Phase IIa Exploratory Clinical Trial, to Examine the Safety and Efficacy of tPCS on Paediatric ADHD Participants

Children with ADHD display a certain brainwave profile which might be different to that of a child who does not have ADHD. Treatment with tPCS (transcranial pulsed current stimulation) has shown that this brainwave profile could possibly be altered to more closely resemble a brainwave profile of a child who does not have ADHD. Researchers believe that by changing this brainwave profile it might lessen symptoms of ADHD.

tPCS is a name used to describe the type of current this device produces. It involves randomly (in no specific pattern) produced pulses of current at different times that the brain picks up. These pulses of low current stimulate the brain in a certain way and affect the brainwave activity.

Treatment is given by applying a low frequency current using small electrodes clipped to the earlobes. The current comes from an external battery source. The pulses of current generated by this device stimulate certain parts of the brain which result in a possible increased control of attention and behaviour. This treatment has already been proven to be safe and will not hurt your child.

Due to these specific parts of the brain being stimulated, and the positive results of previous research, it seems possible to control certain functions in children suffering from inattention and hyperactivity.

The idea of using tPCS stimulation as a possible way for helping children with confirmed ADHD opens a new window to future research. The final goal of this device and research is to offer a safe, non-invasive (conservative treatment that does not require piercing into the body or the removal of tissue) treatment that can be used on a long-term basis and shows a clear improvement of ADHD symptoms for children and even adults with ADHD.

- Inspection of Records: Investigators and institutions involved in the trial will permit trial-related monitoring, audits, Independent Ethics Committee (IEC) review, and regulatory inspection(s) by providing direct access to all trial records. In the event of an audit, the investigator agrees to allow the sponsor, representatives of the sponsor and applicable regulatory authorities access to all trial records. The confidentiality of records that can identify participants will be protected, respecting the privacy and confidentiality rules in accordance with regulatory requirements.

The investigator must promptly notify the sponsor of any audits scheduled by any regulatory authorities and promptly forward copies of any audit reports received to the sponsor.

In order to ensure data accuracy, data for individual participant visits must be completed as soon as possible/ during/ immediately following the visit. All completed data will be reviewed, signed, and dated by the investigator in a timely manner.

- Database Management and Quality Control: Data management, including the development and management of a database, will be performed in accordance with regulatory requirements. The designated data management vendor will review the CRF data for completeness and accuracy. A formal querying process will be followed whereby the data management group will request the site personnel to clarify any apparent erroneous entries or inconsistencies and will request additional information from the site as required.

Medical history/current medical conditions and adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology.

- Sample Size: As this research is exploratory in nature a sample size was calculated based on some assumptions as there is no current data to compare in pediatrics, tPCS, and ADHD. Since no preliminary data is available a clinically relevant improvement is regarded as a 15% shift on the total range of the two ADHD sub-scales (Inattention and Hyperactivity/Impulsivity), with 9 items in each, i.e. 4.05 (=0.15 x 27 where items score 0 to 3 Likert scale). The standard deviation is estimated as range/6 = 27/6 = 4.5, i.e. the total range of a Gaussian distribution was 6 standard deviation. A sampling ratio of 2:1 is used. A sample size of 48 children (32:16) will have 80% power to detect a difference of 4.05 points between the groups when testing two-sided using Students t-test at the 0.05 level of significance.

Continuous data will be summarised using descriptive statistics. Categorical data will be presented using N and % (using the number of participants without missing data in the calculation). 95% confidence intervals will be determined for all data, where applicable. No imputation of missing values will be performed in the calculation of summary statistics.

- Safety Data Analysis: The safety analyses will be performed for the safety population only. All safety parameters (adverse events, physical examination findings, vital signs, physical measurements and qEEG findings) will be summarised descriptively by treatment group. The descriptive statistics will include the number of observations, mean, standard deviation, median, minimum and maximum for continuous variables and number of observations and their percentages for categorical variables. Changes from baseline as well as shift tables will be provided for the safety laboratory parameters (within, below or above normal range).

The analysis of adverse events will include all treatment emergent adverse events. Adverse events will be coded using MedDRA and will be presented by system organ class and preferred term for each treatment group.

