Sublingual Glycine vs. Placebo on Attentional Difficulties and Hyperactivity in Prepuberal Children

Effects of Sublingual Microencapsulated Glycine on Attentional Difficulties and Hyperactivity in Prepuberal Children - A Placebo-controlled, Double-blind, Randomized, Cross-over Study

This study is designed to investigate effects on attentional performance and motoric activity of 100 mg microencapsulated glycine (Bidicin® from Biotiki®) compared to placebo after treatment with t.i.d. sublingual doses over 3 weeks each. The primary objective of the study is to determine the effects on attentional performance and motoric activity of 100 mg microencapsulated Glycine (Bidicin® from Biotiki® ) compared to placebo after treatment with t.i.d. sublingual doses over 3 weeks each in children with low attentional performance and high motoric activity. A number of 30 prepuberal boys and girls aged 6 - 14 years with low attentional performance and high motoric activity will be enrolled in this study. The prepuberal status will be determined by Tanner stages ≤ 3.

Trial Design: This study has a double-blind, randomized, two-period, cross-over design. The study population will be randomized equally to the sequence 1 (first 3 weeks microencapsulated Glycine, second 3 weeks placebo) or sequence 2 (first 3 weeks placebo, second 3 weeks microencapsulated Glycine). Study Agent/Placebo - Dosage and Route of Administration: Study Agent/Placebo will first be dispensed at Visit 2 (day 0). Treatment assignments will be made in accordance with the randomization. At each visit (Visit 2 and Visit 3), subjects will receive two blisters for the 3 following weeks. Only qualified personnel may dispense study Agent/Placebo. Investigational and reference treatment: 100 mg microencapsulated Glycine (Bidicin® from Biotiki® ) Placebo from Biotiki® Study design: This study will employ a double blind, randomized, placebo-controlled cross-over design. SKAMP raters and teachers will be blinded concerning the study Agent/Placebo. Planned Study Time Schedule: The study ends 10 weeks after enrollment of the last patient (total study end). Study duration for each patient is between 7 and 10 weeks (from inclusion) until the last visit (close-out visit). Statistics: Sample size calculation is based on the primary endpoint "mean of the SKAMP Combined score over all time points in the classroom setting". The study should have sufficient power to detect a difference between treatments if a moderate effect size (corresponding to Cohen's d=0.5) were present in parallel-group study in two independent patient groups. Assuming a correlation between measurements in the same patient of 0.6, this translates into an effect size of 0.56 in a cross-over trial comparing within patient measurements. With this effect size, 27 patients have to be included in the study, to achieve a power of 0.8 at a two-sided significance level of alpha=0.05. To account for a small number of drop-outs, 30 patients have to be randomized. Data analysis: The trial will be analyzed according to the intention-to-treat principle. Efficacy measures will be evaluated by linear mixed models for repeated measurements. Safety analyses will be performed for subjects who received at least one dose of microencapsulated Glycine/ placebo. Incidences of adverse events and of serious adverse events will be calculated.

100 mg microencapsulated Glycine (Bidicin® from Biotiki® ) t.i.d. for the first three weeks and then Placebo t.i.d. from Biotiki® for the second three weeks.

Placebo t.i.d. from Biotiki® for the first three weeks and then 100 mg microencapsulated Glycine (Bidicin® from Biotiki® ) t.i.d. for the second three weeks.

SKAMP-Combined rating performed at 25 minutes before and 0:50 h, 1,55 h, 2:50 h, 4:05 h, 5:50 h, 7:40 h and 8:35 h after first microencapsulated Glycine/ placebo intake in a laboratory classroom setting after a 3 week treatment period. The primary efficacy endpoint is the mean of the SKAMP-Combined score over all time points in the classroom setting.

SKAMP- Attention subscale rating performed at 25 minutes before and 0:50 h, 1,55 h, 2:50 h, 4:05 h, 5:50 h, 7:40 h and 8:35 h after first microencapsulated Glycine/ placebo intake in a laboratory classroom setting after a 3 week treatment period. The secondary efficacy endpoint is the mean of the SKAMP- Attention subscale score over all time points in the classroom setting.

SKAMP- Deportment subscale rating performed at 25 minutes before and 0:50 h, 1,55 h, 2:50 h, 4:05 h, 5:50 h, 7:40 h and 8:35 h after first microencapsulated Glycine/ placebo intake in a laboratory classroom setting after a 3 week treatment period. The secondary efficacy endpoint is the mean of the SKAMP- Deportment subscale score over all time points in the classroom setting.

The assessment of the child behaviour scale (CBCL) is performed by the primary caregivers due to the last week before the visit of a classroom. The CBCL global score and the CBCL subscores are used for evaluation.

The instrument provides a QoL total score and several domains of QoL regarding family, school, peers, interests, physical and mental health, and also the impact of the respective disorder. These scores are used for evaluation.

In this study, saliva cortisol samples are collected for determination of the cortisol awakening response (CAR) as well as before and after the supposedly stressful situation of the classroom math test. For the CAR, cortisol will be measured on three consecutive days before Visit 2, 3 and 4 at awakening, 30 minutes after awakening and before bedtime. For assessment of cortisol levels under acute stress, cortisol samples will be taken before and after classroom III of Visit 2, as well as before and after classroom III and VI of Visits 3 and 4.

The ADHD Rating Scale-IV is a reliable and easy-to-administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale is linked directly to DSM-IV diagnostic criteria for ADHD. Outcome Measure are the summed total score for "Inattention, Hyperactivity and Impulsivity" and the sub-scores for "Inattention" and for "Hyperactivity and Impulsivity".

All adverse events no matter how intense will be observed by the investigator until resolved or until they can be sufficiently medical explained. All AEs must be described by diagnosis or symptoms, duration, frequency, severity, an assessment of its cause, its relationship to the study Glycine or placebo, whether it influenced the course of the study Glycine or placebo, whether it required specific therapy and its outcome. All documented AEs will be evaluated.

Inclusion Criteria: Subjects who meet all of the following inclusion criteria will be eligible for enrollment in the study: Male and female subjects aged 6-14 years with Tanner stages 0 to 3 and attentional and/or hyperactivity problems. Subjects with parents or a legal guardian, who will give written informed consent for the child to participate in the study. Additionally, assent to participate must be obtained from all children entering the study if the child is able to judge the nature, the meaning and the significance of the trial. Assent will be documented by the child´s signature on the consent form. Health Status: Subjects must not have clinically significant diseases or clinically significant abnormal laboratory values as assessed during medical history and physical exam. Subjects meeting minimum intelligence requirements: In the opinion of the investigator the subject must generally be functioning at age-appropriate levels academically, which should take into account any prior cognitive or academic testing (basic knowledge of reading, writing and calculating). Subject has an ADHD-RS-IV total score ≥18. Subjects already receiving behavioral therapies for HKS/ADHD or oppositional defiant disorder may continue to do sor during the course of the trial. Exclusion Criteria: subjects with psychiatric disorders requiring current pharmacological treatment (e.g. major depression, psychosis) Subjects with psychiatric or somatic conditions that may contraindicate the trial or confound efficacy or safety assessments. Subjects with a history of drug abuse or current use of recreational drugs. History of hypersensitivity to microencapsulated Glycine or placebo. Subjects who are judged by the investigator as likely to be non-compliant with study procedures. Use of any investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin.