Least 25% Improvement in ABC-I | 6 weeks | ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity). |
| Change in Fasting Glucose (mg/dL) at 6 Months | Baseline and 6 months | — |
| Change in Insulin Resistance (IR) at 6 Months | Baseline and 6 months | Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus. |
| Change in Insulin Resistance (IR) at 6 Weeks | Baseline and 6 weeks | Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Double-blind Period. Oral solution for 6 weeks. | 35 |
| Risperidone Low Dose Double-blind Period. Risperidone oral solution 0.125 mg (if \<45 kg) or 0.175 mg (if \>=45 kg) for 6 weeks. | 30 |
| Risperidone High Dose Double-blind Period. Risperidone oral solution 1.25 mg (if \<45 kg) or 1.75 mg (if \>=45 kg) for 6 weeks. | 31 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| DOUBLE BLIND | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| DOUBLE BLIND | Lack of Efficacy | 6 | 1 | 0 | 0 | 0 | 0 |
| DOUBLE BLIND | Lost to Follow-up | 0 | 1 | 1 | 0 | 0 | 0 |
| DOUBLE BLIND | OTHER | 0 | 2 | 1 | 0 | 0 | 0 |
| DOUBLE BLIND | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 |
| DOUBLE BLIND | Withdrawal by Subject | 1 | 1 | 3 | 0 | 0 | 0 |
| OPEN LABEL | Adverse Event | 0 | 0 | 0 | 4 | 0 | 1 |
| OPEN LABEL | Lack of Efficacy | 0 | 0 | 0 | 2 | 2 | 3 |
| OPEN LABEL | Lost to Follow-up | 0 | 0 | 0 | 2 | 1 | 1 |
| OPEN LABEL | OTHER | 0 | 0 | 0 | 0 | 0 | 2 |
| OPEN LABEL | Protocol Violation | 0 | 0 | 0 | 2 | 1 | 0 |
| OPEN LABEL | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Risperidone High Dose | Risperidone Low Dose | Placebo |
|---|---|---|---|---|
| Age Categorical <12 years | 74 participants | 24 participants | 20 participants | 30 participants |
| Age Categorical >=12 years | 22 participants | 7 participants | 10 participants | 5 participants |
| Age, Categorical <=18 years | 96 Participants | 31 Participants | 30 Participants | 35 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.3 years STANDARD_DEVIATION 3.07 | 9.3 years STANDARD_DEVIATION 3.11 | 10.2 years STANDARD_DEVIATION 3.42 | 8.6 years STANDARD_DEVIATION 2.57 |
| Region of Enrollment United States of America | 96 participants | 31 participants | 30 participants | 35 participants |
| Sex: Female, Male Female | 12 Participants | 3 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 84 Participants | 28 Participants | 25 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 35 | 12 / 30 | 27 / 31 | 39 / 79 |
| serious Total, serious adverse events | 1 / 35 | 0 / 30 | 0 / 31 | 1 / 79 |
Outcome results
Primary
Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale
Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity).
Time frame: Baseline and 6 weeks
Population: All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward \[LOCF\]).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale | -3.5 units on a scale | Standard Deviation 10.67 |
| Risperidone Low Dose | Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale | -7.4 units on a scale | Standard Deviation 8.12 |
| Risperidone High Dose | Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale | -12.4 units on a scale | Standard Deviation 6.52 |
Comparison: A step-down testing procedure was employed with the risperidone high dose versus placebo comparison tested first. If this comparison was significant the risperidone low dose versus placebo comparison would be performed.~A clinically relevant difference in the change from baseline on the ABC Irritability subscale was assumed to be 6 with a standard deviation of 8. To achieve 80% power with Type I error rate of 5%, 93 subjects were required.p-value: <0.00195% CI: [-12.19, -3.52]ANCOVA
p-value: 0.16495% CI: [-7.36, 1.27]ANCOVA
Secondary
Change in Clinical Global Impression Severity (CGI-S)
Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1=not ill, 2=very mild, 3=mild, 4=moderate, 5=marked, 6=severe, 7=extremely severe).
