ADHD
Conditions
Keywords
ADHD,Adults,MG01CI,METADOXINE
Brief summary
The purpose of this study is to evaluate efficacy, safety and tolerability of metadoxine (MG01CI) extended release formulation for the treatment of adults diagnosed with ADHD
Detailed description
This will be a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in adult subjects with ADHD. Eligible subjects will be randomly assigned in a 1:1 ratio to one of two treatment groups, 1400 mg Metadoxine (MG01CI) and Placebo. The study will consist of three periods: a screening period of up to 2 weeks, a 6-week double-blind treatment period, and a 2-week safety follow-up period. The total duration of subject participation will be \ 10 weeks. Overview of Study Visits Screening Period: Visit 1 - Screening/Baseline Visit (up to 14 days prior to dosing) Treatment Period: Visit 2 - Day 0 (Randomization Visit) Visit 3 - Day 7 ± 2 days Visit 4 - Day 14 ± 2 days Visit 5 - Day 28 ± 2 days Visit 6 - Day 42 ± 2 days Follow-up period: Visit 7 - Day 56 ± 3 days
Interventions
MG01CI 1400 mg, that will be taken daily by the patients for a duration of 6 weeks.
Sponsors
Alcobra Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Adult males and females, 18 to 50 years old, inclusive, at screening visit 2. Diagnosed with ADHD based on 1. DSM-IV criteria for ADHD as assessed by the Adult ADHD Clinician Diagnostic Scale (ACDS V1.2) 2. SCID clinical interview 3. Clinical severity of at least a moderate level (Clinical Global Impression score of 4 or above) 4. Female subjects with childbearing potential must agree to use effective contraceptive and have negative urine pregnancy test at screening visit 5. Able to attend the clinic regularly and reliably 6. Able to swallow tablets/capsules 7. Able to understand, read, write and speak Hebrew fluently to complete study related materials 8. Able to understand and sign written informed consent to participate in the study
Exclusion criteria
1. Subjects who were non-responder to at least two ADHD treatments 2. Subjects with any medical or psychiatric condition (e.g. schizophrenia, personality disorder as diagnosed by DSM-IV) or clinical significant or unstable medical or surgical condition that may preclude safe and complete study participation as determined by medical history, physical examination, neurological exam, laboratory tests or ECG or based on the opinion of the Investigator; common diseases such as hypertension, type 2 diabetes mellitus, hyperlipidemia, etc. are allowed per the Investigator's judgment, as long as they are stable and controlled by medical therapy that is constant for at least 8 weeks prior to randomization and throughout the study 3. Any prescription or non-prescription ADHD medications during the 7 days prior to the screening visit 4. Known or suspected HIV-positive or with advanced diseases such as AIDS, Hepatitis C, Hepatitis B or tuberculosis 5. History of allergy or sensitivity to B complex vitamins 6. History or suspicion of PDD, NLD or other psychotic conditions 7. Use of Vitamin B throughout the study 8. Use of ADHD medications throughout the study 9. Use of any psychiatric medications throughout the study 10. Use of investigational medication/treatment in the past 30 days prior to the screening visit per the discretion of the Investigator 11. Use of any medication or food supplement not considered acceptable by the clinical Investigator or the medical monitor during the 14-day period before randomization 12. Current (or history within the last 6 months) of drug dependence or substance abuse disorder according to DSM-IV-TR criteria (excluding nicotine). Subjects should also agree to refrain from consuming abnormally high amounts of caffeine during the study. 13. Suicidality, defined as either active suicidal plan/intent or active suicidal thoughts, in the 6 months before the Screening Visit or no lifetime suicide attempt. 14. Blind subjects 15. Any relation to the Sponsor, Investigator or study staff 16. Any condition, which in the opinion of the Principal Investigator would place the subject at risk or influence the conduct of the study or interpretation of results, including (but not limited to) abnormally low intellectual capacity. 17. Subjects who cannot fully comprehend the implications of the protocol or comply with its requirements or are capable to follow the study schedule for any reason 18. Pregnancy, lactation or inadequate contraceptive method \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Conners' Adult ADHD Rating Scales (CAARS™) | 6 weeks (from visit 1 baseline to visit 6) | The primary efficacy endpoint is the difference in change (decrease) in CAARS (Total ADHD Symptoms Score) between the study groups. The CAARS assess the presence and severity of ADHD symptoms and behaviors in adults. Respondents are asked to report their own experiences by rating items pertaining to their behavior/problems using a 4-point Likert-style format ranging from 0 ('Not at all', 'never') to 3 ('Very much', 'very frequently'). The scale measures ADHD symptoms using a 30-item