Clinical trial NCT04839562
Conditions: Attention Deficit Hyperactivity Disorder
Keywords: attention deficit hyperactivity disorder clinical trial solriamfetol
Sponsor: Massachusetts General Hospital
Start date: 2021-08-06; Completion date: 2023-01-27
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A double-blind, placebo controlled study of solriamfetol for adults age 18 to 65 with diagnosis of Attention Deficit Hyperactivity Disorder.

Detailed description:
Subjects will be between 18 and 65 years old, have at least 5 current symptoms of inattentive or impulsive-hyperactive traits, and childhood onset of ADHD symptoms, defined as two symptoms of inattentive or of impulsive/hyperactive traits by the age of 12. Subjects will also have a score of 20 or more on the Adult ADHD Investigator Symptom Report Scale (AISRS).

The investigators will exclude individuals who are contraindicated by current FDA label recommendations, which elaborates appropriate use of solriamfetol for individuals with sleep apnea and narcolepsy.

This will be a a six week, double blind, dose-optimization study. After giving informed consent to participate, participants will undergo a comprehensive assessment including a psychiatric assessment reviewing eligibility.

Arms: arm 1: Participant will receive daily doses of solriamfetol, at 75 mg at week one and 150 mg at week 2, and with intention that dosing remain stable for the last four weeks of study participation, such that investigators will ask a subject to go back down to 75 mg during any of the weeks following week 2 only if only if 150 mg is not tolerated. arm 2: Participant will receive daily doses of placebo, at 75 mg at week one and 150 mg at week 2, and with intention that dosing remain stable for the last four weeks of study participation, such that investigators will ask a subject to go back down to 75 mg during any of the weeks following week 2 only if only if 150 mg is not tolerated.
Interventions: intervention 1: Solriamfetol 75 MG intervention 2: Solriamfetol 150 MG intervention 3: Placebo
Intervention descriptions: intervention 1: Daily oral consumption intervention 2: Daily oral consumption intervention 3: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
Solriamfetol for ADHD in Adults: A Double-Blind Placebo Controlled Pilot Study 
 
 
 
Craig B.H. Surman, MD 
Clinical and Research Program in Adult ADHD and Pediatric Psychopharmacology 
Massachusetts General Hospital, Harvard Medical School 
 
Final version posted as of October, 2022 
 
 
I. 
BACKGROUND AND SIGNIFICANCE 
There is need to improve options for management of Attention Deficit Hyperactivity Disorder 
Attention-deficit hyperactivity disorder (ADHD) is a neurobiological disorder associated with 
high levels of impairment in adulthood1-4, 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 ADHD8-11. Over 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 nonresponders12-14. Moreover, adults who are considered responders 
clinically often show a 50% or less reduction in the core symptoms of ADHD13. In addition to residual 
ADHD symptom burden, pharmacologically treated patients also have residual burden in other 
cognitive capacities such as executive function challenges. 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 executive control.15 Therefore there is significant clinical need for interventions that 
support the self-regulatory challenges that are not managed by current pharmacotherapies.  
Investigation into the neurobiological basis of ADHD has identified that a circuit involving 
prefrontal, subcortical and parietal regions is implicated in the pathological basis of ADHD.16-20 Delay 
in cortical maturation of cortex might impair executive functions, resulting in the poor working 
memory, attention, and response inhibition in ADHD children.21 
Solriamfetol is a dopamine and norepinephrine reuptake inhibitor that the FDA has approved 
for treatment of excessive daytime sleepiness in patients with narcolepsy or obstructive sleep 
apnea22. It is a class IV controlled substance, and clinical trials suggest it is well tolerated.  
Conventional therapies for ADHD, including the stimulants methylphenidate and mixed amphetamine 
salts, and the nonstimulant atomoxetine, are thought to work in part through reuptake blockade 
and/or increased release of the catecholamines dopamine and norepinephrine. 13 Prior studies with 
modafinil and bupropion and mazindol also suggest ADHD benefit from these agents with dopamine 
and norepinephrine reuptake properties. Solriamfetol is thought to support dopamine and/or 
norepinephrine activity.  
Prior clinical data to support efficacy in sleep disorder indications, and the product's well-
elaborated safety profile, also suggest potential favorable application for ADHD care. Other agents 
approved by the FDA for ADHD are closely controlled substances (stimulant agents) or may take 
longer to work than first-line stimulants or have less effect than stimulants (e.g. atomoxetine and 


 
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guanfacine). If Solriamfetol had moderate effect size for ADHD symptoms, it may open up an option 
for a new method of treating ADHD. 
Because Solriamfetol could have positive effects on ADHD symptoms, has not been evaluated 
in ADHD, and is expected to be and well tolerated, we propose to conduct a double-blind pilot study 
enrolling 60 adults with ADHD.  Such a pilot study can determine whether Solriamfetol is likely to 
have a moderate effect size for this indication.  Using a dose-optimization protocol, we will maximize 
ability to estimate clinical effects. To assess the safety and efficacy of Solriamfetol, we will use ratings 
of spontaneously reported adverse events and ADHD symptoms as primary outcome measures.  
Adults with moderate levels of ADHD will be enrolled.  We choose to evaluate response over six 
weeks, as this has been a typical format sensitive to mild to moderate effects on ADHD, allows for 
dose titration, and sufficient exposure durations for participants to notice and evaluate a clinically 
useful effect.   
 
