Q10 Ubiquinol in Autism Spectrum Disorder and in Phelan-McDermid Syndrome.

NCT ID: NCT04312152

Last Updated: 2020-03-18

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-09
• Study Completion Date: 2023-08-31

Brief Summary

This double-blind, cross-over, randomized, controlled trial (RCT) has the aim of evaluating the effectiveness of a metabolic support therapy in two cohorts of patients with idiopathic Autism Spectrum Disorder or Phelan-McDermid syndrome, commonly associated with syndromic autism. Each patient will receive Q10 ubiquinol + Vit. E and B for 4 months and only Vit. E and B for 4 months in a double-blind, cross-over design. Primary outcome measures of efficacy include Vineland Adaptive Behavior Scales, Childhood Autism Rating Scale, Clinical Global Impression-Improvement and Visual Analog Scales; secondary outcome measures include several questionnaires and tests of autism, cognitive function, problem behaviors, quality of life, communication and comorbid disorders, as well as measures of oxidative stress.

Detailed Description

Autism Spectrum Disorder (ASD) is a clinically and genetically heterogeneous collection of different conditions, sharing socio-communicative deficits, repetitive behaviors, restricted interests, and dysfunctional sensory processing. Currently there are no pharmaceutical compounds effective on core ASD symptoms. Enhanced oxidative stress and mitochondrial dysfunction represent one of the most replicated abnormalities detected both systemically and in the Central Nervous System (CNS) of autistic individuals. Abnormalities in redox parameters are significantly correlated with the severity of autistic behaviors. Although oxidative stress usually represents the consequence and not the primary cause of ASD, reduced ATP production and oxidative damage can seemingly contribute an additional burden to the dysfunction directly produced by ASD-causing genetic or epigenetic defects. Importantly, redox abnormalities have been detected also in young autistic children and are not correlated with age. Therefore, enhanced oxidative stress and mitochondrial dysfunction represent an ASD-related "state-dependent" characteristic present in a consistent number of autistic individuals regardless of their age and of their specific underlying pathogenetic underpinnings. Sustaining mitochondrial function while controlling redox imbalance thus represents a viable "indirect" therapeutic approach, potentially able to ameliorate behavioral and neuropsychological deficits in many autistic individuals.

Coenzyme Q10 (CoQ10, ubiquinone or ubiquinol) is a lipid soluble compound present in the majority of living cells. By increasing energy production and antioxidant capacity, CoQ10 is predicted to limit the damage generated by the neuroinflammation and excitotoxicity well documented in ASD brains, ultimately leading to excessive neuritic pruning and/or cell apoptosis. Administration of Q10 ubiquinol to autistic children, as frequently prescribed to children with mitochondrial disorders, yielded promising results with an extremely low incidence and minor impact of side effects in two open trials and in three RCTs involving numerous other active compounds. In the present RCT, each patient will receive Q10 ubiquinol (50-100 mg b.i.d.) + Vit. E (60 mg/die) and polyvitamin B for 4 months and only Vit. E and B for another 4 months (total duration 8 months) in a double-blind, cross-over design. The focused co-administration of Q10 ubiquinol with only two known antioxidants, vitamin E and a multivitamin B complex, is designed to synergistically boost the increase in energy production and cell protection viewed as deriving primarily from Q10 ubiquinol administration. This study was also designed to overcome two limitations present in previous RCTs evaluating the effects of Q10 Ubiquinone (precursor of Q10 ubiquinol) in ASD children and adults: (a) The administration of a very limited number of active compounds, as compared to cocktails containing many active substances, allows to focus here on the efficacy of Q10 ubiquinol; (b) the administration of Q10 ubiquinol, rather than its precursor Q10 ubiquinone, avoids the potential risk of reduced response due to pharmacokinetic interference with the biotransformation of the precursor into the active compound.