Time frame: Baseline and 6 weeks
Population: All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward \[LOCF\]).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Clinical Global Impression Severity (CGI-S) | -0.3 units on a scale | Standard Deviation 0.79 |
| Risperidone Low Dose | Change in Clinical Global Impression Severity (CGI-S) | -0.4 units on a scale | Standard Deviation 0.73 |
| Risperidone High Dose | Change in Clinical Global Impression Severity (CGI-S) | -1.0 units on a scale | Standard Deviation 0.78 |
p-value: <0.00195% CI: [-1.02, -0.33]ANCOVA
p-value: 0.76995% CI: [-0.39, 0.29]ANCOVA
Secondary
Change in Fasting Glucose (mg/dL) at 6 Months
Time frame: Baseline and 6 months
Population: All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Glucose (mg/dL) at 6 Months | 4.0 mg/dL | Standard Deviation 12.27 |
| Risperidone Low Dose | Change in Fasting Glucose (mg/dL) at 6 Months | 3.5 mg/dL | Standard Deviation 12.26 |
| Risperidone High Dose | Change in Fasting Glucose (mg/dL) at 6 Months | 2.3 mg/dL | Standard Deviation 8.7 |
Secondary
Change in Fasting Glucose (mg/dL) at 6 Weeks
Time frame: Baseline and 6 weeks
Population: All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline fasting laboratory samples. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward \[LOCF\]).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Glucose (mg/dL) at 6 Weeks | -0.4 mg/dL | Standard Deviation 8.2 |
| Risperidone Low Dose | Change in Fasting Glucose (mg/dL) at 6 Weeks | -0.1 mg/dL | Standard Deviation 8.81 |
| Risperidone High Dose | Change in Fasting Glucose (mg/dL) at 6 Weeks | -0.3 mg/dL | Standard Deviation 9.74 |
Secondary
Change in Insulin Resistance (IR) at 6 Months
Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.
Time frame: Baseline and 6 months
Population: All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Insulin Resistance (IR) at 6 Months | 0.09 units on a scale | Standard Deviation 2.67 |
| Risperidone Low Dose | Change in Insulin Resistance (IR) at 6 Months | 0.36 units on a scale | Standard Deviation 0.89 |
| Risperidone High Dose | Change in Insulin Resistance (IR) at 6 Months | 0.75 units on a scale | Standard Deviation 0.91 |
Secondary
Change in Insulin Resistance (IR) at 6 Weeks
Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.
Time frame: Baseline and 6 weeks
Population: All randomized subjects with \>=1 dose of study medication and fasting glucose and insulin at baseline and at \>=1 postbaseline time point. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period. Means are adjusted for baseline weight (\<45 kg, \>=45 kg) and baseline IR.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change in Insulin Resistance (IR) at 6 Weeks | 0.36 units on a scale |
| Risperidone Low Dose | Change in Insulin Resistance (IR) at 6 Weeks | -0.10 units on a scale |
| Risperidone High Dose | Change in Insulin Resistance (IR) at 6 Weeks | 0.45 units on a scale |
Secondary
Number of Participants Who Had at Least 25% Improvement in ABC-I
ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity).
Time frame: 6 weeks
Population: All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward \[LOCF\]).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Who Had at Least 25% Improvement in ABC-I | 14 participants |
| Risperidone Low Dose | Number of Participants Who Had at Least 25% Improvement in ABC-I | 15 participants |
| Risperidone High Dose | Number of Participants Who Had at Least 25% Improvement in ABC-I | 24 participants |
p-value: 0.004Cochran-Mantel-Haenszel
p-value: 0.817Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved.
Investigator impression of change over time from double-blind baseline on a 7-point scale (1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse).
Time frame: 6 weeks
Population: All randomized subjects with at least one dose of study medication and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward \[LOCF\]).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. | 5 participants |
| Risperidone Low Dose | Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. | 5 participants |
| Risperidone High Dose | Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. | 19 participants |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: 0.985Cochran-Mantel-Haenszel