Clinical trial NCT01853280
Conditions: Attention Deficit Hyperactivity Disorder
Keywords: ADHD Attention Deficit Hyperactivity Disorder Deplin L-methylfolate Natural Treatments Medical Food
Sponsor: Massachusetts General Hospital
Start date: 2014-05-01; Completion date: 2017-09-01
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study seeks to evaluate initial evidence for the effect of L-methylfolate supplementation to OROS-Methylphenidate pharmacotherapy on ADHD symptoms and associated features in adults with ADHD, as well as tolerability of this supplementation. The investigators will conduct a 12-week double-blind randomized placebo-controlled trial with L-methylfolate supplementing open-label OROS-Methylphenidate (OROS-MPH). The investigators propose to examine 40 adult (ages 18-55) subjects satisfying the DSM-IV diagnostic criteria for ADHD.

Detailed description:

Arms: arm 1: 15 mg of L-Methylfolate (Deplin®) daily for 12 weeks as a supplement to OROS-Methylphenidate. arm 2: 15 mg matched placebo comparator, with open-label OROS-Methylphenidate
Interventions: intervention 1: L-methylfolate intervention 2: OROS-Methylphenidate intervention 3: Placebo
Intervention descriptions: intervention 1: 15mg/day L-methylfolate. intervention 2: All subjects will be treated with open-label OROS-MPH intervention 3: 15 mg matched placebo comparator, with open-label OROS-Methylphenidate

Protocol documents:
Prot_000.pdf: 
 
Protocol: 
L-methylfolate supplementation to OROS-Methylphenidate Pharmacotherapy in ADHD: A Double-Blind, 
Placebo-Controlled, Randomized Clinical Trial 
 
 
 
 
Craig B.H. Surman, MD 
Massachusetts General Hospital 
Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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I. 
BACKGROUND AND SIGNIFICANCE 
There is need to improve management of Attention Deficit Hyperactivity Disorder 
Attention-deficit hyperactivity disorder (ADHD) is a neurobiological disorder associated with high levels 
of impairment in adulthood 1-4, and is estimated to affect up to 5% of adults worldwide 5-7.  While currently 
approved pharmacotherapies for adults with ADHD are often effective, there are limits to their clinical utility. 
Stimulants are the mainstay of treatment for adults with ADHD due to larger effects than nonstimulants on 
ADHD 8-11. Two decades of study by our research team and others, including controlled studies of stimulant 
medications and open studies of tricyclic, monoamine oxidase inhibitor, and atypical antidepressants, reveal that 
20-50% of adults with ADHD are considered pharmacologic nonresponders [Wender, 1998 #24880; Wilens, 1998 
#10538; Biederman, 2010 #24878]. Moreover, adults who are considered responders clinically often show a 50% 
or less reduction in the core symptoms of ADHD12. In addition to residual ADHD symptom burden, 
pharmacologically-treated patients also have residual EFD burden. For example, In a recent study of robust open 
label dosing with the amphetamine lisdexamfetamine, 40% of adults with ADHD were considered to have 
unresolved and clinically significant impairment in essential elements of behavioral control [Brown, 2010 
#25825]. 
L-methylfolate is a medical food that may support catecholamine activity  
L-methylfolate (also known as 5-methyltetrahydrofolate) is identified by the FDA as a medical food.  A 
medical food, by FDA definition, is a specially formulated product with components that are “generally 
recognized as safe” [Section 5(b) of the Orphan Drug Amendments (21 U.S.C. 360ee]. L-methylfolate is 
approved as Deplin for suboptimal folate levels in depressed individuals or hyperhomocysteinemia in 
schizophrenia [Deplin [package insert]. Covington, LA: PamLab, L.L.C.; 2011 May]. 
 
Conventional therapies for ADHD are thought to work in part through reuptake blockage and/or 
increased release of the catecholamines dopamine and norepinephrine 13, 14. Because of its role in the synthesis of 
the monoamine neurotransmitters serotonin, dopamine, and norepinephrine, supplementation with L-methylfolate 
could support higher levels of these neurotransmitters. Specifically, folate influences the rate of synthesis of 
tetrahydrobiopterin, which is a cofactor in the hydroxylation of phenylalanine and tryptophan – rate-limiting steps 
in the formation of the catecholamines dopamine, serotonin and norepinephrine 15 [Stahl, 2008 #25823]. 
Furthermore, L-methylfolate is actively transported across the blood-brain barrier. Once it crosses this 
barrier, L-methylfolate may bind to presynaptic glutamate receptors, where it might modulate release of 
catecholamines or other neurotransmitters 16. 
The hypothesis that L-methylfolate supplementation can improve mental health through effect on 
catecholamines is supported by evidence that L-methylfolate may aid depression symptoms, both in combination 
with antidepressant treatment and as monotherapy. Improvement in depressive symptoms has been observed in 
individuals with both normal and low folate levels [Fava, 2009 #25817; Godfrey, 1990 #25819; DiPalma, 1994 
#25824; Passeri, 1993 #25820]. A recent chart review demonstrated that addition of either 7.5 mg or 15 mg of l-
methylfolate supplementation to an antidepressant was associated with greater and faster reduction in depression 
symptoms. Over two and a half times as many individuals experienced a ≥ 2-point improvement in Clinical 
Global Impression Severity ratings, and occurrence of major improvement occurred 43% faster 17. In two recently 
completed multi-center double-blind placebo controlled trials, 223 patients determined to be inadequately 
responding to an SSRI for depression were given either L-methylfolate or placebo.  L-methylfolate 
supplementation at 15 mg was associated with greater response rate (defined as 50% reduction in Hamilton 
depression scale rating) and reduction in depression symptoms. Only one patient that had an undetected history of 
bipolar disorder discontinued the trial, due to mood elevation 18. Furthermore, evidence from these trials suggests 
that L-methylfolate may be particularly effective in the presence of particular biomarkers, such as a body mass 
index (BMI) greater than 30 kg/m2 19.  
 


