Clinical trial NCT06623227: Effect of Increasing Total Antioxidant Capacity in Autism Spectrum Disorder
Official title: Randomized, Placebo-controlled, Double-blind Study of Increasing Total Antioxidant Capacity with Vitamin E and C in Two Cohorts of Patients with Autism Spectrum Disorders
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Autism Spectrum Disorder
Keywords: Total antioxidant capacity
Autism
Clinical symptoms
Aberrant behavior
Quality of life
Vitamin E
Vitamin C
Lead sponsor: Hasanuddin University
Sponsor class: OTHER
Collaborators: name: University of Modena and Reggio Emilia
name: Indonesia University
name: RSUP Dr. Wahidin Sudirohusodo
First posted: 2024-10-02
Enrollment: 50
Sex: ALL
Minimum age (years): 3
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Each patients treated with Risperidone and Behavior Therapy as maintanence therapy will divided into a controled group which receive plasebo and the other as intervention group which received Vitamin E (150-200 IU/d) and C (100-200 mg/d) for 3 months. Patients are assessed at T0, T6 and T12 wk. Administration of active compound and placebo is in double-blind.
Primary purpose: TREATMENT

Brief summary: This double-blind, randomized, controlled trial (RCT) has the aim to evaluating the effectiveness of increasing Total Antioxidant Capacity (TAC) as add-on intervention in two cohorts of patients with Autism Spectrum Disorder (ASD) who have received Risperidone (0.02-0.06 mg/KgBW) and Behavior Therapy as maintenance therapy. Both groups will receive placebo pill or Vitamin E and C pill using randomization. Clinical Symptoms, Aberrant Behavior and Quality of Life in Children with ASD will be assessed after 12 weeks of treatment in this study. Primary outcome measures of efficacy is Aberrant Behavior Checklist- Irritability (ABC-Irritability) and Secondary outcome measures include Childhood Autism Rating Scale (CARS), Clinical Global Impression Scale - Improvement (CGI-I), The PedsQL and The WHOQOL BREF.

Detailed description: The continuation of ASD throughout life makes all efforts to optimize the abilities of children with ASD as early as possible so that their quality of life becomes better important. Management to improve current symptoms and overcome aberrant behavior in children with ASD generally focuses on behavioral intervention, psychotherapy and even pharmacotherapy, but the results are not satisfactory because it takes time, is expensive and unexpected side effects often occur after administering pharmacotherapy. On the other hand, research related to the role of oxidative stress has suggested a potential relationship between oxidative stress and autism pathophysiology that is not correlated with age and the underlying pathogenesis, but damage caused by oxidative stress will exacerbate dysfunction in children with ASD through chronic inflammatory responses, DNA and protein damage and mitochondrial superoxide production. Oxidative stress will influence the clinical symptoms and pathogenesis of ASD. Therefore, efforts to control the balance of oxidative stress to improve symptoms and neuropsychological deficits in patients with ASD are important. Lack of antioxidant capacity in children with ASD to neutralize and remove oxidants has been associated with the severity of clinical symptoms and aberrant behavior in children with ASD. Therefore, efforts to increase antioxidant capacity through providing antioxidants can offer a new strategy for dealing with accompanying symptoms in children with ASD.

Vitamin E and Vitamin C are non-enzymatic antioxidants which function to strengthen the work of enzymatic antioxidants in the oxidant-elimination, oxidation-reduction cycle process that occurs in the brain. Its includes in group of antioxidants which also referred as chain breaking. When used together with vitamin C which can function as a water-soluble antioxidant and other enzyme cofactors, reduced vitamin C can directly regenerate vitamin E which simultaneously undergoes oxidation to become ascorbate. Therefore, the use of vitamin C will be more effective when used together with vitamin E. Research has shown that administration with antioxidants such as vitamin E and vitamin C has a good effect on clinical symptoms and behavior in children with ASD.

In this randomized controlled trial (RCT), patients with Autism Spectrum Disorder (ASD) who have received Risperidone and Behavior Therapy as maintenance therapy will be randomly assigned to receive either a placebo or a combination of Vitamins E (150-200 IU per day) and C (100-200 mg per day) for a duration of 3 months. This study was designed to verify whether increasing the TAC using Vitamin E and C improves clinical symptoms, aberrant behaviors, and quality of life in children with ASD.

This study shall include 50 patients with ASD, aged 3-9 years old. The study design of this RCT was balanced to all of patients treated with maintenance therapy as usual, so that half of the patients will receive placebo, and the remaining half will receive Vitamin E and C during 3 months. The purpose is to observe whether the increase of TAC could improve the clinical symptoms, aberrant behavior and quality of life in ASD patients. In addition to clinical and psychometric parameters, TAC will be measured at baseline, after 6 weeks and 12 weeks, by collecting 30-60 ml of fresh urine, a general urinalysis examination to rule out acute urinary tract infections, The TAC examination is carried out when the urine pH is normal and measurement with a calorimetric kit with enzyme method, ABTS.