Just as telemedicine has expanded the scope of clinical care, it is also expanding the scope of 
clinical trials23. The outpatient psychiatry clinics at Massachusetts General Hospital have used 
telemedicine for routine clinic appointments for qualifying patients after an in-person consultation. 
Telemedicine significantly lessens patient burden, as the patient does not have to come into the office 
for appointments, but still receives the same level of clinical care through the face-to-face video 
conference. Our research unit has conducted telemedicine research with positive experiences. As 
such, we propose to offer the option of telemedicine visits in this study. 
 
II. 
SPECIFIC AIMS 
Aim 1: Assess effect of solriamfetol on ADHD symptoms and associated ADHD features.  
Hypothesis 1: Compared to pre-administration baseline, solriamfetol will be associated with a greater 
reduction than placebo of ADHD symptoms (1a). We also expect drug exposure to be correlated with 
a greater rate of individuals achieving an a priori definition of clinical improvement, with at least a 25% 
reduction in ADHD symptoms, and a CGI of much or very much improved (1b).  
We secondarily will explore whether there are reduced symptoms of executive dysfunction (defined 
by a 0.5 standard deviation improvement on the Brief Rating Inventory of Executive Function-Adult 
Version (BRIEF-A) self-report total or subscale scores).  We also will explore whether baseline ratings 
of sleepiness, or deficits on BRIEF predict improvements on the Adult ADHD Investigator Symptom 
Rating Scale (AISRS) or BRIEF measures.   
Aim 2:  Assess the safety of solriamfetol in the treatment of ADHD among adults 
 Hypothesis 2: Solriamfetol will be well tolerated by adults with ADHD.  
 
III. SUBJECT SELECTION 
We plan to enroll 60 subjects of any gender identity between the ages of 18-65 in the study. No 
pediatric subjects will be recruited for this study. We will recruit subjects through advertisement in the 
general community, using flyer and internet advertisements, via postings on Rally, Research Match, 
and from the referral pool of patients of the Clinical and Research Program in Pediatric 
Psychopharmacology and Adult ADHD at Massachusetts General Hospital. As noted elsewhere, 
however, the informed consent process with a subject must occur with a different clinician than one 
they have seen as a treating provider.  
 
Individuals who express interest in the study will be screened for eligibility by the study 
coordinator or a research assistant via phone. A phone script will be used that is IRB-approved. If 
they meet criteria, the participant will be asked to complete study scales online via RedCap, a secure 


 
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online data capture system. These self-report scales will include the ADHD Rating Scale (ADHD-RS), 
Adult Self-Report Form (ASR), BRIEF-A, Epworth Sleepiness Scale (ESS), and the Pittsburgh Sleep 
Quality Index (PSQI). If a subject completed any of these scales for another study in our department 
or through the adult ADHD clinical program within the past year prior to screening they may not have 
to repeat the scale(s) for the current study unless asked to do so by a study staff member based upon 
clinician judgment. However, in the case where scales completed previously will be reviewed, verbal 
permission will be obtained from the participant that it is okay to review these previously completed 
scales to assess inclusion and exclusion criteria. 
 
Subjects who have participated in research in our program may be eligible to participate in this 
study. Other medical records on a subject will not be used at any point, unless explicit written 
permission is provided by the subject.  
 
Many subjects referred to this study will first participate in our general screening protocol 
entitled, “Screening Protocol for Adults with Attention Deficit Hyperactivity Disorder” (Protocol # 2002-
P-001856). Under this protocol, advertisements from our research group include a link that allows 
individuals to contact us by email, phone, or via a URL link to a REDCap form. After participating in 
this screening protocol, subjects are referred to specific studies based upon eligibility requirements 
(i.e. age, prior medication efficacy or tolerability). 
 
Study Entry Criteria 
 
Inclusion Criteria: 
1. Adults ages 18-65 years of age. 
2. A diagnosis of childhood-onset ADHD, meeting the DSM-V criteria for ADHD in adulthood, 
including at least 5 current symptoms of inattentive or impulsive-hyperactive traits, and childhood 
onset by age 12, defined as two symptoms of inattentive or of impulsive/hyperactive traits by the 
age of 12. 
3. A score of 20 or more on the Adult ADHD Investigator Symptom Report Scale (AISRS) 
 
Exclusions 
1. Individuals with known renal insufficiency or renal impairment.  
2. A history of intolerance to solriamfetol  
3. Pregnant or nursing females, and individuals unwilling to use adequate contraceptive methods to 
avoid conception while they are receiving study agent and for 1 month after the last dose of study 
agent. For female subjects of childbearing potential adequate contraceptive methods  will include: a 
medically acceptable form of birth control (such as male or female condoms with or without 
spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, hormonal 
contraceptives like birth control pills, or abstinence). For male subjects this will include use of male 
condom, being status post vasectomy at least 4 months prior to initiation of study drug exposure, or 
abstinence during the study.  
4. A known unstable major medical illness including hepatic, renal, gastroenterological, respiratory, 
cardiovascular (including hypertension ≥ 140/90 mmHg), endocrinologic (e.g. thyroid), neurologic 
(e.g. seizure), immunologic, hematologic, or psychiatric (including an active substance use disorder, 
psychosis, bipolar disorder, major depression) disorder.  


 
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5. Any medical condition that the Principal Investigator (PI) believes will be exacerbated by study 
participation.  
6. A history of cancer (except localized skin cancer without metastases or in situ cervical cancer) 
within 5 years prior to screening.  
7. A known history of narrow-angle glaucoma.  
8. Current (within 3 months) DSM-V criteria for abuse or dependence with any psychoactive 
substance other than nicotine.  
9. Multiple adverse drug reactions, defined as previous moderate to severe adverse experiences 
while on two or more chemically unrelated compounds, where these reactions were unpredictable 
from the known pharmacology of the drug. 
 
10. Any other concomitant medication with primarily central nervous system activity that are 
catecholaminergic such as stimulants or atomoxetine, or have strong noradrenergic mechanisms of 
action such as duloxetine or venlafaxine or buproprion.  Subjects may be included who are taking 
stable doses of agents with primary serotonergic (such as selective serotonin reuptake inhibitors or 
buspirone), gabaergic (such as gabapentin, pregabalin), or other anticonvulsants. We will also allow 
participation by individuals with rare (predicted to be less than twice a week) use of prn 
benzodiazepines or sedative-hypnotics. 
11. Current use of MAO Inhibitor or use within the past two weeks.  
12. Concomitant medications with high potential for dopaminergic or sympathomimetic effects.  
13. Investigator and his/her immediate family; defined as the investigator’s spouse, parent, child, 
grandparent, or grandchild.  
14, Reasonable suspicion of inability, in the judgement of the investigator, to appropriately monitor 
experiences during the study and take steps to report these experiences or respond in a manner 
preserving personal health and safety.  
15. If clinically appropriate, any subjects taking medication exclusionary to the study (including agents 
used for management of  ADHD) 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 several days or otherwise sufficient period of time to allow assessment of eligibility for 
participation off medication. 
16. Any condition, including a moderate to severe untreated sleep disorder or other mental health 
disorder, that renders inability, in the investigator’s judgement, to determine whether ADHD 
symptoms are primarily due to ADHD. 
 
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 is 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.  


 
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V. STUDY PROCEDURES 
We will conduct a 6-week double-blind pilot clinical trial exploring efficacy and tolerability of 
solriamfetol in adults with ADHD who fulfill the inclusion and exclusion criteria for participation. 
Enrollment will stop once 60 subjects have consented and been exposed to study agent or placebo.   
Virtual or written informed consent will be obtained via Adobe esign or courier mail service 
after subjects are screened for potential participation, prior to the performance of other protocol 
procedures, and prior to administration of study drug. Screening of participants will involve use of a 
survey, which may be reviewed in person or via televisit or telephone.  We also may post all or part of 
this form on REDCap, for participants to complete at their convenience if they prefer. During 
screening, we will collect minimum identifying information that allows communication or re-contacting, 
such as first name or telephone number. The information collected from this phone survey will be 
reviewed by study staff, and if they appear likely to meet criteria for safe inclusion in the study, the 
participant will be asked to schedule for an evaluation visit.  As part of this evaluation, they will 
complete study scales online via RedCap, a secure online data capture system. 
Informed consent will be obtained by a licensed study clinician or study staff. The study, risks 
and benefits will be explained in simple terms, and any questions from participants will be answered. 
Participants will be given as much time as they feel is necessary to make a decision regarding their 
consent. Subjects will be informed that participation is entirely voluntary, and they may withdraw 
consent at any time without penalty.  
After providing study information and obtaining IRB approved informed consent, participants 
will undergo a comprehensive assessment including a psychiatric assessment with a clinician 
reviewing current and lifetime DSM-V Axis I conditions, medical history including history of any 
cardiac symptoms or abnormalities reported on routine clinical exams, and eligibility per inclusion and 
exclusion criteria.  This assessment will also include staff-review of forms filled out online by study 
participants in REDCap. The information obtained at this visit will be reviewed to assure that all 
inclusion and exclusion criteria are met prior to receiving study agent at the baseline visit. Subjects 
who do not meet all the criteria for enrollment after these assessments will be discontinued. 
We anticipate that a small minority of 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 equivalent evaluation with one of the study 
clinicians within the previous year 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, and document this data and when it was collected in our 
substantiation of how the individual meets diagnostic criteria in the evaluation documentation for the 
current study. 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 all study entrance criteria.   
 
