Autism Spectrum Disorders
Conditions
Keywords
mitochondria, purinergic signaling, cell danger response
Brief summary
This study is designed to test the safety and efficacy of a single, intravenous dose of suramin in autism spectrum disorders (ASD).
Detailed description
This study is designed to test a new theory of the origin and treatment of ASD. In this theory, ASD is caused by both genes and environment interacting to produce a persistent cell danger response (CDR; Naviaux RK, 2014) that interferes with and alters normal child brain development. Gut microbiome and immune systems are also affected. In this theory, the pathological persistence of the cell danger response is traceable to mitochondria, and maintained by purinergic signaling mediated by the release of extracellular nucleotides like adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate (UTP), and uridine diphosphate (UDP). Suramin inhibits excess purinergic signaling by acting as a competitive inhibitor of nucleotide signaling at both ionotropic purinergic (P2X) receptors, and G-protein coupled, metabotropic purinergic (P2Y) receptors. Suramin has been found to correct the symptoms, metabolism, and brain synaptic abnormalities in two classical genetic and environmental mouse models of autism (Naviaux JC, et al. 2015; Naviaux JC, et al. 2014; Naviaux RK, et al. 2013). This study will test the safety and efficacy of a single dose of suramin in children with ASD. While it is not anticipated that a single dose will produce benefits for more than a few weeks, if successful, this study may lead to the development of newer and safer drugs for autism treatment.
Interventions
DRUGSuramin
20 mg/kg IV in 50 ml saline over 30 minutes
DRUGSaline
50 ml IV over 30 minutes
Sponsors
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
4 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Autism diagnostic observation schedule (ADOS) score of ≥ 7 * Diagnosis of autism spectrum disorder by Diagnostic and Statistical Manual, 5th edition (DSM-V) * Stable treatment and diet regimen for ≥ 2 months * Resident of San Diego region
Exclusion criteria
* Any prescription medications * Hospitalization within the previous 2 months * Active medical problem such as seizures, heart, liver, kidney, or adrenal disease * Planning to start a new drug, diet, or behavioral intervention during the study * Weight under the 5th percentile for age * Unable to tolerate venipuncture, urine collection, or an indwelling intravenous catheter for 3-4 hours * Plasma creatinine ≥ 1.4 mg/dl * Liver function alanine amino transferase (ALT) or aspartate amino transferase (AST) ≥ 1.5-fold above the upper limit of normal * Known intolerance to suramin or other antipurinergic drugs * Unable to perform or cooperate with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Autism Diagnostic Observation Schedule, 2nd Edition (ADOS2) | 6 weeks compared to baseline | ADOS2 comparison scores are units on a scale of 0-10. A score of 7-10 was required for enrollment. A score of 7-10 is diagnostic for autism spectrum disorder (ASD). The higher the score, the more severe the core symptoms of autism spectrum disorder. Scores of 6 and below are considered off the ASD spectrum. |
| Expressive Language | 6 weeks compared to baseline | Expressive One Word Picture Vocabulary Test (EOWPVT) scores are normalized for age. Typical language development produces a mean score of 100 with a standard deviation of 15. Outcomes for EOWPVT were expressed as the mean of the child-specific difference before and 6-weeks after treatment. For example, if the 6-week standard EOWPVT score was 59.6 and the baseline score was 63.8, the difference is -4.2 (= 59.6 - 63.8). A decrease in score at 6 weeks would corresponds to a decrease in language performance, while an increase, a positive difference, would reflect an increase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aberrant Behavior Checklist (ABC) | 6 weeks compared to baseline | The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. Stereotypy is reported, and scores range from 0 to 21, with higher scores indicating worse behavior. A negative difference corresponds to decreased symptoms after treatment. A positive difference corresponds to increased symptoms after treatment. |
| Autism Treatment Evaluation Checklist (ATEC) | 6 weeks | The reported value is the Language sub-score of the ATEC, and the range for the language sub-score is 0-20. The higher the score, the worse the disability. Outcomes were measured at 6 weeks after treatment compared to baseline. A negative difference corresponds to a decrease in language disability, i.e an improvement in speech and language. A positive difference reflects an increase in language disability, i.e. a decrease in speech and language. |
| The Clinical Global Impression - Improvement Scale (CGI-I) | Overall ASD symptoms at 6 weeks | The CGI-I is scale that ranges from 1-7, reflecting the change in core autism behaviors after treatment. 1 is much improved, 4 is unchanged, and 7 is much worse. |
| Repetitive Behavior Questionnaire | 6 weeks compared to baseline | Total repetitive behavior was assessed using the Repetitive behavior questionnaire (RBQ), which has a scale from 0-87. Higher scores correspond to more severe repetitive behavior. Outcomes were analyzed as the difference in the score 6 weeks after treatment compared to baseline. A negative difference corresponds to improved behavior compared to baseline. A positive difference corresponds to worse behavior. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Suramin 20 mg/kg IV x 1 | 5 |
| Saline (Placebo) IV infusion x 1 | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Suramin | Saline (Placebo) | Total |
|---|---|---|---|
| Age, Continuous | 8.9 years STANDARD_DEVIATION 3.3 | 9.2 years STANDARD_DEVIATION 3.8 | 9.1 years STANDARD_DEVIATION 3.3 |
| Autism Diagnostic Observation Schedule, 2nd edition (ADOS2) | 8.6 units on a scale STANDARD_DEVIATION 0.9 | 9.4 units on a scale STANDARD_DEVIATION 1.3 | 9.0 units on a scale STANDARD_DEVIATION 1.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 5 / 5 | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Autism Diagnostic Observation Schedule, 2nd Edition (ADOS2)
ADOS2 comparison scores are units on a scale of 0-10. A score of 7-10 was required for enrollment. A score of 7-10 is diagnostic for autism spectrum disorder (ASD). The higher the score, the more severe the core symptoms of autism spectrum disorder. Scores of 6 and below are considered off the ASD spectrum.
