Autism, Autism Spectrum Disorder (ASD)
Conditions
Keywords
autism, autism spectrum disorder, diet, gluten, casein, intervention, peptide, randomised, controlled, adaptive design, Autism Diagnostic Observation Schedule (ADOS), Gilliam Autism Rating Scale (GARS), Vineland Adaptive Behaviour Scale (VABS), Attention-Deficit Hyperactivity Disorder (ADHD)-IV Scale
Brief summary
A growing body of research indicates that dietary intervention excluding foods containing the proteins, gluten and casein, from the diet of children diagnosed with an autism spectrum disorder (ASD) may have a positive effect on behaviour and developmental outcome. In this single-blind, randomised-controlled, matched-pair adaptive trial, we introduced a gluten- and casein-free (GFCF) diet to a group of pre-pubescent children diagnosed with ASD concurrently with an abnormal urinary profile. Following random allocation to a diet or non- diet group, stage 1 of the study saw an intervention group follow the GFCF diet for eight months initially - progressing to 12 months if required. A non-diet control group continued with a normal diet. Assuming significant changes for the dietary group on the various outcome measures of behaviour and development, stage 2 of the study saw both groups assigned to GFCF dietary intervention for a further 12 months when outcome measures were again assessed at study end.
Detailed description
Eligibility criteria: diagnosis of autism, no co-morbid diagnosis of Fragile X syndrome, epilepsy or tuberous sclerosis, aged between 4-10y11m. Experimental hypothesis: children with an autism spectrum disorder (ASD) on a GFCF diet would show a significantly improved group developmental outcome in the medium- and long-term with regards to core autism and/or secondary symptoms. Main outcome measures: change in scores of dietary participants on one or more measures against predefined statistical thresholds as evidence of improvement, alongside changes to intra- and inter-group scores at study endpoint. Main outcome measures ascertained by: Autism Diagnostic Observation Schedule (ADOS), Gillam Autism Rating Scale (GARS), Vineland Adaptive Behaviour Scales (VABS), Attention Deficit Hyperactivity Disorder - IV (ADHD-IV) scales.
Interventions
Removal of foods containing gluten (cereal produce) and casein (dairy produce)
Sponsors
Norway: Bo Nils og Seim Family Settlement
The Robert Luff Foundation, United Kingdom
Eric Birger Christensen Fond, Denmark
Norsk Proteinintolerance, Norway
Center for Autisme, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Autism Spectrum Disorder (ASD) * Diagnosis received at Centre for Autism or a psychiatric clinic * Abnormal urinary peptide profile
Exclusion criteria
* Medical treatment * Epilepsy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | Baseline - 8 months - 12 months - 24 months | ADOS (Autism Diagnostic Observation Schedule): module 1 cutoff scores (communication+social): autism=12, autism spectrum (AS)=7; module 2 cutoffs: autism=12, AS=8; module 3 cutoffs: autism=10; AS=7. GARS (Gilliam Autism Rating Scale): \<80 low probability of autism, 81-90 below average, 91-110 average, \>110 above average probability of autism. VABS (Vineland Adaptive Behaviour Scale): \<69 (low ability), 70-84 (moderate/low), 85-115 (adequate), 116-130 (moderate/high), \>130 (high). ADHD-IV: 0=no problems indicated. \>11 attention & \>11 hyperactivity = ADHD diagnosis. |
Secondary
| Measure | Time frame |
|---|---|
| Changes to Appearance of Multiple Compounds in Urine Samples | Baseline - 8 months -12 months - 24 months |
Participant flow
Recruitment details
Recruitment via multiple associations
Pre-assignment details
92 participants were initially identified for possible study recruitment. 82 participants were available for possible study allocation; 10 participants dropped out prior to randomisation for various reasons, leaving 72 participants.