Safety Assessments: 
Vital signs (blood pressure, pulse) will be monitored at each visit during the study. If there is 
suspicion that the participant’s eligibility to participate has changed (e.g., evidence they have taken 
an illicit drug), he/she will have a discussion with the doctor to determine if he/she can be in the study.  
It will be up to the principal investigator’s judgement to determine if the subject continues to meet 
study inclusion and exclusion criteria.  For example, subjects will be discontinued if there is suspicion 
of ongoing substance abuse by history or by confirmation of ongoing abuse by positive drug test, or 
evidence of inability to adhere to study procedures (e.g. missing two visits in a row, or otherwise 
insufficient participation to monitor safety in the judgement of the investigators).  Drug testing will not 


 
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be done systematically but will be available to clinical investigators to determine participant eligibility 
and safety before and throughout study participation. Participants will be told at the time of consent 
that random drug screening may occur at the choice of study investigators. 
Females who are able to have children will also have a urine pregnancy test at evaluation, and 
week 6 or study completion. If a participant has a positive pregnancy test she will not be able to take 
part in the study. As detailed in the exclusion criteria, all participants will be required to use 
contraception adequate to avoid conception, or to not participate.  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. In the event that a subject reports contributing 
sperm to a pregnancy during the study period, we will also 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. 
We will increase our chances of identifying exclusionary mental health conditions by 
supplementing the clinical interview for study eligibility with review of self-report on the Adult Self-
Report (ASR), a self-report scale validated to identify major mental health conditions, prior to 
participation.   
 
Subject Dosing and Visit schedule: 
Visits will occur for evaluation, baseline, and weekly for weeks 1, 2, 3, 4, 5 and 6. Visits will be 
conducted at 7 day intervals, +/- 3 days. Doses will be assigned at each study visit for the period of 
time until the next visit, with forced-dose up-titration as tolerated from 75 mg at week one to 150 mg 
at week 2, and with intention that dosing remain stable for the last four weeks of study participation, 
such that investigators will ask a subject to go back down to 75 mg during any of the weeks following 
week 2 only if only if 150 mg is not tolerated.  Thus, the most robust titration would be 75 mg until 
week 1, and 150 mg for the rest of study. The least robust titration where a subject maintains 
participation would be 75 mg for the duration of the study.  
This study will preferentially utilize synchronous visit telemedicine assessments in all visits to 
minimize subject burden.  Efforts to maximize subject safety and convenience will include the option 
to have in-person meetings if public health conditions allow or are preferred by either a subject or 
study clinicians. Throughout the study, efforts will be made to maximize comfort of subjets primarily 
and, secondarily, meaningful research participation.  
Subjects will be offered treatment follow-up for two visits with staff at the MGH Clinical and 
Research Program in Pediatric Psychopharmacology at the end of the study to facilitate transition to 
ongoing care. Subjects who complete the study will have the option of receiving two clinical care visits 
(one approximately monthly appointment over up to three months’ time) at the completion of the study 
in which they will be seen by study staff. The three months of follow-up care are a courtesy that is 
offered to help find long-term care if needed. Subjects will receive referrals to clinicians in their 
communities. No research data will be collected at these follow-up visits.  
 
Phone calls will be conducted by a study research assistant before and during visits to assess 
medication compliance and change in medication treatments. Pill counts will be done by study staff at 
every other study visit by visualization in person or by remote televisit. At any time, contact can occur 
by phone or in person as needed with a clinician or research assistant, based on the judgement of the 
study staff, or by needs of the subjects as they arise. Study clinicians are also available to subjects 24 
hours each day by pager.  
 


 
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Randomization and Maintenance of double-blind 
 
Randomization to active or placebo will occur once a subject is scheduled for a baseline visit, 
when the clinical trials pharmacy will be given a subject name that the pharmacy will associate with a 
number identifier.  We have extensive experience maintaining blinding, wherein we have our central 
Mass General Hospital Clinical Trials Pharmacy pharmacy serve as the only part of the greater trial 
team that is aware of the assignment to active or placebo during study participation.  The trials 
pharmacy will receive products identified by the sponsor as active or placebo fill, over-encapsulate 
these products to look identical, bottle these products with unique identifiers, maintains the placebo-
active ratio, and maintain blinding until study completion.  For the purpose of the final analysis, the 
official clinical database will not be unblinded until medical/scientific review has been completed, 
protocol violators have been identified (if appropriate), and data collection has been declared 
complete. In the extreme event where subject safety will be compromised by maintaining the blind, 
eg. an adverse event where treatment is dependent on knowing if they were on active or placebo 
medication, we will unblind the status of the subject’s study agent, following emergency protocols in 
place in our department and institution.  
Assessments and Instruments: 
Our primary endpoint will be change in the Adult ADHD Investigator Symptom Rating Scale 
(AISRS), the instrument we will use to evaluate ADHD symptom burden. We also will evaluate 
spontaneously reported adverse events as our main outcome of tolerability. At screening evaluation,   
AISRS ratings and concurrent medication treatments will be recorded.  In addition, at screening or 
baseline, a brief demographic interview will be conducted to obtain information used to calculate 
socioeconomic status. 
Demographic information, including socioeconomic status data, will collected for each 
participant.24 
During the study, the following assessments and instruments will be used: 
Clinician rated assessments (rated at each in-office study visit, unless otherwise noted): 
• Global Assessment of Functioning (GAF) scale. The GAF will assess global functioning using 
a scale from 1 (worst) to 100 (best). This will be collected at all study visits, excluding the 
screening visit. 
• Clinical Global Impressions (CGI) scale for ADHD. The CGI is a measure of illness severity, 
improvement, and efficacy of treatment.  
• Adult ADHD Investigator Symptom Rating Scale (AISRS). Each of the individual symptoms of 
ADHD is rated 0 to 3 on a scale of severity. 
• Adverse Experiences (collected at all visits excluding the screening and baseline visits) and 
Concomitant Medications. 
Subject rated scales (all scales rated at baseline and week 6 or drop visit: 
• The 18-item ADHD Rating Scale to evaluate frequency of ADHD symptoms on a scale of 0 to 
4 (ADHD-RS).  
• The 86-item Behavior Rating Inventory of Executive Function – Adult Form (BRIEF-A) to 
assess levels of executive function deficits. 25 
• Pittsburgh Sleep Quality Index.  This Index is a widely used measure which consists of 19 
items which assess sleep quality over  one month time period.  
• Epworth Sleepiness Scale 


 
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Subject rated scale at baseline only 
• In addition, at baseline the The Adult Self-Report Form (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. 26 
 
 
 
Adverse Event Assessment and Reporting 
All solriamfetol treatment-emergent serious adverse events (initial and follow-up) that require 
collection per protocol will be reported to Axsome Therapeutics via email within 1 business day of 
awareness of the serious adverse event. 
As noted above, adverse events will be recorded at all visits other than screening and 
baseline.  Investigators will characterize adverse event by description, note the severity (mild, 
moderate, or severe), whether it is expected (yes or no), relatedness (unrelated, definite, probable, or 
possible).   
We will operate the study in compliance with our Human Research Committee’s guidelines 
titled “Reporting Unanticipated Problems including Adverse Events” revised May 2020 – the full 
document is accessible at https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Reporting-Unanticipated-Problems-including-Adverse-Events.pdf . In general, we are 
required to and will follow all guidelines and practices elaborated by our Human Research Protection 
Program as outlined in https://www.massgeneralbrigham.org/researcher-support-and-
resources/resources-collaborators-and-sponsors/human-research-protection-program-policy-
guidance.  In the “Unanticipated Problems” guideline, possibly related to the research means there is 
a reasonable possibility that the adverse event, incident, experience or outcome may have been 
caused by the procedures involved in the research (modified from the definition of associated with 
use of the drug in FDA regulations at 21 CFR 312.32(a)). Reasonable possibility means that the 
event is more likely than not related to participation in the research or, in other words, there is a >50% 
likelihood that the event is related to the research procedures. 
Other key elements of this guideline are summarized here: 
 Unanticipated problems must be reported promptly to the Human Research Committee so that 
the Committee can consider whether (1) the risks to subjects are still minimized and reasonable in 
relation to anticipated benefits, if any, and the importance of the knowledge that may reasonably be 
expected to result; and (2) any changes to the research or other corrective actions are warranted in 
order to protect the safety, welfare, or rights of subjects or others.  
Per Mass General Brigham Human Research Committee standards, any adverse event that is 
an unanticipatedd untoward or unfavorable medical occurrence, including abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, that indicates that the 
research places subjects at increased risk of physical or psychological harm than previously known or 
recognized will be submitted through a electronic reporting system (called Insight) to the Human 
Research Committee as an Other Event, Adverse Event. The following information will be included in 
the report:  


 
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(1) a detailed description of the adverse event;  
(2) the basis for determining that the event is unexpected in nature, severity, or frequency;  
(3) the basis for determining that the event is related or possibly related to the research 
procedures;  
(4) the basis for determining that the research places subjects at an increased risk of harm 
(i.e., a serious adverse event); and  
(5) whether any changes to the research or other corrective actions are warranted  
 
Such unanticipated problems involving risks to subjects or others will be submitted to the 
Human Research Committee within 5 working days/7 calendar days of the date the investigator first 
becomes aware of the problem. 
 
Serious adverse event means any event temporally associated with the subject’s participation 
in research that meets any of the following criteria: 
• results in death; 
• is life threatening (places the subject at immediate risk of death from the event as it occurred); 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive treatment in 
the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse).  
 