This trial addresses the efficacy of Q10 ubiquinol, paired with Vit. E and B, not only in "idiopathic" ASD, but also in "syndromic" ASD, using Phelan-McDermid syndrome (PMS) as a paradigm. PMS, also known as chromosome 22q13.3 deletion syndrome, represents one of the most studied syndromic forms of ASD. It is characterized by autism in as many as 70-80% of deletion carriers, in addition to early onset severe muscle hypotonia, developmental delay, facial dysmorphisms, absence of spoken language or severe language development disorder. Deletions or mutations of the SHANK3 gene, encoding a synaptic scaffold protein critical to glutamatergic synapse function, are primarily responsible for the syndrome, although larger 22q13.3 deletions encompass additional disease genes.

This study shall include up to 140 patients with idiopathic ASD and 60 patients with PMS. The study design of this RCT was balanced, so that half of the patients with ASD or PMS will receive Q10 ubiquinol during the first 4 months, and the remaining half will receive Q10 ubiquinol during the second 4 months. The purpose of this balancing is to observe not only whether Q10 ubiquinol produces and improvement in primary and secondary measures, but also if this improvement is sustained over time despite Q10 discontinuation or requires continued Q10 administration. In addition to clinical and psychometric parameters, oxidative stress will be measured at baseline and after 4 and 8 months, by drawing 8-10 ml of blood, isolating leukocytes by Ficoll gradient and assessing (a) protein carbonylation levels by oxyblot; (b) the activity of mitochondrial respiratory chain complexes normalized by citrate synthase activity; (c) the expression levels of mitochondrial respiratory chain complexes measured by Western-Blotting.

Conditions

Autism Spectrum Disorder; Phelan-McDermid Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

PMS Placebo

If body weight is up to 20 kg:

• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (1.05 mg), Vit. B2 (1.2 mg), Niacin (9 mg), Pantothenic acid (4.5 mg), Vit. B6 (1.5 mg), Vit. B12 (4.5 mcg), Folic acid (0.1 mg), Biotin (0.1125 mg)

If body weight is above 20 kg:

• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (2.1 mg), Vit. B2 (2.4 mg), Niacin (18 mg), Pantothenic acid (9 mg), Vit. B6 (3 mg), Vit. B12 (9 mcg), Folic acid (0.2 mg), Biotin (0.225 mg)

Group Type: ACTIVE_COMPARATOR

Vitamin E

Intervention Type: DIETARY_SUPPLEMENT

Vitamin E (30 mg b.i.d. regardless of body weight) in capsules containing also Vit. B complex, and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Multi-Vitamin B complex

Intervention Type: DIETARY_SUPPLEMENT

Multi-Vitamin B complex including Vit. B1, B2, B3, B5, B6, B8, B9, and B12, in capsules containing also Vit. E and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

ASD Placebo

If body weight is up to 20 kg:

• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (1.05 mg), Vit. B2 (1.2 mg), Niacin (9 mg), Pantothenic acid (4.5 mg), Vit. B6 (1.5 mg), Vit. B12 (4.5 mcg), Folic acid (0.1 mg), Biotin (0.1125 mg)

If body weight is above 20 kg:

• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (2.1 mg), Vit. B2 (2.4 mg), Niacin (18 mg), Pantothenic acid (9 mg), Vit. B6 (3 mg), Vit. B12 (9 mcg), Folic acid (0.2 mg), Biotin (0.225 mg)

Group Type: ACTIVE_COMPARATOR

Vitamin E

Intervention Type: DIETARY_SUPPLEMENT

Vitamin E (30 mg b.i.d. regardless of body weight) in capsules containing also Vit. B complex, and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Multi-Vitamin B complex

Intervention Type: DIETARY_SUPPLEMENT

Multi-Vitamin B complex including Vit. B1, B2, B3, B5, B6, B8, B9, and B12, in capsules containing also Vit. E and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

PMS Active compound

If body weight is up to 20 kg:

