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Safety and Tolerability Study of Metadoxine Extended Release (MDX) (Previously Known as MG01CI) in PI-ADHD Adolescent Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02189772
Recruitment Status : Completed
First Posted : July 15, 2014
Last Update Posted : March 4, 2015
Information provided by (Responsible Party):
Alcobra Ltd.

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of a single administration of Metadoxine Extended Release (MDX) formulation for the treatment of adolescents diagnosed with ADHD that have predominantly inattentive symptoms. The study will also try to evaluate the efficacy of MDX and its level in the blood.

Condition or disease Intervention/treatment Phase
ADHD, Predominantly Inattentive Type Drug: Metadoxine extended release Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 83 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Randomized, Double-blind, Placebo-controlled, Multi-center, Fixed Dose Study Designed to Evaluate the Safety and Tolerability of a Single Administration of MG01CI (Metadoxine Extended Release, MDX) in Adolescents With Predominantly Inattentive Attention Deficit Hyperactivity Disorder
Study Start Date : August 2014
Actual Primary Completion Date : January 2015
Actual Study Completion Date : January 2015

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: MDX (metadoxine extended release)

Route of administration: oral

The dose of MDX (approximately 14-22 mg/kg) will be determined by the subject's weight at the baseline visit as follows:

  • 40-49 kg 700 mg consisting of a 700 mg tablet
  • 50-64 kg 1050 mg consisting of a 700 mg tablet, a 350 mg tablet
  • 65-100 kg 1400 mg consisting of two 700 mg tablets
Drug: Metadoxine extended release
Other Name: MDX

Placebo Comparator: placebo
Placebo tablets will be similar in appearance (color and size) to the investigational product
Drug: Placebo
Inactive drug
Other Name: Sugar pill

Primary Outcome Measures :
  1. Safety and Tolerability [ Time Frame: Up to 6 weeks ]
    Frequency of treatment emergent adverse events (AEs). Frequency of subjects who withdrew early from the study due to AE.

Secondary Outcome Measures :
  1. Efficacy [ Time Frame: Up to 5 weeks ]

    Change in TOVA 8 API from Baseline to 3-5 hours post-dose for all subjects and for subjects who have an abnormal TOVA 8 API at baseline (score <0). Change in TOVA sub-scores1 from Baseline to 3 -5 hours post-dose for all subjects and for subjects who have an abnormal TOVA 8 API at baseline (score<0).

    TOVA Response Rates: Change in TOVA 8 API from abnormal (ADHD score below zero, sub-scores below 85) to normal value post-dose. Improvement of 0.8 points in TOVA 8 API or 8 points in any sub-score for all subjects and for those subjects who have an abnormal TOVA 8 API at baseline (score<0).

    Change in each of WISC-IV subtests (Digit Span, Coding, Letter Number Sequencing, and Symbol Search) from Baseline to post-dose. Change in Working memory and Processing Speed from Baseline (derived from subtests)

  2. PK [ Time Frame: Up to 5 weeks ]
    Blood samples for baseline plasma concentration of metadoxine will be collected at Screening. On study visit 2 (Day 1), subjects will have another PK blood sample at 1-2 hours and 3-4 hours post-dose. The PK samples will be sent to the bioanalysis laboratory for assay.

Other Outcome Measures:
  1. Exploratory endpoint [ Time Frame: Up to 5 weeks ]
    Change in TASS score from Baseline to 3-5 hours post-dose

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   13 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Adolescent males and females, 13-17 years old, inclusive, at screening visit, with visible axillary hair.
  2. Diagnosed with predominantly inattentive ADHD based on DSM V criteria for ADHD as assessed by the Adolescent ADHD Clinician Diagnostic Scale (Adol-CDS V1.2).
  3. Clinical severity of at least a moderate level (Clinical Global Impression-Severity score of 4 or above).
  4. STAI State score of <52, STAI Trait score of <52 and BDI score of <19.
  5. Sexually active subjects of childbearing potential must agree to use an effective contraceptive throughout the study (e.g., oral contraceptives or Norplant®; a reliable double barrier method of birth control [diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam]; intrauterine devices; vasectomy; or abstinence) and for at least a month after the study, and must have a negative serum pregnancy test at the Screening Visit. Females of childbearing potential are defined as women who are between menarche and 2 years post-menopause and who are not surgically sterilized. Males and Female subjects who are not sexually active, and who agree to be abstinent throughout the study, will not be required to use birth control.
  6. Subject is able to attend the clinic regularly and reliably.
  7. Subject is able to swallow tablets and capsules.
  8. Able to understand, read, write and speak Hebrew fluently to complete study related materials.
  9. Parents or legal authorized guardians (LAR), and subject, able to understand and sign written informed consent/assent to participate in the study
  10. Subject and parents/LARs provide assent/consent to participate in the study. per applicable laws and regulations
  11. Subject weighs ≥40 kg or ≤100 kg