Eligibility criteria: Inclusion Criteria:

1. Both parents or a legally authorized patient representative (LAR) must provide written informed consent. The parents and guardian must be able to understand and comply with the experimental protocol with a minimum of junior high school education.
2. Parents earn no less than IDR 3,434,298 (South Sulawesi Province Minimum Wage for 2024).
3. Subjects of both sexes, aged between 3-9 years old, may be included in the study.
4. The subject must meet DSM-5 criteria for a primary diagnosis of Autism.
5. Patients treated with Risperidone (0.02-0.06 mg/KgBW) are enrolled only if the treatment and dosage of these drugs has been constant for at least 2 months prior to enrollment in the trial and is kept constant throughout the 3-month duration of the trial.
6. Patients undergoing any kind of behavioral intervention must have must have underwent the intervention at least 2 sessions prior to enrollment and the intervention must remain unchanged throughout the 3-month duration of the trial.
7. Baseline Clinical Global Impression - Severity (CGI-S) score below 7.
8. The patient is able to swallow the capsule or his/her parents are available to open it and administer immediately its content in a small quantity of juice or soft-drink.

Exclusion Criteria:

1. Patients with organic disease and/or congenital malformation including known genetic syndromes for example, Rett syndrome, fragile-X syndrome, and Down Syndrome etc.).
2. Patients with autism secondary to epileptic encephalopathy or with idiopathic autism co-morbid with seizures more frequent than one episode every 6 months despite ongoing anti epileptic drug therapy.
3. Patients treated with anticoagulants.
4. Patients with serious medical illnesses (chronic renal disease, severe liver disease, cardiovascular disorders, malignant tumors, HIV infection).
5. Patients with a history of acute cerebrovascular episodes.
6. Patients with a history of stomach bleeding or active peptic ulcer.
7. Patients with documented allergy, hypersensitivity or intolerance to one of the excipients of the experimental or comparative product.
8. Patients have been consuming other antioxidants.
9. Patients with active urinary tract infections.
10. Patients with poor compliance and or no control back to the Hospital.

Trial interruption criteria:

1. Patients whose medical conditions require starting treatment with anticoagulants.
2. Patients with severe medical conditions starting during the 3-month duration of the trial.
3. Patients who undergo a change in psychopharmacological or behavioral treatment during the 3-month duration of the trial.