Data Collection: 
 
All data will be collected and entered into electronic data capture systems using a combination 
of Study Trax and/or REDCap, or an equivalent privacy-rule compliant electronic data capture system 
that streamlines data collection and data integrity. As a convention, we will refer to REDCap in the 
rest of this protocol.  These software programs allows researchers to design and implement study 
surveys electronically for collecting, storing, retrieving, and manipulating data. Study subjects will 
enter survey responses and research staff will enter gathered data from study visit evalutions into 
electronic assessment forms using computers remotely or at the research site. The responses will 
then be transmitted securely via an encrypted connection and stored in a secured database. 
Electronic data capture of self-report and clinician data entry eliminates the need for subsequent data 
entry by staff, thus minimizing human error. However, in the event that an electronic data capture 
system is unavailable or malfunctioning, study staff will print all study instruments and study data will 
be collected in paper form.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 remotely or at the research site under the supervision 
of study staff. 
 
Concomitant Medications / Treatments: 
A detailed past and present treatment history will be taken as part of initial evaluation. 
Concomitant medications with primarily central nervous system activity, other than ADHD 
pharmacotherapy as noted above, are not allowed in this study. Non-pharmacological treatments 
thought to be effective for ADHD such as individual, family or group therapy will be allowed if they 
were in place before the patient joined the study.  Any such therapy regimen must remain the same 
throughout the study.  


 
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If clinically appropriate, 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 several days to assess the 
participant off medication.  Individuals may participate if they prefer not to take a previously optimized 
treatment for documentable reasons such as side effects, perceived risks, personal preference, or 
lack of sufficient benefit. However, subjects will not enter the study if it would require tapering or 
otherwise stopping a medication that is optimally and comfortably managing a clinical concern likely 
to cause unaccommodated suffering of the participant.  For example, a participant may prefer to 
participate in the trial after stopping a stimulant treatment that causes side effects but helps them in 
school, during a summer vacation period where the consequences of stopping and participating will 
be accommodated by lack of school participation and more time to complete daily tasks. Medication 
tapers will be monitored by the study clinician in agreement with the research subject and in 
consultation with the prescribing physician. No subject will be removed from a stable and effective 
treatment regimen for the purposes of participating in the study. 
Subjects will be instructed not to take any medications or supplements that are contraindicated 
by exclusion criteria for the study. All new medications and supplements started during the study will 
be reviewed by the PI, and subjects may be dropped from study participation, but their data will be 
retained in the safety and intent-to-treat analyses with PI discretion. 
In addition, any subject found to be taking medication listed as exclusionary during the course 
of the study or the seven days prior to randomization will be evaluated by the PI for ongoing eligibility. 
 
Study Discontinuation Criteria 
Examples of individuals who will discontinue study participation include those who: 1) develop 
intolerable adverse events (AEs) despite dose adjustments; 2) have (a) clinically relevant serious 
AE(s) as determined by the investigator; 3) have worsening ADHD symptoms (much worse or very 
much worse as rated on CGI-Improvement at two consecutive visits); or 4) have emergent adverse 
mental health state including psychosis, suicidality, substance use, or worsening mood and/or 
anxiety; 5) are non-adherent to study procedures or withdraw from the study; 6) intend to be or 
become pregnant. 
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. 
Subjects found to be taking substances listed as exclusionary during the course of the study may be 
discontinued based on PI evaluation of their eligibility.  
VI. 
BIOSTATISTICAL ANALYSIS 
Data processing and management followed procedures developed by the investigators and 
used in ongoing studies. Up to 30 subjects will receive Solriamfetol, and up to 30 subjects will receive 
placebo. Changes in outcome ratings within and between study groups will be tested. 
Hypothesis 1 will be our main testable hypothesis, tested by evaluating whether the group 
receiving stimulant treatment has a significantly greater improvement in ADHD symptom rating.  We 
will also explore exploratory hypotheses. This will include comparing the active and placebo arms on: 
the rate of individuals achieving an a priori definition of clinical improvement, with at least a 25% 
reduction in ADHD symptoms, and a CGI of much or very much improved (1b), and the rate of 
reduced symptoms of executive dysfunction (defined by a 0.5 standard deviation improvement on 
BRIEF-A self-report total or subscale scores) (1c).  


 
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All other analyses will be exploratory and p-values will be reported as nominal, and not used to infer 
significance. We will also explore descriptively whether baseline sleep problems, sleepiness, or 
deficits in domains of the BRIEF predict improvement on AISRS or BRIEF ratings.  
Our primary test of Hypothesis 2 will be review of the occurrence of moderate or severe 
adverse events, and description of reasons for study dropout.  We will also report rates of the same 
adverse event in active and placebo arms occurring two or more times for a particular subject. 
 
We will also report whether there is a difference in change in baseline to endpoint sleepiness 
and changes in sleep quality during the study.   
 
Data processing and management will follow procedures developed by the investigators and 
used in ongoing studies.   
. 
 
