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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
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| METADOXINE | Experimental | Eligible subjects will be randomly assigned to receive MG01CI (1,400 mg) |
|
| Placebo | Placebo Comparator | Eligible subjects will be randomly assigned to receive Placebo (1,400 mg) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metadoxine (MG01CI) | Drug | MG01CI 1400 mg, that will be taken daily by the patients for a duration of 6 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Conners' Adult ADHD Rating Scales (CAARSâ„¢) | 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 | 6 weeks (from visit 1 baseline to visit 6) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Adult males and females, 18 to 50 years old, inclusive, at screening visit
Diagnosed with ADHD based on
Clinical severity of at least a moderate level (Clinical Global Impression score of 4 or above)
Female subjects with childbearing potential must agree to use effective contraceptive and have negative urine pregnancy test at screening visit
Able to attend the clinic regularly and reliably
Able to swallow tablets/capsules
Able to understand, read, write and speak Hebrew fluently to complete study related materials
Able to understand and sign written informed consent to participate in the study
Exclusion Criteria:
Subjects who were non-responder to at least two ADHD treatments
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
Any prescription or non-prescription ADHD medications during the 7 days prior to the screening visit
Known or suspected HIV-positive or with advanced diseases such as AIDS, Hepatitis C, Hepatitis B or tuberculosis
History of allergy or sensitivity to B complex vitamins
History or suspicion of PDD, NLD or other psychotic conditions
Use of Vitamin B throughout the study
Use of ADHD medications throughout the study
Use of any psychiatric medications throughout the study
Use of investigational medication/treatment in the past 30 days prior to the screening visit per the discretion of the Investigator
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
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.
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.
Blind subjects
Any relation to the Sponsor, Investigator or study staff
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.
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
Pregnancy, lactation or inadequate contraceptive method
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| Name | Affiliation | Role |
|---|---|---|
| Iris Manor, MD | Geha MC, Israel | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cognitive Neurology unit Rambam Health Care Campus | Haifa | Israel | ||||
| ADHD Unit, Geha Mental Health Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23933905 | Derived | Manor I, Newcorn JH, Faraone SV, Adler LA. Efficacy of metadoxine extended release in patients with predominantly inattentive subtype attention-deficit/hyperactivity disorder. Postgrad Med. 2013 Jul;125(4):181-90. doi: 10.3810/pgm.2013.07.2689. | |
| 23290324 | Derived | Manor I, Ben-Hayun R, Aharon-Peretz J, Salomy D, Weizman A, Daniely Y, Megiddo D, Newcorn JH, Biederman J, Adler LA. A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of extended-release metadoxine in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2012 Dec;73(12):1517-23. doi: 10.4088/JCP.12m07767. |
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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.
subjects recruitment was done in two medical centers Geha and Rambam during Feb 2011-June 2011.
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| ID | Title | Description |
|---|---|---|
| FG000 | METADOXINE(MG01CI) | Eligible subjects who received 1400 mg of Metadoxine |
| FG001 | Placebo | Eligible subjects who received 1400 mg of Placebo |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | METADOXINE(MG01CI) | Eligible subjects who received 1400 mg of Metadoxine |
| BG001 | Placebo | Eligible subjects who received 1400 mg of Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Conners' Adult ADHD Rating Scales (CAARSâ„¢) | 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 | The ITT population included all randomized subjects who completed at least one post-randomization visit. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks (from visit 1 baseline to visit 6) |
|
8 weeks (from time of informed consent to end of study)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | METADOXINE(MG01CI) | Eligible subjects who received 1400 mg of Metadoxine |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Appendicitis | Infections and infestations | (MedDRA) Version 12. | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | (MedDRA) Version 12. | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Yaron Daniely CEO | Alcobra | 972-072-2204662 | yaron@alcobra-pharma.com |
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| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C037845 | metadoxine |
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| 6 weeks( visit 1 baseline to visit 6) |
| 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). | 6 weeks (from visit 1 baseline to visit 6) |
| 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. | 6 weeks from visit 1 baseline to visit 6 |
| Petah Tikva |
| Israel |
| Physician Decision |
|
| sponsor decision |
|
| non compliance |
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Eligible subjects who received 1400 mg of Placebo |
|
|
|
| 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. | The ITT population included all randomized subjects who completed at least one post-randomization visit. | Posted | Mean | Standard Deviation | Z score | 6 weeks( visit 1 baseline to visit 6) |
|
|
|
|
| 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). | The ITT population included all randomized subjects who completed at least one post-randomization visit | Posted | Mean | Standard Deviation | units on a scale | 6 weeks (from visit 1 baseline to visit 6) |
|
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks from visit 1 baseline to visit 6 |
|
|
| 1 |
| 58 |
| 44 |
| 58 |
| EG001 | Placebo | Eligible subjects who received 1400 mg of Placebo | 0 | 59 | 41 | 59 |
| Neuroendocrine tumour | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | (MedDRA) Version 12. | Systematic Assessment |
|
| Asthenia | General disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Bacteriuria | Infections and infestations | (MedDRA) Version 12. | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Disturbance in attention | Psychiatric disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Dizziness | Nervous system disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Dysmenorrhoea | Reproductive system and breast disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Fatigue | General disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Headache | Nervous system disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Impatience | Psychiatric disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Initial insomnia | Psychiatric disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Memory impairment | Nervous system disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Nervousness | Psychiatric disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Pyrexia | General disorders | (MedDRA) Version 12. | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | (MedDRA) Version 12. | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | (MedDRA) Version 12. | Systematic Assessment |
|
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