questionnaire.Total score is the sum of all the items ,min=30 Max=90 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Test of Variables of Attention (TOVA) (Change in ADHD Score From Screening to Visit 6) | 6 weeks( visit 1 baseline to visit 6) | The TOVA is a computerized test that provides information about an individual's sustained attention, speed and consistency of responding, and behavioral self-regulation and executive functioning. ADHD score is a comparison of the subject's response to the CPT test to those of an ADHD group, and is reported as a Z-score. An ADHD score of -1.80 and less fits the profile of the ADHD sample. A score of more than -1.80 (more positive) does not fit the ADHD profile. When comparing ADHD scores the higher the ADHD score the better the performance. |
| Adult ADHD Quality of Life (AAQoL)- Measuring Change in Total Score of AAQoL From Visit 1 to Visit 6 | 6 weeks (from visit 1 baseline to visit 6) | The AAQoL scale provides a validated disease-specific measure of the impact of ADHD on quality of life.It is scored as an overall score (29 items) and four subscale scores: life productivity (11 items), psychological health (6 items), life outlook (7 items) and relationships (5 items). Individual items are scored on a five-point Likert-like scale from 'Not at all/Never' (1) to 'Extremely/Very Often' (5). |
| Clinical Global Impression Scale (CGI-I)Score | 6 weeks from visit 1 baseline to visit 6 | The CGI is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). CGI-I scores range from 1 ('very much improved') through to 7 ('very much worse'). During the conduct of the study, CGI-I evaluations were not done correctly and thus data interpretation is limited. |
Countries
Israel
Participant flow
Recruitment details
subjects recruitment was done in two medical centers Geha and Rambam during Feb 2011-June 2011.
Pre-assignment details
subjects were screened for study eligibility according to the inclusion exclusion criteria. Each subject underwent a battery of rating scales including confirmation of ADHD diagnosis and exclusion of other psychological disorders.In addition medical history was checked and lab test and Electrocardiogram (ECG) were preformed.
Participants by arm
| Arm | Count |
|---|---|
| METADOXINE(MG01CI) Eligible subjects who received 1400 mg of Metadoxine | 60 |
| Placebo Eligible subjects who received 1400 mg of Placebo | 60 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | non compliance | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | sponsor decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | METADOXINE(MG01CI) | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 60 Participants | 60 Participants |
| Region of Enrollment Israel | 120 participants | 60 participants | 60 participants |
| Sex: Female, Male Female | 47 Participants | 26 Participants | 21 Participants |
| Sex: Female, Male Male | 73 Participants | 34 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 58 | 41 / 59 |
| serious Total, serious adverse events | 1 / 58 | 0 / 59 |
Outcome results
Primary
Conners' Adult ADHD Rating Scales (CAARS™)
The primary efficacy endpoint is the difference in change (decrease) in CAARS (Total ADHD Symptoms Score) between the study groups. The CAARS assess the presence and severity of ADHD symptoms and behaviors in adults. Respondents are asked to report their own experiences by rating items pertaining to their behavior/problems using a 4-point Likert-style format ranging from 0 ('Not at all', 'never') to 3 ('Very much', 'very frequently'). The scale measures ADHD symptoms using a 30-item questionnaire.Total score is the sum of all the items ,min=30 Max=90
Time frame: 6 weeks (from visit 1 baseline to visit 6)
Population: The ITT population included all randomized subjects who completed at least one post-randomization visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| METADOXINE(MG01CI) | Conners' Adult ADHD Rating Scales (CAARS™) | -12 units on a scale | Standard Deviation 9.69 |
| Placebo | Conners' Adult ADHD Rating Scales (CAARS™) | -8.93 units on a scale | Standard Deviation 9.26 |
Comparison: For the primary endpoint (CAARS change), median test was applied as the primary analysis due to outlier numbers observed ; secondary analysis of the primary endpoint utilized ANCOVA with adjustment to age, gender and site (which is usually expected to influence the endpoint) as well as baseline values. Additional parametric T-test was applied, but was found less effective due to outlier values.p-value: 0.0093Median
Secondary
Adult ADHD Quality of Life (AAQoL)- Measuring Change in Total Score of AAQoL From Visit 1 to Visit 6
The AAQoL scale provides a validated disease-specific measure of the impact of ADHD on quality of life.It is scored as an overall score (29 items) and four subscale scores: life productivity (11 items), psychological health (6 items), life outlook (7 items) and relationships (5 items). Individual items are scored on a five-point Likert-like scale from 'Not at all/Never' (1) to 'Extremely/Very Often' (5).