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Because L-methylfolate could facilitate reduction of ADHD symptoms via effects on catecholamine 
levels, we propose to conduct a double-blind clinical trial enrolling and exposing 40 adults with ADHD through 
midpoint of the study with an enrollment cap of 50 subjects. Half will be receiving standard OROS-
methylphenidate treatment, and half receiving OROS-methylphenidate augmented by L-methylfolate.  We thus 
propose to study augmentation of standard of care treatment.  We would start both agents simultaneously, and 
monitor change in ADHD symptoms as well as adverse events weekly over six weeks, and then at nine and 
twelve weeks.  Six weeks is a typical interval over which stimulant effect on ADHD may be seen, and we will 
extend observation to 12 weeks to measure L-methylfolate effects that might occur during a reasonable timeframe 
for clinical intervention. 
 
II. 
SPECIFIC AIMS 
Aim 1:  Assess the safety of L-methylfolate in the treatment of ADHD among stimulant treated ADHD 
adults. Hypothesis 1: L-methylfolate will be well tolerated when used in combination with OROS-
methylphenidate for treating adults with ADHD. Adverse events occurring during combined use of L-
methylfolate plus OROS-methylphenidate will be similar to those experienced by participants on OROS-
methylphenidate alone. 
Aim 2: Assess effect of L-methylfolate on ADHD symptoms and associated features in stimulant treated 
ADHD adults. Hypothesis 2: Compared to OROS-MPH treatment alone, L-methylfolate supplementation of 
OROS-methylphenidate treatment will yield a greater or more rapid reduction of (2a) ADHD symptoms (as 
measured by the AISRS and CGI), (2b) symptoms of executive dysfunction (as measured by BRIEF-A subscales) 
and (2c) functioning (as measured by the GAF). These are reasonable hypotheses given that OROS-
methylphenidate and other stimulants are not fully effective in treating ADHD symptoms 20. 
 
EXPLORATORY AIMS 
Aim 3: Assess whether biomarker measurements predict response to L-methylfolate.  As detailed elsewhere 
in this protocol, ongoing research suggests that biomarkers, including body-mass index, may be suitable for 
predicting response to L-methylfolate augmentation in depression.  In this protocol, we detail storage of blood 
samples suitable to explore biomarker-related hypotheses. Lists of biomarkers of interest (both serum biomarkers 
and genetic biomarkers) for this study have been provided as attachments. 
 
III. SUBJECT SELECTION 
We plan to enroll up to 50 subjects in the study. We will recruit subjects from the pool of existing subjects and 
new referrals to the Pediatric Psychopharmacology and Adult ADHD Program at the MGH.  If a potential 
subject's clinician ascertains that the patient has an interest in study participation, the clinician will offer contact 
information for the study to him or her.  The patient can then contact the study coordinator independently for 
more information on the actual study. If a subject is enrolled from among an investigator’s own patients through 
the aforementioned referral process, the process of informed consent must be completed by a physician colleague 
who is on the approved study staff and whom the potential subject has not seen privately. Under no circumstances 
will a physician investigator complete informed consent with his or her own private patient. All subjects that enter 
the study will undergo standard screening and diagnostic procedures. Clinical records are not scanned in order to 
recruit subjects. Subjects who have completed a previous medication trial in our program may be eligible to 
participate in this study. Other medical records on a subject will not be used at any point. 
The majority of subjects referred to our program first participate in our general screening protocol entitled, 
“Screening Protocol for Adults with Attention Deficit Hyperactivity Disorder” (Protocol # 2002-P-001856). After 


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participating in this screening protocol, subjects are assigned to specific studies based upon eligibility 
requirements (i.e. age, prior medication efficacy or tolerability).  
Our study is designed to allow a future exploratory analysis of whether biomarkers (serum biomarkers, genetic 
biomarkers, and body mass index (BMI)) predict response to L-methylfolate.  Because we wish to have an 
adequate sample of adults with biomarkers of interest, including BMI, we will enroll all eligible adults, and assess 
midway through enrollment whether the number of individuals with biomarkers of interest is projected to be 
sufficient for the analysis. If necessary, we will submit an amendment to increase enrollment to ensure the number 
of participants will be sufficient for the analysis 21. 
Study Entry Criteria 
Inclusion 
1. Male or female adults ages 18-55 years of age. 
2. A diagnosis of childhood onset ADHD, meeting all but the age of onset criteria according to the Diagnostic 
and Statistical Manual of Mental Disorders, Fourth Edition [American Psychiatric Association, 2000 #23616] 
(DSM-IV), based on clinical assessment.  Childhood onset will be defined according to established research 
criteria, requiring onset of two symptoms of inattentive or of impulsive/hyperactive traits by the age of 12 22. 
3. A score of 24 or more on the Adult ADHD Investigator Symptom Report Scale (AISRS). 
Exclusion 
1. A history of non-response or intolerance to methylphenidate at adequate doses as determined by the clinician.  
2. A history of intolerance to L-methylfolate supplementation.  
3. Pregnant or nursing females. 
4. Serious, unstable medical illness including hepatic, renal, gastroenterological, respiratory, cardiovascular, 
endocrinologic (thyroid), neurologic (seizure), immunologic, or hematologic disease.  
5. Glaucoma. 
6. Clinically unstable psychiatric conditions including suicidality, homicidality, bipolar disorder, psychosis, 
history of or current marked anxiety, tension or agitation potentially exacerbated by a stimulant, or lifetime 
history of any other clinically serious condition potentially exacerbated by a stimulant, such as mania or 
psychosis. 
7. Significant impairment due to tics, based on clinician judgment. 
8. A family history or diagnosis of Tourette’s syndrome 
9. Current (within 3 months) DSM-IV criteria for abuse or dependence with any psychoactive substance other 
than nicotine. 
10. Multiple adverse drug reactions. 
11. Any other concomitant medication considered to be effective for management of ADHD; individuals on 
stable treatment with agents with central nervous system activity will be allowed to participate, as detailed in 
the Concomitant Medication portion of the protocol. 
12. Current use of MAO Inhibitor or use within the past two weeks. 
13. Investigator and his/her immediate family; defined as the investigator’s spouse, parent, child, grandparent, or 
grandchild. 
14. Use of supplemental folic acid greater than 400 mcg per day, L-methylfolate, or Omega-3 Fatty Acids greater 
than 800 mg per day within two weeks prior to the baseline study visit. 