Primary outcomes:
measure: Aberrant Behavior Checklist - Irritability (ABC-I)
timeFrame: At 0, 6 and 12 weeks duration of trial
Secondary outcomes:
measure: Childhood Autism Rating Scale (CARS)
timeFrame: At 0, 6 and 12 weeks duration of trial
measure: Clinical Global Impression Scale- Improvement (CGI-I)
timeFrame: At 0, 6 and 12 weeks duration of trial
measure: The Pediatric Quality of Life TM (The PedsQL)
timeFrame: At 0, 6 and 12 weeks duration of trial
measure: WHOQOL-BREF
timeFrame: At 0, 6 and 12 weeks duration of trial
Other outcomes:
Locations:
city: Makassar
country: Indonesia
facility: Doctoral Programme at Hasanuddin University
state: South Sulawesi
Study officials:
affiliation: Hasanuddin University
name: Rinvil Renaldi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Persico AM, Arango C, Buitelaar JK, Correll CU, Glennon JC, Hoekstra PJ, Moreno C, Vitiello B, Vorstman J, Zuddas A; European Child and Adolescent Clinical Psychopharmacology Network. Unmet needs in paediatric psychopharmacology: Present scenario and future perspectives. Eur Neuropsychopharmacol. 2015 Oct;25(10):1513-31. doi: 10.1016/j.euroneuro.2015.06.009. Epub 2015 Jun 20.
citation: Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr. 2011 Dec 12;11:111. doi: 10.1186/1471-2431-11-111.
citation: Zambrelli E, Lividini A, Spadavecchia S, Turner K, Canevini MP. Effects of Supplementation With Antioxidant Agents on Sleep in Autism Spectrum Disorder: A Review. Front Psychiatry. 2021 Jun 28;12:689277. doi: 10.3389/fpsyt.2021.689277. eCollection 2021.
citation: Wang L, Wang B, Wu C, Wang J, Sun M. Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy. Int J Mol Sci. 2023 Jan 17;24(3):1819. doi: 10.3390/ijms24031819.
citation: Vargason T, Kruger U, Roth E, Delhey LM, Tippett M, Rose S, Bennuri SC, Slattery JC, Melnyk S, James SJ, Frye RE, Hahn J. Comparison of Three Clinical Trial Treatments for Autism Spectrum Disorder Through Multivariate Analysis of Changes in Metabolic Profiles and Adaptive Behavior. Front Cell Neurosci. 2018 Dec 19;12:503. doi: 10.3389/fncel.2018.00503. eCollection 2018.
citation: Traber MG. Vitamin E: necessary nutrient for neural development and cognitive function. Proc Nutr Soc. 2021 Aug;80(3):319-326. doi: 10.1017/S0029665121000914. Epub 2021 Apr 26.
citation: Teleanu DM, Niculescu AG, Lungu II, Radu CI, Vladacenco O, Roza E, Costachescu B, Grumezescu AM, Teleanu RI. An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int J Mol Sci. 2022 May 25;23(11):5938. doi: 10.3390/ijms23115938.
citation: Silvestrini A, Meucci E, Ricerca BM, Mancini A. Total Antioxidant Capacity: Biochemical Aspects and Clinical Significance. Int J Mol Sci. 2023 Jul 1;24(13):10978. doi: 10.3390/ijms241310978.
citation: Pangrazzi L, Balasco L, Bozzi Y. Natural Antioxidants: A Novel Therapeutic Approach to Autism Spectrum Disorders? Antioxidants (Basel). 2020 Nov 26;9(12):1186. doi: 10.3390/antiox9121186.
citation: Hughes HK, R J Moreno, Ashwood P. Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD). Brain Behav Immun. 2023 Feb;108:245-254. doi: 10.1016/j.bbi.2022.12.001. Epub 2022 Dec 6.
citation: Liu X, Lin J, Zhang H, Khan NU, Zhang J, Tang X, Cao X, Shen L. Oxidative Stress in Autism Spectrum Disorder-Current Progress of Mechanisms and Biomarkers. Front Psychiatry. 2022 Mar 1;13:813304. doi: 10.3389/fpsyt.2022.813304. eCollection 2022.
citation: Logan SL, Carpenter L, Leslie RS, Garrett-Mayer E, Hunt KJ, Charles J, Nicholas JS. Aberrant Behaviors and Co-occurring Conditions as Predictors of Psychotropic Polypharmacy among Children with Autism Spectrum Disorders. J Child Adolesc Psychopharmacol. 2015 May;25(4):323-36. doi: 10.1089/cap.2013.0119. Epub 2015 Apr 28.
citation: Lee KH, Cha M, Lee BH. Neuroprotective Effect of Antioxidants in the Brain. Int J Mol Sci. 2020 Sep 28;21(19):7152. doi: 10.3390/ijms21197152.
citation: Imataka G, Yui K, Shiko Y, Kawasaki Y, Sasaki H, Shiroki R, Yoshihara S. Urinary and Plasma Antioxidants in Behavioral Symptoms of Individuals With Autism Spectrum Disorder. Front Psychiatry. 2021 Sep 3;12:684445. doi: 10.3389/fpsyt.2021.684445. eCollection 2021.
citation: Goel R, Hong JS, Findling RL, Ji NY. An update on pharmacotherapy of autism spectrum disorder in children and adolescents. Int Rev Psychiatry. 2018 Feb;30(1):78-95. doi: 10.1080/09540261.2018.1458706. Epub 2018 Apr 25.
citation: Gabriele S, Sacco R, Persico AM. Blood serotonin levels in autism spectrum disorder: a systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014 Jun;24(6):919-29. doi: 10.1016/j.euroneuro.2014.02.004. Epub 2014 Feb 19.
citation: Frye RE. Mitochondrial Dysfunction in Autism Spectrum Disorder: Unique Abnormalities and Targeted Treatments. Semin Pediatr Neurol. 2020 Oct;35:100829. doi: 10.1016/j.spen.2020.100829. Epub 2020 Jun 23.
citation: Doyle CA, McDougle CJ. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan. Dialogues Clin Neurosci. 2012 Sep;14(3):263-79. doi: 10.31887/DCNS.2012.14.3/cdoyle.
citation: Cucinotta F, Ricciardello A, Turriziani L, Mancini A, Keller R, Sacco R, Persico AM. Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review. Front Psychiatry. 2022 Mar 3;13:829516. doi: 10.3389/fpsyt.2022.829516. eCollection 2022.
citation: Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology. 2006 Aug;13(3):171-81. doi: 10.1016/j.pathophys.2006.05.007. Epub 2006 Jun 12.
citation: Casanova MF, Frye RE, Gillberg C, Casanova EL. Editorial: Comorbidity and Autism Spectrum Disorder. Front Psychiatry. 2020 Nov 20;11:617395. doi: 10.3389/fpsyt.2020.617395. eCollection 2020. No abstract available.
citation: Baraskewich J, von Ranson KM, McCrimmon A, McMorris CA. Feeding and eating problems in children and adolescents with autism: A scoping review. Autism. 2021 Aug;25(6):1505-1519. doi: 10.1177/1362361321995631. Epub 2021 Mar 2.
citation: Aishworiya R, Valica T, Hagerman R, Restrepo B. An Update on Psychopharmacological Treatment of Autism Spectrum Disorder. Neurotherapeutics. 2022 Jan;19(1):248-262. doi: 10.1007/s13311-022-01183-1. Epub 2022 Jan 14.
citation: Bjorklund G, Waly MI, Al-Farsi Y, Saad K, Dadar M, Rahman MM, Elhoufey A, Chirumbolo S, Jozwik-Pruska J, Kaluzna-Czaplinska J. The Role of Vitamins in Autism Spectrum Disorder: What Do We Know? J Mol Neurosci. 2019 Mar;67(3):373-387. doi: 10.1007/s12031-018-1237-5. Epub 2019 Jan 3.