• Q10 ubiquinol, 50 mg b.i.d.
• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (1.05 mg), Vit. B2 (1.2 mg), Niacin (9 mg), Pantothenic acid (4.5 mg), Vit. B6 (1.5 mg), Vit. B12 (4.5 mcg), Folic acid (0.1 mg), Biotin (0.1125 mg)

If body weight is above 20 kg:

• Q10 ubiquinol, 100 mg b.i.d.
• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (2.1 mg), Vit. B2 (2.4 mg), Niacin (18 mg), Pantothenic acid (9 mg), Vit. B6 (3 mg), Vit. B12 (9 mcg), Folic acid (0.2 mg), Biotin (0.225 mg)

Group Type: EXPERIMENTAL

Q10 Ubiquinol

Intervention Type: DIETARY_SUPPLEMENT

Q10 Ubiquinol (50 or 100 mg b.i.d. depending on body weight) in capsules containing also Vit. E and Vit. B complex, as described above. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Vitamin E

Intervention Type: DIETARY_SUPPLEMENT

Vitamin E (30 mg b.i.d. regardless of body weight) in capsules containing also Vit. B complex, and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Multi-Vitamin B complex

Intervention Type: DIETARY_SUPPLEMENT

Multi-Vitamin B complex including Vit. B1, B2, B3, B5, B6, B8, B9, and B12, in capsules containing also Vit. E and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

ASD Active compound

If body weight is up to 20 kg:

• Q10 ubiquinol, 50 mg b.i.d.
• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (1.05 mg), Vit. B2 (1.2 mg), Niacin (9 mg), Pantothenic acid (4.5 mg), Vit. B6 (1.5 mg), Vit. B12 (4.5 mcg), Folic acid (0.1 mg), Biotin (0.1125 mg)

If body weight is above 20 kg:

• Q10 ubiquinol, 100 mg b.i.d.
• Vitamin E 30 mg b.i.d.
• Multivitamin B complex b.i.d., including Vit. B1 (2.1 mg), Vit. B2 (2.4 mg), Niacin (18 mg), Pantothenic acid (9 mg), Vit. B6 (3 mg), Vit. B12 (9 mcg), Folic acid (0.2 mg), Biotin (0.225 mg)

Group Type: EXPERIMENTAL

Q10 Ubiquinol

Intervention Type: DIETARY_SUPPLEMENT

Q10 Ubiquinol (50 or 100 mg b.i.d. depending on body weight) in capsules containing also Vit. E and Vit. B complex, as described above. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Vitamin E

Intervention Type: DIETARY_SUPPLEMENT

Vitamin E (30 mg b.i.d. regardless of body weight) in capsules containing also Vit. B complex, and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Multi-Vitamin B complex

Intervention Type: DIETARY_SUPPLEMENT

Multi-Vitamin B complex including Vit. B1, B2, B3, B5, B6, B8, B9, and B12, in capsules containing also Vit. E and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Interventions

Q10 Ubiquinol

Q10 Ubiquinol (50 or 100 mg b.i.d. depending on body weight) in capsules containing also Vit. E and Vit. B complex, as described above. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Intervention Type: DIETARY_SUPPLEMENT

Vitamin E

Vitamin E (30 mg b.i.d. regardless of body weight) in capsules containing also Vit. B complex, and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Intervention Type: DIETARY_SUPPLEMENT

Multi-Vitamin B complex

Multi-Vitamin B complex including Vit. B1, B2, B3, B5, B6, B8, B9, and B12, in capsules containing also Vit. E and, in the active arms, Q10 ubiquinol. Capsules can be opened and the content drunk or chewed, if children have difficulties with swallowing capsules.