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Subjects need not be methylphenidate-naïve; however, no individual will be removed from an effective and stable 
treatment regimen for the purposes of participating in the current study. 
IV. SUBJECT ENROLLMENT 
Informed consent will be obtained prior to the performance of any protocol procedures and prior to administration 
of study drug. The informed consent document will be used to explain in simple terms the risks and benefits of 
study participation to the subject. The nature of the study will be fully explained to the subject by a board-
certified physician who is either the primary investigator or a co-investigator. The subject will be encouraged to 
ask questions pertaining to their participation in the study and the subject may take as much time as they feel 
necessary to consider his/her participation in the study as well as consult with family members or their physicians.  
Participation in this study is voluntary and the subjects may withdraw from the study at any time. The IRB-
approved informed consent documents will be signed and dated by the subject and the physician obtaining 
consent, and a copy of this document will be provided to the subject.  
V. STUDY PROCEDURES 
We will conduct a 12-week, double blind, placebo-controlled, randomized clinical trial to compare efficacy and 
tolerability of L-methylfolate as a supplement to OROS-methylphenidate (OROS-MPH) in ADHD adults. We 
will randomize 20 subjects to L-methylfolate plus OROS-MPH and 20 to placebo plus OROS-MPH. This is 
ecologically valid because long-acting stimulants are first line treatments for ADHD.  
After providing study information and obtaining IRB approved informed consent, participants will undergo a 
comprehensive assessment including a psychiatric assessment reviewing current and lifetime DSM-IV Axis I 
conditions, medical history including history of any cardiac symptoms or abnormalities reported on routine 
clinical exams, and a neuropsychological evaluation that can be completed at evaluation or baseline. If a patient 
has never had a cardiac physical exam a clinician will conduct one. The information obtained at this visit will be 
reviewed to assure that all inclusion and exclusion criteria are met prior to receiving study medication at the 
baseline visit. Subjects who do not meet all the criteria for enrollment after these assessments will be 
discontinued. 
We anticipate that subjects may enter this trial following completion of withdrawal from other protocols in our 
office, and that there may be procedural overlap. So as to not burden subjects with redundant time commitments, 
we will use the following diagnostic data previously collected:  If a subject has completed an evaluation with one 
of the study clinicians within the previous 90 days prior to entrance into this study, they will not be asked to 
repeat any overlapping diagnostic procedures. With subjects’ permission, we will use the diagnostic data that had 
been previously collected. However, the study clinician will review the interval time period to assess for clinically 
significant medical or psychiatric history, to ensure that the subject meets appropriate study entrance criteria.  
Any subjects taking medication exclusionary to the study must be tapered off this medication prior to baseline 
visit for the length of 5 half-lives of the medication, corresponding to 95% of the agent leaving the participant’s 
system), plus sufficient time to assess the eligibility of the participant off medication. Only subjects with 
inadequate response to their current treatment will be tapered from medication. Subjects will not enter the study if 
it would require tapering a medication that is optimally and comfortably managing a clinical concern.  Medication 
tapers will be monitored by the study clinician in agreement with the research subject and in consultation with the 
prescribing physician. 
Participants who fulfill the inclusion and exclusion criteria will be randomized to receive either OROS-
methylphenidate and placebo or OROS-methylphenidate and L-methylfolate treatment for the period of 12 weeks. 
We will create the randomization schedule with the RALLOC procedure from STATA.  
Vital signs (blood pressure, pulse, weight) will be measured at every visit. Height, waist circumference, and body 
mass index will be measured at baseline and at the end of the study. An EKG will be conducted at the beginning 
and the end of the study to monitor cardiac safety. A urine drug screen will be performed at evaluation, week 6, 
and week 12. If the participant is found to have taken an illicit drug, he/she will have a discussion with the doctor 


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to determine if he/she can be in the study; subjects will be discontinued if there is suspicion of ongoing substance 
use. Females who are able to have children will also have a urine pregnancy test at evaluation, week 6, and week 
12. If a participant has a positive pregnancy test she will not be able to take part in the study. Female subjects of 
childbearing potential must agree to use a medically acceptable form of birth control (such as male for female 
condoms with or without spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed 
IUD, hormonal contraceptives like birth control pills, or abstinence) while they are receiving study medication 
and for 1 month after the last dose of study medication.  In the event that a subject becomes pregnant, we will ask 
the subject’s permission to obtain information about the outcome of the pregnancy and the condition of the 
newborn. Those subjects who terminate study participation before the completion of the study will be asked to 
complete all tasks scheduled to take place on the final study visit at the time of study discontinuation. 
Subjects will be evaluated at weeks 1, 2, 3, 4, 5, 6, 9 and 12 in the office, with optional phone contact between 
these visits. The need for phone contact between visits will be established by the clinician at office visits, or by 
needs of the subjects as they arise. At each office visit assessment of safety and efficacy will be obtained by 
administering measures of efficacy (CGI at every visit excluding the screening visit, AISRS at every visit, and 
GAF at baseline, week 6 and study endpoint), tolerability (adverse events), and safety (vital signs).  
Neuropsychological assessments will be repeated at study endpoint.   
Although every effort will be made to encourage subjects to keep regularly scheduled appointments, in the event 
that a subject is unable to come into the office within a reasonable timeframe of a scheduled visit, and the treating 
research clinician feels that subject safety will not be jeopardized by doing so, the clinician can conduct the visit 
with the subject over the telephone. However, study evaluation visit, baseline visit, mid-point visit (week-6) or the 
final study visit may not be conducted over the phone. Additionally, phone visits may not replace scheduled office 
visits for two consecutive visits. This interval of office visits with phone contact as needed has proven utility in 
both clinical care and in a recent methylphenidate trial conducted in adults at our research unit. If a study visit 
occurs over the phone, all assessments and rating scales for that visit will be conducted by phone, excluding vital 
signs, as these can only be collected in person and links to the subject rating form may be sent to the subject in an 
encrypted email for remote completion.  
 