Time frame: 6 weeks compared to baseline
Population: Patients receiving either suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | Autism Diagnostic Observation Schedule, 2nd Edition (ADOS2) | -1.6 units on a scale | Standard Deviation 0.55 |
| Saline (Placebo) | Autism Diagnostic Observation Schedule, 2nd Edition (ADOS2) | -0.4 units on a scale | Standard Deviation 0.55 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.002895% CI: [-2.3, -0.9]t-test, 2 sided
Primary
Expressive Language
Expressive One Word Picture Vocabulary Test (EOWPVT) scores are normalized for age. Typical language development produces a mean score of 100 with a standard deviation of 15. Outcomes for EOWPVT were expressed as the mean of the child-specific difference before and 6-weeks after treatment. For example, if the 6-week standard EOWPVT score was 59.6 and the baseline score was 63.8, the difference is -4.2 (= 59.6 - 63.8). A decrease in score at 6 weeks would corresponds to a decrease in language performance, while an increase, a positive difference, would reflect an increase.
Time frame: 6 weeks compared to baseline
Population: Subjects receiving either suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | Expressive Language | -4.2 units on a scale | Standard Deviation 8.3 |
| Saline (Placebo) | Expressive Language | 2.0 units on a scale | Standard Deviation 4.6 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.3295% CI: [-14.5, 6.1]t-test, 2 sided
Secondary
Aberrant Behavior Checklist (ABC)
The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. Stereotypy is reported, and scores range from 0 to 21, with higher scores indicating worse behavior. A negative difference corresponds to decreased symptoms after treatment. A positive difference corresponds to increased symptoms after treatment.
Time frame: 6 weeks compared to baseline
Population: Subjects receiving either suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | Aberrant Behavior Checklist (ABC) | -4.0 units on a scale | Standard Deviation 2.3 |
| Saline (Placebo) | Aberrant Behavior Checklist (ABC) | 1.0 units on a scale | Standard Deviation 4.3 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.01995% CI: [-6.9, -1.1]t-test, 2 sided
Secondary
Autism Treatment Evaluation Checklist (ATEC)
The reported value is the Language sub-score of the ATEC, and the range for the language sub-score is 0-20. The higher the score, the worse the disability. Outcomes were measured at 6 weeks after treatment compared to baseline. A negative difference corresponds to a decrease in language disability, i.e an improvement in speech and language. A positive difference reflects an increase in language disability, i.e. a decrease in speech and language.
Time frame: 6 weeks
Population: Subjects receiving either suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | Autism Treatment Evaluation Checklist (ATEC) | -2.0 units on a scale | Standard Deviation 1.4 |
| Saline (Placebo) | Autism Treatment Evaluation Checklist (ATEC) | -0.2 units on a scale | Standard Deviation 2.9 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.03495% CI: [-2.7, -0.49]t-test, 2 sided
Secondary
Repetitive Behavior Questionnaire
Total repetitive behavior was assessed using the Repetitive behavior questionnaire (RBQ), which has a scale from 0-87. Higher scores correspond to more severe repetitive behavior. Outcomes were analyzed as the difference in the score 6 weeks after treatment compared to baseline. A negative difference corresponds to improved behavior compared to baseline. A positive difference corresponds to worse behavior.
Time frame: 6 weeks compared to baseline
Population: Subjects receiving suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | Repetitive Behavior Questionnaire | -3.2 units on a scale | Standard Deviation 5.8 |
| Saline (Placebo) | Repetitive Behavior Questionnaire | -0.8 units on a scale | Standard Deviation 3.3 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.2895% CI: [-10.4, 4]t-test, 2 sided
Secondary
The Clinical Global Impression - Improvement Scale (CGI-I)
The CGI-I is scale that ranges from 1-7, reflecting the change in core autism behaviors after treatment. 1 is much improved, 4 is unchanged, and 7 is much worse.
Time frame: Overall ASD symptoms at 6 weeks
Population: Subjects receiving either suramin or saline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suramin | The Clinical Global Impression - Improvement Scale (CGI-I) | -1.8 units on a scale | Standard Deviation 1.04 |
| Saline (Placebo) | The Clinical Global Impression - Improvement Scale (CGI-I) | 0.0 units on a scale | Standard Deviation 0.34 |
Comparison: In this analysis, each child was used as their own control to examine before and after suramin treatment effects in a paired t-test design. This study was a small pilot study of safety and activity of suramin. The small subject numbers of just 5 per group make it impossible to draw any strong conclusions about efficacy. Future studies are required.p-value: 0.0595% CI: [-3.4, -0.15]ANOVA