Clinical trial NCT04284059: Adjuvant Effects of Vitamin A and Vitamin D Supplementation on Treatment of Children With ADHD
Official title: Adjuvant Effects of Vitamin A and Vitamin D Supplementation on Treatment of Children With ADHD:A Randomized, Double Blind, Placebo-controlled, Multicentric Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: ADHD
Keywords: Vitamin A
Vitamin D
Methylphenidate
ADHD
Lead sponsor: Children's Hospital of Chongqing Medical University
Sponsor class: OTHER
First posted: 2020-02-25
Enrollment: 504
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The patients showed deficiency or insufficiency in vitamin A (≤1.05 umol/ L) and vitamin D (≤50 nmol/L) are randomly assigned in double-blind fashion in a 1:1:1 ratio to the vitamin AD supplementation group, vitamin D supplementation group or the placebo group. Vitamin AD supplementation group will be administrated vitamin AD capsules (3 capsules/time, once a day for 8 weeks), which contain vitamin A (2000 IU/capsule) and vitamin D (700 IU/capsule). Vitamin D supplementation group will be administrated vitamin D capsules (400 IU/capsule, 6 capsules/time, once a day for 2 weeks, then change to 5 capsules/time, once a day for 6 weeks). The placebo capsules given to the placebo group (3 capsules/time, once a day for 8 weeks), consists of oily liquids which do not contain vitamin A and vitamin D, and were produced in strict accordance with China's drug management and packaging requirements for placebo by Shandong DYNE Marine Biopharmaceutical Co., Ltd in China.
Primary purpose: TREATMENT

Brief summary: Around 7.2% of children around the world are suffering from ADHD. On account of current medical treatment, a high remission rate can be reached for ADHD. Nevertheless, patients have to face a number of side effects associated with the treatment. It was informed that patients of ADHD have a tendency to vitamin A and vitamin D deficiency. The aim of the study is to determine the effect of vitamin A and vitamin D supplementation as adjunctive therapy to methylphenidate on symptoms of ADHD. 504 subjects aged 6-12 years with a diagnosis of ADHD based on DSM-5 criteria are randomly assigned into three groups to receive vitamin A 6000 IU/day and vitamin D 2100 IU/day, or vitamin D 2100 IU/day or placebo adding to methylphenidate for 8 weeks. Symptoms severity is assessed by Vanderbilt Assessment Scales and Questionnaire - Children with Difficulties at weeks 0, 4, and 8. Serum levels of retinol and 25(OH)D are measured at baseline and after 8 weeks. All the other sociodemographic data are assessed. The study can give more references on the application of vitamin A and vitamin D in addition to methylphenidate to ADHD. Future research is needed to clarify mechanism of vitamin A and vitamin D on ADHD.