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

tocopherols

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;

2. Subjects of both sexes, aged between 2 and 40 years old, may be included in the study;

3. The subject must meet DSM-5 criteria for a primary diagnosis of Autism Spectrum Disorder (idiopathic autism) or carry a documented deletion of human chromosome 22q13.33 or mutation in the SHANK3 gene (Phelan-McDermid Syndrome);

4. Subjects with idiopathic autism must pass the threshold score for Autism of the Autism Diagnostic Observation Schedule;

5. Baseline Children's Global Assessment Scale score must be between 45 and 59;

6. Patients treated with psychoactive drugs (neuroleptics, antiepileptics, etc.) are enrolled only if the treatment and dosage of these drugs has been constant for at least 3 months prior to enrollment in the trial and is kept constant throughout the 8-month duration of the trial;

7. Patients undergoing any kind of behavioral intervention must have must have started the intervention at least 3 months prior to enrollment and the intervention must remain unchanged throughout the 8-month duration of the trial;

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

Patients who meet any of the following criteria will not be recruited in the study:

1. Patients with autism secondary to known genetic syndromes other than Phelan-McDermid syndrome (for example, Rett syndrome, fragile-X syndrome, etc.);

2. Presence of brain malformations or major structural anomalies visible by magnetic resonance imaging;

3. Patients with autism secondary to epileptic encephalopathy or with idiopathic autism comorbid with seizures more frequent than one episode every 6 months despite ongoing antiepileptic drug therapy;

4. Patients with autism accompanied by marked facial dysmorphism and/or congenital malformations;

5. Patients treated with anticoagulants;

6. Patients with serious medical illnesses (chronic renal disease, severe liver disease, cardiovascular disorders, uncontrolled hypertension with systolic pressure values> 170 and diastolic pressure> 100 mm Hg, malignant tumors, HIV infection);

7. Patients with a history of acute cerebrovascular episodes;

8. Patients with a history of stomach bleeding or active peptic ulcer;

9. Patients with documented allergy, hypersensitivity or intolerance to one of the excipients of the experimental or comparative product.

Trial interruption criteria:

1. Patients whose medical conditions require starting treatment with anticoagulants.

2. Patients with severe medical conditions starting during the 8-month duration of the trial.

3. Patients who undergo a change in psychopharmacological or behavioral treatment during the 8-month duration of the trial.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Associazione Italiana Sindrome di Phelan-McDermid (AISPHEM)

UNKNOWN

Sponsor Role: collaborator

University of Bari

OTHER

Sponsor Role: collaborator

Antonio Persico

OTHER

Sponsor Role: lead

Responsible Party

Antonio Persico

Full Professor in Child & Adolescent Neuropsychiatry

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Antonio M. Persico, MD

Role: PRINCIPAL_INVESTIGATOR

University of Messina

Locations

Interdipartimental Program "Autismo 0-90" at "G. Martino" Universitary Hospital

Messina, ME, Italy

Countries

Italy

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. In: Association AP, editor. Fifth Edition ed: American Psychiatric Publishing, Arlington; 2013.

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 26166453 (View on PubMed)

Kalayci M, Unal MM, Gul S, Acikgoz S, Kandemir N, Hanci V, Edebali N, Acikgoz B. Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats. BMC Neurosci. 2011 Jul 29;12:75. doi: 10.1186/1471-2202-12-75.

Reference Type: BACKGROUND

PMID: 21801363 (View on PubMed)

Kumari S, Mehta SL, Milledge GZ, Huang X, Li H, Li PA. Ubisol-Q10 Prevents Glutamate-Induced Cell Death by Blocking Mitochondrial Fragmentation and Permeability Transition Pore Opening. Int J Biol Sci. 2016 Apr 27;12(6):688-700. doi: 10.7150/ijbs.13589. eCollection 2016.

Reference Type: BACKGROUND

PMID: 27194946 (View on PubMed)

Duberley KE, Heales SJ, Abramov AY, Chalasani A, Land JM, Rahman S, Hargreaves IP. Effect of Coenzyme Q10 supplementation on mitochondrial electron transport chain activity and mitochondrial oxidative stress in Coenzyme Q10 deficient human neuronal cells. Int J Biochem Cell Biol. 2014 May;50:60-3. doi: 10.1016/j.biocel.2014.02.003. Epub 2014 Feb 15.