Collection of blood sample for future biomarker analysis 
We are aware of recently completed research and ongoing data analysis that suggests that particular biomarkers 
may predict clinical response to L-methylfolate augmentation. As such, we intend to collect blood samples from 
subjects to conduct analyses on some or all of the biomarkers listed in the protocol attachments.  
 
After informed consent has been obtained, a single blood draw will be performed for serum and plasma 
biomarkers A blood sample of 20ml (approximately 1.5 tablespoons) following overnight fasting will be drawn at 
the screening visit or baseline visit. From this sample, we will prepare three types of blood samples suitable for 
the analyses we anticipate: plasma (suitable for possible analysis of homocysteine, hs-CRP, SAMe, ADMA, 
MDA, and F2-isopropstane), serum (suitable for possible analysis of folate, vitamins B12 and B6), and whole 
blood hemolysate (suitable for possible analysis of red cell folate). These blood samples will be prepared by our 
department and will be stored in Pediatric Psychopharmacology on Warren 6, or delivered to the Brigham 
Research Assay Core (BRAC) lab at BWH, while other samples formerly assayed by Dr. Sluss' lab have 
been transferred to secure freezers on Bulfinch 5 until a) biomarker analyses are completed or b) samples are 
no longer suitable for biomarker analysis or of use to the current project and are destroyed. The samples will then 
be sent to Dr. Raina Fichorova at BWH for aliquoting of serum and further analyses. Dr. Fichorova’s lab will 
prepare an aliquot for transfer to Dr. Robert Cabrera’s lab at Dell Medical School in Austin, Texas for 
analysis for presence of antibodies to the folate receptor. Unique identifiers will be linked to the aliquots in a 
locked password protected database which only approved study staff will have access to. All efforts will be made 
to protect subject privacy, and samples will be labeled with codenames and medical record numbers. The sponsor 
will not have access to information that identifies participants’ samples. Results from laboratory testing will 


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become a part of the subjects’ MGH medical records, however no information regarding participation in the study 
will become a part of the medical record. In the event that a subject completes screening procedures but is found 
ineligible for participation in the clinical trial, their blood samples will be destroyed.  
 
Upon signing consent for the study, subjects will also be given the option of providing an additional 10 mL 
sample (about 1 tablespoon) during their blood draw that will be suitable for future analysis of MTHFR genetic 
polymorphisms. The genotyping of these samples will be conducted at the Psychiatric & Neurodevelopmental 
Genetics Unit (PNGU) at MGH, under the supervision of Dr. Jordan Smoller, M.D.  Samples will be stored at 
PNGU in the Simches Research Building until the proposed biomarker analyses are completed, or samples are no 
longer suitable for analysis, after which they will be destroyed. This genetic sample will be collected for research 
purposes only, and no individual results will be given back to study participants. Any record of participation in 
the genetic analysis will not be included in the subject’s medical record. Those subjects who choose not to 
provide a sample for genetic analysis may still participate in the study. Furthermore, it will be explained in the 
consent form that, should a subject choose to provide a sample for genetic analysis, he/she may request that their 
samples be destroyed at any time by contacting a member of the study staff. If a subject is found ineligible after 
completing screening procedures, their sample will also be destroyed. 
 
Samples for genetic analysis will be labeled with codes only. The key to this code will be maintained by the study 
coordinator in a password-protected, encrypted file, and the sponsor will not have access to this document. In the 
event that a re-draw is recommended after DNA extraction, PNGU will notify a member of the study staff. At that 
time the clinician will determine if the subject should be contacted for a second sample; subjects will not be 
required to provide a second sample if they do not wish to do so.  
 
A complete list of the possible biomarkers to be analyzed using these blood samples is included as an attachment.  
 
During the study, the following, assessments and instruments will be used: 
Brief neuropsychological measures: 
 
Wechsler Abbreviated Scale of Intelligence (WASI-II) Vocabulary and Matrix: to calculate verbal, 
performance, and full-scale IQ. If a subject has completed a neuropsychological evaluation within the 
previous year prior to entrance into this study, we will use the previously collected IQ score, with their 
permission. 
Cambridge Neuropsychological Test Automated Battery (CANTAB):  
CANTAB is a computer-based system designed to look at frontal lobe (executive functioning). Select subtests 
will include the following:  
 
Spatial Working Memory (SWM), tests comprehension, learning and reversal.  
 
Stockings of Cambridge (SOC), assesses spatial planning and motor control.  
 
Intra-Extra Dimensional Set Shifting (IED), tests rule acquisition and attentional set shifting.  
 
Reaction Time (RTI), measures speed of response. 
 
Rapid Visual Information Processing (RVP), tests sustained visual attention.  
 
Affective Go/No-go (AGN), assesses information processing biases for positive and negative stimuli.  
 