Detailed description: 1. Procedures The patients showed deficiency or insufficiency in vitamin A (≤1.05 umol/ L) and vitamin D (≤50 nmol/L) are stratified by gender and randomly assigned in double-blind fashion in a 1:1:1 ratio to the vitamin AD supplementation group, vitamin D supplementation group or the placebo group. The participants will be given the related interventions. Placebo constituents by oily liquids without vitamin A and vitamin D. Placebo, vitamin AD and vitamin D are identical in the appearance to guarantee blind. These patients will be followed up at weeks 4 and 8 to evaluate the changes of ADHD symptoms after adding the adjunctive therapy to methylphenidate. And serum concentration of retinol and 25(OH)D are measured at weeks 8. Accordingly, the placebo group and vitamin D group will be prescribed with vitamin A and vitamin D supplementation on the grounds of retinol and 25 (OH)D concentration after the study.
2. Demographic questionnaire and clinical data The demographic questionnaire is completed by the child's primary caregiver, detailing child's name, gender, date of birth, height, weight, blood pressure, heart rate ; supplementation of vitamin A/D products or vitamin A/D-containing products. Clinical data will be ascertained from the medical records, including information about DSM-5 diagnosis, disease classification, current treatment, and comorbid conditions.
3. Sample size This study is a randomized double-blind controlled trial. Intervention groups are vitamin AD group and vitamin D group, control group is placebo group. The primary outcome index is changes in ADHD symptoms evaluated by Vanderbilt Assessment Scales and Questionnaire - Children with Difficulties (QCD) in the last 4 weeks or 8 weeks. The second outcome is the serum concentration of vitamin A and vitamin D. Conner's Parent Rating Scale (CPRS) was considered as the main outcome in the previous literature, the mean ± SD of ADHD index was 55.84 ± 10.2, 56.79 ± 9.6 for vitamin D + methylphenidate(n = 25), placebo + methylphenidate (n = 29) respectively. The investigators cautiously presume that the mean ± SD for vitamin AD + methylphenidate is 54 ± 9.88. Considering 0.05 of the alpha and 0.80 of power, a sample of 453 subjects divided among 3 groups are calculated by PASS 2020. And 504 subjects are enrolled in the study based on the dropout rate of 10%.
4. Statistical analysis All the data are analyzed using SPSS 19.0. The normality of variables are assessed by Kolmogorov Smirnov test. Comparison of parametric and nonparametric variables between groups are examined by F test and Kruskal-Wallis test, respectively. Paired t-test and Wilcoxon signed-rank test are used to investigate within-group differences. Confounding factors are adjusted by the analysis of covariance.
5. Bias control the investigators will describe both responders and non-responders on demographic questionnaire and clinical data in detail to assess the selection bias. And in order to decrease the dropout rate, the investigators will contact with the patient's parents about compliance to therapy by Wechat, E-mail, sometimes telephone contact is necessary.
6. Ethical matters and data protection The patients participated in the study will sign the informed consent (obtained from the guardian). And this study was approved by the local ethics committee . Patient's name will be abbreviated and the research data will be assigned a code then to provide to the researcher. The authorization from parents on the patient's health information remains valid until the study is completed. After that, researchers will delete private information from the study record.

Eligibility criteria: Inclusion Criteria:

* Diagnose of ADHD according to DSM-5
* Aged 6-12 years
* Intelligence quotient (IQ) ≥70
* Receiving methylphenidate (trade name Concerta) 18-54 mg/day once a day (began with 18 mg/day for a week and titrated gradually to the optimum dose not more than 54 mg/day).

Exclusion Criteria:

* Inconsistent or changing dose of methylphenidate during the participation period
* Use of anticonvulsant drugs or hydrocortisone
* Suffering from other neurological disorders and mental diseases now or in the past, such as convulsions, anxiety and depression
* Suffer from metabolic disorders such as cholestasis, liver dysfunction, pancreatic insufficiency, measles, diarrhea, respiratory illness, severe inflammation or malnutrition, etc.
* Use of vitamins and vitamin-containing products
* IQ≤70
* The serum concentration of vitamin A \>1.05 umol/L and/ or vitamin D \>50 nmol/L

Primary outcomes:
measure: The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt parent assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt teacher assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt parent assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt teacher assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt parent assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt teacher assessment scale
timeFrame: at baseline
measure: The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt parent follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms-Predominantly Inattentive subtype estimated by Chinese version of Vanderbilt teacher follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt parent follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms-Predominantly Hyperactive/Impulsive subtype estimated by Chinese version of Vanderbilt teacher follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt parent follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms-ADHD Combined Inattention/Hyperactivity estimated by Chinese version of Vanderbilt teacher follow-up assessment
timeFrame: at weeks 4 and 8
measure: The changes in ADHD clinical symptoms
timeFrame: at baseline, weeks 4 and 8
Secondary outcomes:
measure: Serum concentration of vitamin A.
timeFrame: at baseline and weeks 8
measure: Serum concentration of vitamin D.
timeFrame: at baseline and weeks 8
Other outcomes:
Locations:
city: Chongqing
country: China
facility: Growth, Development and Mental health of Children and Adolescence Center
state: Chongqing
city: Chang chun
country: China
facility: the First Hospital of Jilin University
state: Jilin
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandonng
Study officials:
affiliation: Children's Hospital of Chongqing Medical University
name: Li Chen, doctor
role: STUDY_DIRECTOR
affiliation: Children's Hospital of Chongqing Medical University
name: yu T Li, MS
role: STUDY_CHAIR
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