VII. 
RISKS AND DISCOMFORTS 
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 
the study agent have been considered in developing 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 they wish. 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.  
Risks of Study Agent – Solriamfetol:  
Solriamfetol is approved by the US Food and Drug Administration to improve wakefulness in 
adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep 
apnea (OSA). 
FDA indications for Solriamfetol include recommendation for starting at 75 mg in patients with 
daytime fatigue in narcolepsy, and titration from 75 mg to 150 mg after three days. Our protocol 
titrates more conservatively, following the weekly pattern of dose increase that is more typical of 
clinical trials in ADHD. While this interval for increase was chosen primarily to give subjects longer to 
evaluate ADHD symptom experiences, and to mimic pattern of study assessments in other ADHD 
trials, it will also give greater time for subjects to evaluate adverse effects before increasing them with 
a dose increase.   
We chose not to exceed 150 mg in this study in keeping with FDA approved dosing for 
individuals with excessive daytime sleepiness.  The package label notes that heart rate and blood 
pressure changes appear to be dose-dependent in populations studied, such that doses above 150 
mg could be expected to add more risk.  The label advises to avoid patients with known 
cardiovascular and cerebrovascular disease, preexisting hypertension, and patients with advanced 
age, advice we follow in this protocol. 
Most common adverse reactions (≥5% and greater than placebo) were headache, nausea, 
decreased appetite, insomnia, and anxiety. The product label carries suggestions to dose medication 
at least 9 hours before bedtime, advice we will give patients.  It also suggests to “measure heart rate 
and blood pressure prior to initiating and periodically throughout treatment. Control hypertension 
before and during therapy. Avoid use in patients with unstable cardiovascular disease, serious heart 
arrhythmias, or other serious heart problems” and “Use caution in treating patients with a history of 


 
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psychosis or bipolar disorders. Consider dose reduction or discontinuation of SUNOSI (solriamfetol) if 
psychiatric symptoms develop”.  Our protocol is sensitive to identifying these risk categories. 
We do not have reason to believe that individuals taking solriamfetol would be risking greater 
negative outcomes than those observed in sympathomimetic agents already used for ADHD.   
Commonly observed side effects associated with the use of these FDA-approved stimulants include 
insomnia, decreased appetite, dry mouth, headache, or increased pulse.  Other less common side 
effects include irritability, stomach pain, onset of tics, or mood changes. Stimulants have also been 
associated with more rare, but serious, adverse effects such as sudden death, stroke, and heart 
attack in adults with a history of heart disease.  Side effects of atomoxetine are similar to those of 
stimulants, but notably include fatigue, nausea, increase in heart rate, increase in blood pressure, 
sexual side effects, agitation or changes in mood.  The label for atomoxetine carries warnings about 
rare reports of liver failure and of suicidal ideation.  If solriamfetol produced side effects similar to 
these other catecholamine agents, our assessment schedule and clinical expertise give high 
likelihood of both identifying and supporting any clients who experience such negative experiences. 
 
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. Results of 
urine or drug 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, but no 
subjects will be identified individually in these publications. 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. 
Email communication: 
Any email communication will be done using Send Secure encryption per Partners polcy, 
unless a subject has authorized non-secure email communication. Before sending or responding to 
an unencrypted email message to an individual, the individual must acknowledge understanding of, 
and agreement to, accept the risks as communicated to them via the following language “The 
Partners standard is to send email securely. This requires you to initially set up and activate an 
account with a password. You can then use the password to access secure emails sent to you from 
Partners HealthCare. If you prefer, we can send you “unencrypted” email that is not secure and could 
result in the unauthorized use or disclosure of your information. If you want to receive 
communications by unencrypted email despite these risks, Partners HealthCare will not be held 
responsible. Your preference to receive unencrypted email will apply to emails sent from this research 
group/study only.”  This language will be copied into an email response to an individual, or may be 
read over the phone to the individual, or an individual could agree by reading this in person and 
signing this statement, or simply by agreeing verbally. 
 
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 a supplement that could be continued after the 


 
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study, and the opportunity to contribute to medical science and thus help others with similar 
difficulties. 


 
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VIII.  Visual Timeline of Key Study Elements 
 
Eval. 
Baseline    
(Visit 0) 
Week   
1          
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6/drop 
Consent 
X 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
Vital Signs 
(BP, pulse) 
 
X* 
X 
X 
X 
X 
X 
X 
Clinician 
Evaluation 
X 
 
 
 
 
 
 
 
AISRS 
X 
X 
X 
X 
X 
X 
X 
X 
ADHD-RS 
X* 
 
 
 
 
 
 
X 
CGI ratings 
 
X 
X 
X 
X 
X 
X 
X 
GAF 
 
X 
X 
X 
X 
X 
X 
X 
Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
BRIEF-A 
 
X* 
 
 
 
 
 
X 
ASR 
X* 
 
 
 
 
 
 
 
ESS 
 
X* 
 
 
 
 
 
X 
PSQI 
 
X* 
 
 
 
 
 
X 
Pill counting 
 
 
 
X 
 
X 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
X 
* Can be completed at either evaluation or baseline visit as long as those visits are within 10 days 
**If a subject terminates participation early, all assessments at week 6 will be made at study completion.  
 