Verbal Recognition Memory (VRM), assesses immediate free recall, and immediate and delayed 
recognition memory 
Background Information: 


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 
Subjects will complete a brief interview after the informed consent process to obtain demographic 
information including: socioeconomic status, educational history, occupation, marital status, smoking 
status, past head injuries, and past traumas.  
Clinician rated assessments: 
 DSM-IV Global Assessment of Functioning (GAF) scale. The GAF will assess global functioning using a 
scale from 1 (worst) to 100 (best). 
 Clinical Global Impressions (CGI) scale for ADHD. The CGI is a measure of illness severity, 
improvement, and efficacy of treatment. 
 DSM-IV based Adult ADHD Investigator Symptom Rating Scale (AISRS). Each of the individual 
symptoms of ADHD is rated 0 to 3 on a scale of severity. 
 Hamilton Depression (HAM-D) and Anxiety 23 (HAM-A) Scales to evaluate depression/anxiety 
symptoms. 
 Adverse Experiences and Concomitant Medications. 
Subject rated scales: 
 The 18-item Adult ADHD Self-Report Scale (ASRS) to evaluate frequency of ADHD symptoms on a 
scale of 0 to 4.  
 The 86-item Behavior Rating Inventory of Executive Function – Adult Form (BRIEF-A) to assess levels 
of executive function deficits. 
 The Adult Self-Report Form 24 (ASR) to measure a wide range of psychiatric syndromes (i.e., depressive 
problems, anxiety problems, antisocial personality problems) in adults. The ASR provides dimensional 
scale scores for each syndrome that are age- and gender-normed. 
 The Social Adjustment Self Report Questionnaire (SAS) to measure overall social adjustment and 
satisfaction. 
 The 16-item Quality of Life Enjoyment & Satisfaction Questionnaire (Q-LES-Q) to measure overall 
satisfaction across different aspects of daily life. 
 The 8-item Emotional dysregulation subscale of the Barkley Current Behavior Scale—Self-Report (CBS 
DESR) to measure emotional reactivity. 
 The 25-item Endicott Work Productivity Scale (EWPS) to measure behaviors and feelings likely to 
reduce productivity and efficiency in work activities. 
Study participants may request the results of their cognitive testing. In this case, the subject will receive a letter 
providing a basic interpretation of the results and referring the subject to the department's supervising 
neuropsychologist for any questions or concerns. 
Data will be collected using StudyTRAX. StudyTRAX is an electronic data capture system that streamlines data 
collection and management and ensures data integrity. StudyTRAX software allows researchers to design and 
implement study surveys for collected, story, retrieving, and manipulating data electronically.  
Participants and/or research staff enter survey responses into electronic assessment forms, and the responses are 
then transmitted securely via encrypted connection and stored in a secured database. This electronic data capture 
obviates the need for subsequent data entry by staff, thus minimizing human error.  However, it is still possible 
that rating scales will be collected in paper form in the case that StudyTRAX is not working or unavailable. 
 
 
These surveys are completed securely via the internet by using any device with standard web access and browsers. 
For this study, participants and staff will complete the electronic assessments on computer terminals at the 


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research site under the supervision of study staff. If the study visit has been conducted over the telephone or if 
subjects need to leave before completing scales, subjects may have links to subject rating forms securely emailed 
to them for remote completion. The links will be unique to the subject completing the questionnaires, preventing 
them from accessing any other data stored on the password-protected database. Only those subjects who receive 
the links via email will be allowed to access the forms. 
In the event that the electronic data capture system is unavailable during a study visit (due to technical issues), 
rating scales will be collected in paper and then entered into the program manually once the system becomes 
available.  
For quality control purposes, audio of clinician-administered measures completed during the visits may be 
recorded, with subjects’ permission. These recordings will be used to monitor quality control and inter-rater 
reliability in this study by the PI. Each audio file will be coded with subject initials and number to maintain 
confidentiality. These tapes will be de-identified and stored in a password-protected file. 
Upon completion of the study, participants can choose to pursue follow-up care, as possible, at our MGH practice 
or continue treatment with their primary care physician. Study clinicians may also offer psychiatric referrals to 
treaters in their communities.  
Study Medication 
At the baseline visit, subjects will receive a prescription for OROS-MPH and will be randomized to receive either 
L-methylfolate or placebo (under double blind conditions).  
OROS-MPH and L-methylfolate/placebo will be administered concurrently. OROS-MPH will be openly 
prescribed, starting with an initial dose of 36 mg/day. OROS-MPH will be titrated to optimal response (not 
exceeding a maximum daily dose of 1.3 mg/kg or 108 mg/day, whichever is lower), according to clinician 
judgment, during the first six weeks of the trial.  During this titration period, dose will be increased on a weekly 
basis in 18-36 mg/day increments, according to clinician judgment, with the goal of obtaining a well-tolerated and 
effective dose. At any time, the dose may be reduced if adverse effects present or if the subject discontinues 
treatment. At subsequent visits, a higher dose may be resumed if tolerated. 
L-methylfolate dosing will start and remain at 15 mg/day of L-methylfolate for the duration of the study in the 
form of PAMLAB brand L-methylfolate. PAMLAB is also able to make a matched placebo product and will 
provide us with a detailed Certificate of Analysis attesting to the contents of the caplets. Our proposed dosing is 
consistent with the current indication for L-methylfolate as a medical food. The study clinician will be responsible 
for dispensing the L-methylfolate at our research office. In order to maintain the blind, the MGH Clinical Trials 
Pharmacy will prepare the L-methylfolate drug/placebo, and the study clinician will not know whether he/she is 
dispensing active drug or placebo. After the study, subjects can obtain L-methylfolate by prescription from their 
current treater. Study clinicians, in cooperation with the subject and the subject’s treater, may develop a plan for 
continued L-methylfolate treatment after the completion of the study. 
At each visit, measures of safety and effectiveness will be administered and subjects will be evaluated for 
response and side effects to the treatment. To assess and ensure drug accountability and compliance, study 
medication will be returned and counted at study visits.  
Information regarding subjects' status of assignment to medication or placebo will be available at all times 
through the MGH Clinical Trials Pharmacy. In addition, the randomization list will be available to the 
investigator at all times, in case of emergency.  
Concomitant Medications / Treatments 
A detailed past and present treatment history will be taken as part of initial evaluation. Participants treated with 
any psychotropic medication not thought to help ADHD, such as SSRIs, may be eligible to participate, provided 
that they have been on a stable, effective dose for at least two months prior to study enrollment, and have scores 
within the mild range on the HAM-A and HAM-D scales (<17 on the HAM-A scale and <13 on the HAM-D 