Exclusion Criteria:

  1. Subject has any psychiatric condition (e.g., schizophrenia or personality disorder as diagnosed by DSM-V) or clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation as determined by the investigator using medical history, physical examination, neurological examination, laboratory tests, and electrocardiograms. Common diseases such as mild hypertension, well-controlled type 2 diabetes mellitus (hemoglobin A1C <6.5%), 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 before randomization and subsequently throughout the study. If there are any concerns about the suitability of the subject's medical or surgical condition, the investigator should review the subject's history with the medical monitor.
  2. Subject has a known or suspected human immune deficiency virus positive status or has diseases such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis.
  3. Subject has a history of an allergy or sensitivity to B-complex vitamins.
  4. Subject has a history of intellectual disability or a history or suspicion of autism spectrum disorder.
  5. Subject has a current clinically significant Axis I diagnosis (other than ADHD) according to the K-SADS-PL or has a lifetime history of bipolar disorder or psychosis.
  6. Subject has used mega-dose vitamin B6/pyridoxine during the 28 days before the Randomization Visit. Subjects will be allowed to have a 28-day washout of mega-dose vitamin B6/pyridoxine after the Screening visit. Routine multivitamin supplements will be allowed.
  7. Subject has used high-dose supplements of omega-3 fatty acids ≥ 500 mg on at least 1 day (such as softgels, capsules, or fish oils; regular daily dietary consumption of fish is allowed) or folic acid supplements (other than routine multivitamin supplements) during the 2 weeks before the Randomization Visit.
  8. Subject has used an investigational medication/treatment in the 30 days before the Screening Visit
  9. Subject has used any medication or food supplement that the investigator or the medical monitor considers unacceptable during the 14-day period before randomization. This includes, but is not limited to, sympathomimetic agents, clonidine, guanfacine, norepinephrine reuptake inhibitors, serotonin reuptake inhibitors, sedative-hypnotics, benzodiazepines, sedating antihistamines, herbal preparations that would confound safety or efficacy assessments, and narcotics. Questions regarding the acceptability of medications and food supplements (such as melatonin) will be discussed with the medical monitor before study entry.
  10. Subject has a current drug or alcohol dependence or substance abuse disorder according to DSM-V Text Revision criteria (excluding nicotine) or a history of such dependence within the last 6 months. Subject should also agree to keep their caffeine intake consistent and refrain from consuming ≥300 mg per day of caffeine (no more than three 8-ounce servings of coffee) during the study.
  11. Subject has suicidality, defined as active ideation, an intent or plan, or any significant lifetime suicidal behavior (actual attempt, aborted attempt, interrupted attempt, or act or preparation towards imminently making a suicide attempt). Subjects exhibiting history (within previous 12 months) of non-suicidal self-injurious behavior will be excluded.
  12. Subject has taken any prescription or non-prescription ADHD medications during the 14 days before the randomization visit or 28 days in the case of atomoxetine..
  13. Subject is significantly visually impaired to an extent that is not able to be corrected by prescription glasses or contact lenses
  14. Subject is closely related to the sponsor, investigator, or study staff. Eligibility of subjects with any relationship to the sponsor, investigator, or study staff will be discussed with the medical monitor before study entry.
  15. Subject has any condition that, in the principal investigator's opinion, 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 as judged by the investigator.
  16. Subject cannot fully comprehend the implications of the protocol, cannot comply with its requirements, or is incapable of following the study schedule for any reason.
  17. Subject is pregnant, lactating, or using an inadequate contraceptive method.
  18. Subject is not currently participating in other clinical trials.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02189772

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Rambam Medical Center
Haifa, Israel
Shalvata Mental Health Center
Hod Hasharon, Israel
Hadassah-Hebrew University Medical Center,
Jerusalem, Israel
Geha Medical Centre
Petah Tiqva, Israel
The Chaim Sheba medical center, Tel Hashomer
Ramat Gan, Israel
Assaf Harofeh MC
Zrifin, Israel
Sponsors and Collaborators
Alcobra Ltd.
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Principal Investigator: Iris Manor, MD ADHD Unit, Geha Medical Center, Petah Tikva, Israel
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Responsible Party: Alcobra Ltd. Identifier: NCT02189772    
Other Study ID Numbers: AL015
First Posted: July 15, 2014    Key Record Dates
Last Update Posted: March 4, 2015
Last Verified: December 2014
Keywords provided by Alcobra Ltd.:
Additional relevant MeSH terms:
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Attention Deficit Disorder with Hyperactivity
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Alcohol Deterrents