- Efficacy Data

1. Primary Efficacy analysis:

   The mean change in both the Inattention and Hyperactivity-Impulsive subscales of the SNAP-IV-C rating scale as well as the Conners'3 Parent rating scale from baseline to Day 42 will be calculated for each group. Mean changes from baseline at the other trial time points (Days 0, 14, 28, and 42) will also be calculated.

   The statistical analysis methods will consist of paired t-tests within groups and analysis of Co-variance (ANCOVA) between groups for the change in assessments over time. The paired t-tests will compare the change variable from before tPCS administration to after tPCS within groups (active and sham condition). A one-way ANCOVA, with factor groups (active or sham) and co-variance baseline value, will be employed to compare groups with respect to change from baseline for estimated outcomes, e.g. change in complete scores from baseline to 6-weeks for inattentive and hyperactivity-impulsivity on SNAP-IV-C and Conners'3 Parent rating scales. Groups will also be compared over time (Days 0, 14, 28 and 42) using a linear mixed model analysis and of particular interest will be the interaction between group and time.
2. Secondary Efficacy analysis:

The mean change in the psychometric test-battery from baseline to Day 42 will be calculated for each group. Mean changes from baseline at the other trial time points (Days 0, 14, 28, and 42) will also be calculated.

The statistical analysis methods will consist of paired t-tests within groups and analysis of Co-variance (ANCOVA) between groups for the change in assessments over time. The paired t-tests will compare the change variable from before tPCS administration to after tPCS within groups (active and sham condition). A one-way ANCOVA, with factor groups (active or sham) and co-variance baseline value, will be employed to compare groups with respect to change from baseline for estimated outcomes, e.g. change in complete scores from baseline to 6-weeks for the psychometric test-battery. Groups will also be compared over time (Days 0, 14, 28 and 42) using a linear mixed model analysis for repeated measures and of particular interest will be the interaction between group and time.

EEG analysis Power spectra will be determined for each epoch of data for the frequency-domain analysis. Mean and median power frequencies will be calculated within each of the 4 EEG frequency bands (intraband) and over the entire EEG range (interband). Also, the band power fractions or relative amount of power within an EEG band with respect to the total amount of spectrum power will be determined. The coherence analysis will be completed using two bands (alpha and theta) and four sub-bands (low-alpha (8-10 Hz), high-alpha (10-12 Hz), low-beta (12-20 Hz), and high-beta (20-30 Hz)). We will use the Welch's averaged modified periodogram method to find the estimated coherence of signal x and y, representing each electrode site. It is a function of the power spectral densities of x and y and their cross power spectral density. Groups will also be compared over time (Days 0, 42 and 84) using a linear mixed model analysis for repeated measures and of particular interest will be the interaction between group and time.

Eligibility Criteria:
Inclusion Criteria:

* Completion of the written informed consent process for trial participation, by parent(s) or legal guardian(s), prior to all trial-related procedures
* Completion of written assent for trial participation, by participant, prior to all trial-related procedures
* Male or female participants aged 6 to 12 years
* Newly diagnosed (Diagnosis made by DSM-V criteria), treatment naïve participants
* Participants and parent(s) or legal guardian(s) must have the ability to communicate well with the investigator and to understand and comply with the requirements of the trial
* Participants and parent(s) or legal guardian(s) must agree to stay in contact with the trial site for the duration of the trial and provide updated contact information as necessary.

Exclusion Criteria:

* Existence of a major neurologic or psychiatric condition (epilepsy, severe depression etc.)
* History of head injury resulting in more than a momentary loss of consciousness
* Previous neurosurgery
* Presence of unstable medical conditions, such as: Diabetes Mellitus, Cardiac Pathology, Cancer, Kidney Insufficiency, Acute Thrombosis
* Presence of any implanted metal or electronic medical devices present in the head, excluding any dental implants
* Subjects on any prohibited concomitant medication
* Any other medical condition which, in the opinion of the Investigator, could affect the participant's health during trial participation or could compromise his/her ability to participate in the trial
* In the opinion of the investigator, the participant and his/her parent(s) or legal guardian(s) is not reliable for participation in the trial