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scale) at baseline. Subjects must also remain on the same dose of this medication throughout participation. Any 
other Concomitant medications with FDA indications for the treatment of ADHD or that have probable efficacy 
for the treatment of ADHD as per clinician judgment are not allowed in this study. Any agents that would add 
additional risk which could not be managed using existing study procedures will be exclusionary. No subject will 
be tapered from medication that is useful to him or her.  Non-pharmacological treatments such as individual, 
family or group therapy will be allowed if they were in place before the patient joined the study.  The patient’s 
therapy regimen must remain the same throughout the study.  If a subject is asked to stop a medication with 
central nervous system activity for participation in the study, sufficient time will pass off the medication prior to 
baseline visit, based on the pharmacokinetics of the agent, to ensure that it has been eliminated from the patient’s 
system.   
Study Discontinuation Criteria 
Subjects who: 1) develop intolerable AE(s) despite dose adjustments; 2) have (a) clinically relevant serious AE(s) 
as determined by the investigator including changes in vital signs; 3) have worsening ADHD symptoms (much 
worse or very much worse as rated on CGI-Improvement at two consecutive visits); or 4) have emergent 
psychosis, suicidality, substance use, or worsening mood and/or anxiety (much worse or very much worse per 
clinician assessment at weekly visits); 5) are non-adherent to study procedures or withdraw from the study; 6) 
intend to be or become pregnant will no longer continue in the study. If study participation is discontinued due to 
safety reasons, participants will receive two follow-up visits, giving adequate time for appropriate psychiatric 
referrals to treaters in their communities. 
VI. 
BIOSTATISTICAL ANALYSIS 
Data processing and management will follow procedures developed by the investigators and used in ongoing 
studies. Up to 50 subjects will be randomized (1:1) into one of two treatment groups: the L-methylfolate plus 
OROS-MPH, or placebo plus OROS-MPH. The MGH Clinical Trials Pharmacy will be responsible for creating 
and maintaining the study randomization schema. Changes in outcome ratings within and between study groups 
over time will be tested with longitudinal generalized estimating equation (GEE) regression models estimated 
using STATA within the framework of the general linear model (GLM).  Each model will predict outcome scores 
from treatment group (binary predictor), study visit (ordinal predictor) and the group by visit interaction.  All 
analyses will be intention to treat (ITT). While we hope to find clinically significant improvement in ADHD 
symptoms, as outlined below, this is a pilot study and is not designed to show statistically significant change. 
Our primary test of Hypothesis 1 will be review of the occurrence of moderate or severe adverse events. 
Hypothesis 2 examines side effects associated with the combined use of L-methylfolate plus OROS-MPH.  The 
prevalence of binary side effects reported over the course of the trial (i.e. for each side effect, the cumulative sum 
from the first assessment to endpoint) will be compared between groups using Poisson regression at study 
endpoint. Hypothesis 3 predicts that compare to OROS-MPH treatment alone, L-methylfolate acid treatment as a 
supplement to OROS-methylphenidate treatment will yield a greater reduction of ADHD symptoms (as measured 
by the AISRS and CGI), symptoms of executive dysfunction (as measured by BRIEF-A subscales) and 
functioning (as measured by the GAF). The AISRS will be used as the primary outcome measure for 
improvement in ADHD symptoms. This hypothesis predicts a significant difference in these measures between 
groups at study endpoint, and/or a group by visit interaction in these measures.  We will compare continuous 
measures with longitudinal GEE models. We estimate 0.89 power to detect a medium effect size (Cohen's d=0.5) 
given a repeated measures design with one baseline measurement and eight follow-up measurements, correlation 
of 0.7 between measurements, and a two-sided test with alpha set at 0.05. Although less than the effect size for 
treatments of ADHD symptoms by non-stimulants (~0.7) or stimulants (~0.9) 8, an effect size of 0.5 is similar to 
what is seen for the effects of antidepressants for depression 25 and thus would be considered clinically significant.  
 
  
VII. 
RISKS AND DISCOMFORTS 


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
11
All efforts are made to minimize risks to subjects. Consistent with good clinical practice, safety will be monitored 
by the Principal Investigator, and will reflect the oversight of co-investigator study clinicians. Adverse events will 
be recorded and reported according to institutional policies. Risks of study medication have been incorporated 
into the exclusionary criteria for this proposal. 
Study clinician evaluation and subject questionnaires: Some questions may make subjects feel uncomfortable. 
Subjects may refuse to answer any question. In the event that a participant reports risk of harm to himself or 
herself, or to another person, study clinicians will assess the level of risk, and take appropriate actions, including 
disposition of an immediate referral to a local Psychiatric Emergency Room.  
Study Medication – L-methylfolate: No COMMON side effects have been reported in FDA documentation about 
the medical food L-Methylfolate. Rarely, severe allergic reactions to L-methylfolate might occur, including rash; 
hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue. 
Study Medication – OROS-MPH: The medication used in this study will be one of the most commonly prescribed 
stimulant class of medication; the extended duration methylphenidate, OROS-MPH (Concerta®). OROS MPH is 
currently FDA-approved for ADHD in children, adolescents and adults. Commonly-observed side effects 
associated with the use of OROS MPH include difficulty falling asleep, low appetite, headaches, stomachaches, 
nervousness, and dizziness. Side effects tend to be mild. Rare, but serious side effects of OROS MPH include 
seizures, eyesight changes, and blockage of esophagus, stomach or intestine. There are also reports of changes in 
behavior or cognition with stimulant use, including psychotic symptoms, and aggression/hostility. Persons with a 
history of tics may experience return of symptoms. OROS MPH is a federally controlled substance which can be 
abused or lead to dependence. Heart-related problems including sudden death, stroke and heart attack, have been 
reported with use of methylphenidate and other stimulant medicines. Recently published controlled data from our 
group has demonstrated efficacy and tolerability of OROS MPH in a large sample of healthy adults with ADHD 
(Biederman et al, 2006). Dosing for this protocol is consistent with our clinical experience with this medication. 
 