Reference Type: BACKGROUND

PMID: 24534273 (View on PubMed)

Rossignol DA, Frye RE. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol. 2014 Apr 22;5:150. doi: 10.3389/fphys.2014.00150. eCollection 2014.

Reference Type: BACKGROUND

PMID: 24795645 (View on PubMed)

Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, Bonassi S. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med. 2012 May 15;52(10):2128-41. doi: 10.1016/j.freeradbiomed.2012.03.011. Epub 2012 Apr 18.

Reference Type: BACKGROUND

PMID: 22542447 (View on PubMed)

Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr JM. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J Toxicol. 2009;2009:532640. doi: 10.1155/2009/532640. Epub 2009 Aug 26.

Reference Type: BACKGROUND

PMID: 20107587 (View on PubMed)

Ghezzo A, Visconti P, Abruzzo PM, Bolotta A, Ferreri C, Gobbi G, Malisardi G, Manfredini S, Marini M, Nanetti L, Pipitone E, Raffaelli F, Resca F, Vignini A, Mazzanti L. Oxidative Stress and Erythrocyte Membrane Alterations in Children with Autism: Correlation with Clinical Features. PLoS One. 2013 Jun 19;8(6):e66418. doi: 10.1371/journal.pone.0066418. Print 2013.

Reference Type: BACKGROUND

PMID: 23840462 (View on PubMed)

Adams JB, Holloway C. Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J Altern Complement Med. 2004 Dec;10(6):1033-9. doi: 10.1089/acm.2004.10.1033.

Reference Type: BACKGROUND

PMID: 15673999 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22151477 (View on PubMed)

Adams JB, George F, Audhya T. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. J Altern Complement Med. 2006 Jan-Feb;12(1):59-63. doi: 10.1089/acm.2006.12.59.

Reference Type: BACKGROUND

PMID: 16494569 (View on PubMed)

Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1130-7. doi: 10.1016/j.bbabio.2010.04.018. Epub 2010 May 9.

Reference Type: BACKGROUND

PMID: 20441769 (View on PubMed)

Gvozdjakova A, Kucharska J, Ostatnikova D, Babinska K, Nakladal D, Crane FL. Ubiquinol improves symptoms in children with autism. Oxid Med Cell Longev. 2014;2014:798957. doi: 10.1155/2014/798957. Epub 2014 Feb 23.

Reference Type: BACKGROUND

PMID: 24707344 (View on PubMed)

Mousavinejad E, Ghaffari MA, Riahi F, Hajmohammadi M, Tiznobeyk Z, Mousavinejad M. Coenzyme Q10 supplementation reduces oxidative stress and decreases antioxidant enzyme activity in children with autism spectrum disorders. Psychiatry Res. 2018 Jul;265:62-69. doi: 10.1016/j.psychres.2018.03.061. Epub 2018 Apr 4.

Reference Type: BACKGROUND

PMID: 29684771 (View on PubMed)

Adams JB, Audhya T, Geis E, Gehn E, Fimbres V, Pollard EL, Mitchell J, Ingram J, Hellmers R, Laake D, Matthews JS, Li K, Naviaux JC, Naviaux RK, Adams RL, Coleman DM, Quig DW. Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial. Nutrients. 2018 Mar 17;10(3):369. doi: 10.3390/nu10030369.

Reference Type: BACKGROUND

PMID: 29562612 (View on PubMed)

Harony-Nicolas H, De Rubeis S, Kolevzon A, Buxbaum JD. Phelan McDermid Syndrome: From Genetic Discoveries to Animal Models and Treatment. J Child Neurol. 2015 Dec;30(14):1861-70. doi: 10.1177/0883073815600872. Epub 2015 Sep 8.

Reference Type: BACKGROUND

PMID: 26350728 (View on PubMed)

Other Identifiers

Q10_study_ASD

Identifier Type: -

Identifier Source: org_study_id