Time frame: 6 weeks (from visit 1 baseline to visit 6)
Population: The ITT population included all randomized subjects who completed at least one post-randomization visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| METADOXINE(MG01CI) | Adult ADHD Quality of Life (AAQoL)- Measuring Change in Total Score of AAQoL From Visit 1 to Visit 6 | 10.93 units on a scale | Standard Deviation 11.1 |
| Placebo | Adult ADHD Quality of Life (AAQoL)- Measuring Change in Total Score of AAQoL From Visit 1 to Visit 6 | 5.71 units on a scale | Standard Deviation 15.82 |
Comparison: Analysis of covariance (ANCOVA) was applied for comparing the differences in changes from screening/baseline (Visit 1) to termination (Visit 6) between the study groups with adjustment to confounders (baseline score, site, age, gender, dose and past exposure to any other ADHD drug).p-value: 0.0093ANCOVA
Secondary
Clinical Global Impression Scale (CGI-I)Score
The CGI is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). CGI-I scores range from 1 ('very much improved') through to 7 ('very much worse'). During the conduct of the study, CGI-I evaluations were not done correctly and thus data interpretation is limited.
Time frame: 6 weeks from visit 1 baseline to visit 6
Population: The ITT population included all randomized subjects who completed at least one post-randomization visit.~During the conduct of the study, CGI-I evaluations were not done correctly and thus data interpretation is limited.
Secondary
Test of Variables of Attention (TOVA) (Change in ADHD Score From Screening to Visit 6)
The TOVA is a computerized test that provides information about an individual's sustained attention, speed and consistency of responding, and behavioral self-regulation and executive functioning. ADHD score is a comparison of the subject's response to the CPT test to those of an ADHD group, and is reported as a Z-score. An ADHD score of -1.80 and less fits the profile of the ADHD sample. A score of more than -1.80 (more positive) does not fit the ADHD profile. When comparing ADHD scores the higher the ADHD score the better the performance.
Time frame: 6 weeks( visit 1 baseline to visit 6)
Population: The ITT population included all randomized subjects who completed at least one post-randomization visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| METADOXINE(MG01CI) | Test of Variables of Attention (TOVA) (Change in ADHD Score From Screening to Visit 6) | 4.96 Z score | Standard Deviation 8.86 |
| Placebo | Test of Variables of Attention (TOVA) (Change in ADHD Score From Screening to Visit 6) | 3.01 Z score | Standard Deviation 6.4 |
Comparison: Analysis of Covariance (ANCOVA) was applied for comparing the differences in changes from screening/baseline (Visit 1) to termination (Visit 6) and to Visits 3 through 5 in the primary endpoint, CAARS, and secondary endpoint scales, CGI-S, TOVA and AAQoL between the study groups with adjustment to confounders (baseline score, site, age, gender, dose and past exposure to any other ADHD drug).p-value: 0.0195ANCOVA