Blood Draw: There is a risk of bruising or pain where the blood draw is conducted. There is small risk of 
infection, lightheadedness, or fainting as a result of a blood draw. 
 
Genetic Information: There is a risk that information about taking part in a genetic study may influence insurance 
companies and/or employers regarding a subject’s health. Subjects will be informed of this risk, and it will be 
explained that they can reduce this risk if they do not share information about their study participation. In 
addition, all efforts will be made by the study staff to maintain confidentiality. DNA samples will be coded with 
ID numbers, and they key will only be accessible by study staff. 
 
Confidentiality 
All research-related records initiated as a result of a subject’s participation in this study that reveal the subject’s 
identity will remain confidential except as may be required by law. Subjects will be informed that clinical 
laboratory testing for this study will become part of a subject’s Massachusetts General Hospital medical record. 
However, information regarding their participation in the optional genetic analysis will not be included in their 
medical record. Results of urine drug or pregnancy testing will not become part of the subject’s medical record. 
Data obtained from this study will not identify the subjects individually. Subjects will be assigned code-names 
and ID numbers.  Data obtained from our studies may be published. Original research-related records may be 
reviewed by the Partners Human Research Committee, and regulatory authorities, for the purpose of verifying 
clinical trial procedures and/or data. Information may be held and processed on a computer.  Access to these 
computerized records will be password protected and restricted to study staff. Subjects will only be contacted 
regarding future studies if they indicate that they are interested in being contacted by initialing in the specific 
section of the consent form. 


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
12
 
VIII. 
POTENTIAL BENEFITS 
There may be no direct benefit to subjects participating in this study. Potential benefits to the participants include 
education about ADHD, a trial of medication that could be continued after the study, and the opportunity to 
contribute to medical science and thus help others with similar difficulties.  
 


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
13
 
Eval Baseline  
(Visit 0) 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
9 
Week 12 
(Or Drop) 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
Procedures 
Blood Draw 
X* 
X* 
 
 
 
 
 
 
 
 
Vital 
Signs 
(weight, 
BP, 
pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
X 
Urine 
Drug 
Screen 
X 
 
 
 
 
 
 
X 
 
X 
Urine Pregnancy 
(females only) 
X 
 
 
 
 
 
 
X 
 
X 
EKG 
X 
 
 
 
 
 
 
 
 
X 
Assessments 
WASI 
X 
 
 
 
 
 
 
 
 
 
CANTAB 
X* 
X* 
 
 
 
 
 
X 
 
X 
Clinician 
Interview 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
Clinician Rated Scales 
AISRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D; HAM-A 
 
X 
 
 
 
 
 
X 
 
X 
GAF 
 
X 
 
 
 
 
 
X 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
14
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Rated Scales 
Demographic 
Interview 
X 
 
 
 
 
 
 
 
 
 
BRIEF-A 
 
X 
 
 
 
 
 
X 
 
X 
ASRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASR 
 
X 
 
 
 
 
 
X 
 
X 
SAS 
 
X 
 
 
 
 
 
X 
 
X 
Q-LES-Q 
 
X 
 
 
 
 
 
X 
 
X 
CBS DESR Scale 
 
X 
 
 
 
 
 
X 
 
X 
EWPS 
  
X 
  
  
  
  
  
X 
  
X 
 
* Can be completed at either evaluation or baseline visit 
 
 


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
15
IX. 
REFERENCES 
 
1. 
Biederman J, Faraone SV, Spencer T, Wilens T, Mick E, Lapey KA. Gender differences in a 
sample of adults with attention deficit hyperactivity disorder. Psychiatry Research 1994;53(1):13-29. 
2. 
Murphy K, Barkley RA. Attention deficit hyperactivity disorder adults: comorbidities and adaptive 
impairments. Comprehensive Psychiatry 1996;37(6):393-401. 
3. 
Faraone SV, Biederman J, Spencer T, et al. Attention deficit hyperactivity disorder in adults:  an 
overview. Biological psychiatry 2000;48(1):9-20. 
4. 
Biederman J, Faraone SV, Spencer T, Mick E, Monuteaux M, Aleardi M. Functional Impairments 
in Adults With Self-Reports of Diagnosed ADHD: A Controlled Study of 1001 Adults in the Community. 
Journal of Clinical Psychiatry 2006;67(4):524-540. 
5. 
Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United 
States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006 Apr;163(4):716-
723. 
6. 
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The Worldwide Prevalence of 
ADHD: A Systematic Review and Metaregression Analysis. Am J Psychiatry 2007 Jun;164(6):942-948. 
7. 
Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention-
deficit hyperactivity disorder. Br J Psychiatry 2007 May;190:402-409. 
8. 
Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-
deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry 2009 Dec 29. 
9. 
Alliance CAR. Canadian ADHD Practice Guidelines.  2008  [cited June 1, 2010]; Available from: 
www.caddra.ca  
10. 
Kendall T, Taylor E, Perez A, Taylor C, Guideline Development G. Diagnosis and management of 
attention-deficit/hyperactivity disorder in children, young people, and adults: summary of NICE guidance. 
BMJ 2008;337:a1239. 
11. 
Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis and treatment 
of adult ADHD: The European Network Adult ADHD. BMC Psychiatry 2010;10:67. 
12. 
Wilens T, Biederman J, Spencer T. Pharmacotherapy of attention deficit hyperactivity disorder in 
adults. CNS Drugs 1998;9(5):347-356. 
13. 
Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic 
disorder. Biological psychiatry 1999;46(9):1234-1242. 
14. 
Arnsten AF. Stimulants: Therapeutic Actions in ADHD. Neuropsychopharmacology 2006 Jul 
19;31(11):2376-2383. 
15. 
Bottiglieri T, Hyland K, Laundy M, et al. Folate deficiency, biopterin and monoamine metabolism 
in depression. Psychol Med 1992 Nov;22(4):871-876. 
16. 
Ruck A, Kramer S, Metz J, Brennan MJ. Methyltetrahydrofolate is a potent and selective agonist 
for kainic acid receptors. Nature 1980 Oct 30;287(5785):852-853. 
17. 
Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate Plus SSRI or SNRI from Treatment Initiation 
Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin Neurosci  
Jan;8(1):19-28. 
18. 
Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and 
clinical issues. J Clin Psychiatry 2009;70 Suppl 5:12-17. 
19.  
Mackey I, Papakostas G, Zajecka JM, et al. (2012, May). Adjunctive L-methylfolate in Patients 
with SSRI-Resistant Depression- Opportunities for Personalized Therapy. Poster presented at the 
American Academy of Physician Assistants Annual Meeting, Toronto, Ontario, Canada.  
20. 
Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and 
adolescents using meta-analysis. Eur Child Adolesc Psychiatry 2009 Sep 10. 
21. 
Centers for Disease Control and Prevention. (2011). Healthy Weight: Assessing your Weight: BMI. 
Retrieved from http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html  