Participants by arm
| Arm | Count |
|---|---|
| Gluten- and Casein-free Dietary Intervention Stage 1: Gluten- and casein-free dietary intervention for first 8 or 12 months. 8 or 12 months: Interim analysis based on surpassing statistical thresholds. If showed group significant improvement progressed to stage 2 (continued on a gluten- and casein-free diet for a further 12 months). | 38 |
| No Gluten- and Casein-free Dietary Intervention Stage 1: No special dietary intervention for first 8 or 12 months. 8 or 12 months: Interim analysis based on surpassing statistical thresholds. If dietary intervention group showed group significant improvement progressed to stage 2 (introduction of a gluten- and casein-free diet for 12 months). | 34 |
| Total | 72 |
Baseline characteristics
| Characteristic | No Gluten- and Casein-free Dietary Intervention | Gluten- and Casein-free Dietary Intervention | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 34 Participants | 38 Participants | 72 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 8.13 years STANDARD_DEVIATION 2.03 | 8.22 years STANDARD_DEVIATION 1.99 | 8.15 years STANDARD_DEVIATION 2 |
| Region of Enrollment Denmark | 34 participants | 38 participants | 72 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 31 Participants | 33 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 38 | 0 / 34 |
| serious Total, serious adverse events | 0 / 38 | 0 / 34 |
Outcome results
Primary
Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement.
ADOS (Autism Diagnostic Observation Schedule): module 1 cutoff scores (communication+social): autism=12, autism spectrum (AS)=7; module 2 cutoffs: autism=12, AS=8; module 3 cutoffs: autism=10; AS=7. GARS (Gilliam Autism Rating Scale): \<80 low probability of autism, 81-90 below average, 91-110 average, \>110 above average probability of autism. VABS (Vineland Adaptive Behaviour Scale): \<69 (low ability), 70-84 (moderate/low), 85-115 (adequate), 116-130 (moderate/high), \>130 (high). ADHD-IV: 0=no problems indicated. \>11 attention & \>11 hyperactivity = ADHD diagnosis.
Time frame: Baseline - 8 months - 12 months - 24 months
Population: Per protocol analysis. Analysis was conducted on n=26 (Gluten- and casein-free dietary intervention) and n=29 (No gluten- and casein-free dietary intervention) at 12 months. Analysis was conducted on n=18 and n=17 at 24 months (both on gluten- and casein-free dietary intervention).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (8 months) | 0.23077 Units on a scale | Standard Error 1.35227 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (24 months) | -1.88235 Units on a scale | Standard Error 0.57447 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (12 months) | 0.92308 Units on a scale | Standard Error 2.71629 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Communication (24 months) | -0.16176 Units on a scale | Standard Error 0.1204 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (24 months) | 1.27778 Units on a scale | Standard Error 3.61895 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (8 months) | -1.23077 Units on a scale | Standard Error 0.38554 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (8 months) | 1.53846 Units on a scale | Standard Error 2.03676 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Reptitive behaviours (24 months) | -0.14216 Units on a scale | Standard Error 0.0782 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (12 months) | -4.15385 Units on a scale | Standard Error 2.39467 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (12 months) | -1.47826 Units on a scale | Standard Error 0.37125 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (24 months) | 0.72222 Units on a scale | Standard Error 3.17033 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Social (24 months) | -0.5042 Units on a scale | Standard Error 0.09795 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (8 months) | 3.03846 Units on a scale | Standard Error 2.54043 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (24 months) | -2 Units on a scale | Standard Error 0.42875 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (12 months) | 3.46154 Units on a scale | Standard Error 2.79903 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (8 months) | -1.07692 Units on a scale | Standard Error 0.29382 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (24 months) | -0.16667 Units on a scale | Standard Error 2.94974 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (8 months) | -0.96154 Units on a scale | Standard Error 0.32572 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (8 months) | -2.15385 Units on a scale | Standard Error 0.916 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Social (8 months) | 0.016807 Units on a scale | Standard Error 0.1024 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (12 months) | -2.19231 Units on a scale | Standard Error 0.88582 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (12 months) | -1.46154 Units on a scale | Standard Error 0.33389 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (24 months) | -2.29412 Units on a scale | Standard Error 0.89016 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (12 months) | -1.57692 Units on a scale | Standard Error 0.3097 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Hyperactivity (8 months) | -2.03846 Units on a scale | Standard Error 0.80667 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (24 months) | -0.88235 Units on a scale | Standard Error 0.44459 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Hyperactivity (12 months) | -1.69231 Units on a scale | Standard Error 0.86606 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Repetitive behaviours (8 months) | -0.14706 Units on a scale | Standard Error 0.0894 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV Hyperactivity (24 months) | -2.58824 Units on a scale | Standard Error 1.12805 |
| Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Communication (8 months) | -0.16715 Units on a scale | Standard Error 0.10127 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV Hyperactivity (24 months) | -4.17647 Units on a scale | Standard Error 1.22845 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Communication (8 months) | 0.08235 Units on a scale | Standard Error 0.12096 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Communication (24 months) | 0.18529 Units on a scale | Standard Error 0.11926 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Social (8 months) | 0.02521 Units on a scale | Standard Error 0.12203 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Social (24 months) | 0.02521 Units on a scale | Standard Error 0.13709 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Repetitive behaviours (8 months) | 0.03431 Units on a scale | Standard Error 0.1139 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADOS - Reptitive behaviours (24 months) | -0.0049 Units on a scale | Standard Error 0.10042 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (8 months) | -0.06897 Units on a scale | Standard Error 0.27152 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (12 months) | -0.42308 Units on a scale | Standard Error 0.36867 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Social (24 months) | -1.11765 Units on a scale | Standard Error 0.50645 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (8 months) | -0.51724 Units on a scale | Standard Error 0.40203 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (12 months) | -1.46154 Units on a scale | Standard Error 0.40089 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Communication (24 months) | -1.29412 Units on a scale | Standard Error 0.60491 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (8 months) | -0.7931 Units on a scale | Standard Error 0.41338 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (12 months) | -1.3333 Units on a scale | Standard Error 0.39943 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | GARS - Stereotyped behaviours (24 months) | -1.70588 Units on a scale | Standard Error 0.52696 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (8 months) | 1.25 Units on a scale | Standard Error 1.73176 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (12 months) | 1.85714 Units on a scale | Standard Error 2.05204 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Communication (24 months) | -2.05882 Units on a scale | Standard Error 3.19175 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (8 months) | 0.92857 Units on a scale | Standard Error 2.63369 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (12 months) | -3.25 Units on a scale | Standard Error 2.59406 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Social (24 months) | -3.29412 Units on a scale | Standard Error 4.29412 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (8 months) | -1.64286 Units on a scale | Standard Error 2.90785 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (12 months) | -2.85714 Units on a scale | Standard Error 2.8857 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | VABS - Daily Living (24 months) | -4.64706 Units on a scale | Standard Error 4.46715 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (8 months) | 0.31034 Units on a scale | Standard Error 0.65296 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (12 months) | -0.03704 Units on a scale | Standard Error 0.69488 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Inattention (24 months) | -3.35294 Units on a scale | Standard Error 1.14706 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Hyperactivity (8 months) | -0.17241 Units on a scale | Standard Error 0.60186 |
| No Gluten- and Casein-free Dietary Intervention | Change in Diet Groups Scores on One of Several Measures Used Against Pre-defined Statistical Thresholds as Evidence of Improvement. | ADHD-IV - Hyperactivity (12 months) | -0.92593 Units on a scale | Standard Error 0.55451 |
Comparison: 1st stage analysis (baseline-8m or 12m) used a repeated measures model for all assessment measures. Model included baseline, age, time and time\*treatment interaction. Results informed 2nd stage (8 or 12 months - 20 or 24 months). 2nd stage analysis based on various statistical scenarios (baseline vs 12 months on intervention, 12 months of no intervention vs 12 on intervention, baseline vs 24 months on intervention). No ADOS assessments were used at 12 months because of risk of practice effects.p-value: <0.01Mixed Models Analysis
Secondary
Changes to Appearance of Multiple Compounds in Urine Samples
Time frame: Baseline - 8 months -12 months - 24 months