Study Protocol: L-methylfolate Supplement for ADHD 
Version: Amendment 31, 11/21/16 
 
 
16
22. 
Faraone SV, Biederman J, Spencer TJ, et al. Diagnosing Adult attention deficit hyperactivity 
disorder: Are Late Onset and Subthreshold Diagnoses Valid? American Journal of Psychiatry 
2006;163(10):1720-1729. 
23. 
Hamilton M. A rating scale for depression. Journal of Neurological and Neurosurgical Psychiatry 
1960;23:56-62. 
24. 
Achenbach TM, Rescorla LA. Manual for ASEBA Adult Forms & Profiles. Burlington, VT: 
University of Vermont, Research Center for Children, Youth, & Families; 2003. 
25. 
Faraone SV. Understanding the effect size of ADHD medications:  Implications for clinical care. 
Medscape Psychiatry & Mental Health 2003;8(2). 
 
 
 

SAP_001.pdf: 
 
 
12.22.16 
 
 
 
Original Title of Study: L-methylfolate supplementation to OROS-methylphenidate 
pharmacotherapy in ADHD Adults: A double-blind, placebo-controlled, randomized 
clinical trial. 
 
NCT Number: NCT01853280 
 
Date of SAP Plan: 12/22/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
12.22.16 
 
Deplin Statistical Analysis Plan – Paper 1 
 
1. General Analysis Details 
a. Analyses will be intention to treat and include all subjects that received deplin 
or placebo for at least 1 week.  We will perform a per protocol analysis as a 
secondary analysis.  
 
2. Demographic Characteristics & Baseline Efficacy Measures 
a. We will compare demographic characteristics and baseline efficacy measures 
between those randomized to placebo and those randomized to deplin to 
ensure that the randomization process was successful.  
i. We will compare the groups using standard parametric and non-
parametric tests (Student’s t-test, Wilcoxon rank sum test, Pearson’s 
chi-square test, Fisher’s exact test).  
i. Demographic characteristics will include age, gender, race, and 
socioeconomic status.  
ii. Baseline efficacy measures will include AISRS, CGI, BRIEF-A GEC 
subscale, and GAF.  
 
3. Safety 
a. Individual Adverse Events 
i. We will report a frequency table of recurrent adverse events. No 
statistical analyses will be performed on individual AEs.  
b. Total Number of Adverse Events 
i. We will compare the total number of AEs in each group using a 
Poisson regression model, which is the appropriate model for count 
data. 
c. Time-course of Adverse Events 
i. We will analyze the time-course of AEs using a mixed effects Poisson 
model that predicts the total number of AEs from the drug group, 
study week, and drug group x study week interaction.  The interaction 
will tell us if there is a difference in the occurrence of AEs between the 
groups over the course of the study.  
d. Vitals 
i. We will analyze vital signs using mixed effects regression models with 
the drug group, study week, and drug group x study week interaction 
as predictors.  
 
4. Primary Efficacy Measure (AISRS) 
a. We will analyze the AISRS using a mixed effects Poisson model that includes 
the drug group, study week, and drug group x study week interaction as 
predictors. Using this model is consistent with how we have analyzed the 
AISRS in previous publications.  
i. If there are statistically significant differences in demographic 
characteristics or baseline efficacy measures then we will add 
variables to the model to control for them.  


 
 
12.22.16 
 
 
5. Secondary Efficacy Measures 
a. Secondary outcomes measures will include the following: CGI, BRIEF-A, 
GAF, DESR, HAM-A, HAM-D, ASR, and CANTAB 
i. We will analyze the GAF and BRIEF-A using mixed effects Poisson 
models that include the drug group, study week, and drug group x 
study week interaction as predictors.  
ii. We will analyze the CGI using a mixed effects ordinal logistic 
regression model that includes the drug group, study week, and drug 
group x study week interaction as predictors. 
iii. For the DESR, HAM-A, HAM-D, ASR, CANTAB, and BRIEF-A, 
subjects will be define as having normal or abnormal scores based on 
pre-defined cutoffs from the literature. We will analyze these 
outcomes using mixed effects logistic regression models that include 
the drug group, study week, and drug group x study week interaction 
as predictors.  
 
6. Exploratory Analysis 
a. We plan to examine the following biomarkers: MTHFR C677 CT/TT 
polymorphism, MTHFR A1298C polymorphism, FRa-autoantibody, and body 
mass index ≥30 kg/m2 
i. Biomarkers are defined as typical or atypical based on standard values 
ii. We will use mixed effects Poisson models to test the three-way 
interaction between drug group, study week, and biomarker. The 
outcome of interest will be the AISRS.