 


 
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IX. 
Monitoring and Quality Assurance 
The Principal Investigator will meet regularly with study staff to address procedural issues and 
the study coordinator will audit each subject’s data within 48 hours of each study visit. Furthermore, 
all data will be audited by the study statistician with the assistance of the database manager on a 
regular basis to ensure the progress of the study and confirm that all necessary data is being 
collected and can be transitioned to the statistical package smoothly. Co-investigators are actively 
involved in the monitoring and quality assurance of these trials. Periodic quality assurance audits will 
ensure accuracy and completeness of all subject documents, IRB files and correspondence, and the 
informed consent documentation. 
 
XI. Telehealth Remote study procedures 
Subjects will be offered the option to participate via remote telehealth. Individuals may 
choose a mixture of in-person and telehealth visits, or just one or the other, as suits scheduling 
convenience or prudent safety practice.  For example, during a public health infectious disease crisis 
such as the COVID-19 pandemic, risks to participants may be reduced by remote televisits.  We will 
not conduct in-person visits unless approved by Partners healthcare and Massachusetts General 
Hospital.  
Recent Virtual Visit Clinical Growth for COVID-19 
 
Virtual visits are real-time visits between patients and providers using the audio and video capabilities 
of electronic devices. These visits enable patients to continue their routine and follow-up care with 
Massachusetts General Hospital providers remotely without having to physically visit a hospital or 
outpatient facility. Since March 2020, virtual visit capabilities at Mass General have significantly 
expanded to allow more providers to offer this resource to patients in light of COVID-19. On average 
prior to March 2020, just over 1,000 clinical virtual visits were completed each month (October 2019 – 
February 2020) via audio and video. In May 2020, more than 85,000 telehealth visits were completed 
(includes both via video and audio as well as audio only).   Between March and August 2020, Mass 
General Brigham (the parent company of Massachusetts General Hospital) reported over one million 
telehealth visits occurred within the greater system.  
 
Technology Platform  
The videoconferencing technology which will be used by Dr. Surman’s research group in this protocol 
is currently being used in clinical practice across Massachusetts General Hospital.  It has been 
approved for use by Partners Information Systems and MGH Health Information Services. 
 
This study leverages a videoconferencing platform where clinicians and patients/participants can use 
personal computers, tablets, and smartphones to communicate easily and securely using real-time 
video and audio. Visits will be conducted remotely over the Partners-approved video platform, which 
is HIPAA-compliant. The technology leverages a waiting room functionality so that the provider must 
admit the patient from the virtual waiting room into the meeting, thus preventing unauthorized entry.  
 
Set Up (Patient)  
We will send a letter to patients/study participants with instructions to set up the program on their 
personal devices. We will also send emails with a videoconference link and any required login 
information prior to any visit. When the patient/study participant logs into the meeting, clear and 
concise instructions will appear that instruct the patient to wait in the waiting room until the 
provider/researcher joins the room and admits them.   
 
Training/ Resources  


 
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The MGH Center for TeleHealth will provide training session(s) to educate the lead investigators on 
utilizing telemedicine for virtual visits and the Research Assistants on training patients and clinicians 
to use the technology. The Center will also provide tip sheets and instructions for the team on how to 
use the technology.  
 
The following elements describe methods we will use to ensure clinical and research 
standards are maintained when telehealth is utilized in the study. 
A. Remote Informed Consent Procedures 
Prior to the completion of any study procedures, the study clinician will remotely conduct 
informed consent procedures with the participant. The study clinician will be a licensed physician and 
either the Principal Investigator or a coinvestigator. Study staff will provide the participant with an IRB-
approved consent form via courier mail service or an encrypted email, unless the subject has formally 
allowed non-encrypted email, as described elsewhere in this document. In the event that email 
encryption is waived via verbal consent from the participant, the study coordinator will communicate 
with them via unencrypted email moving forward. This correspondence will include information about 
why they are receiving the consent form and directions to inform study staff when the consent form 
has been received. Study staff will then schedule a time for the study clinician to conduct informed 
consent procedures with the participant via telephone call. The study clinician will call the participant 
at the scheduled time and conduct informed consent procedures, per the following existing 
guidelines: review the informed consent form, explain the risks and benefits of study participation, 
discuss alternatives to participation, and answer any questions the participant may have. If the 
participant decides to participate in this study, they will sign the consent form. All written signed 
form(s) will then be sent via courier mail serivce to the study clinician who performed the informed 
consent procedures for signature. The study clinician will then send the signed form(s) to the study 
coordinator via courier mail service. The study coordinator will perform a completeness check prior to 
the start of any study procedures and provide the participant with a copy of the signed form(s) via 
courier mail service or (un)encrypted email. Copies of all virtually signed form(s) will automatically be 
sent to the study clinician, the study coordinator, and the participant. 
B. Study Visits via Telemedicine 
1. Study Visit Timeline 
To accommodate scheduling and communication logistics, elements of the initial evaluation (pre-
baseline) study visit may occur over more than one day, and other study visits may occur at various 
points within the same day.  
2. Telemedicine 
This study will be preferentially conducted by remote telemedicine methods, with option for in-
person assessments if needed. Audio and visual communication will be required for evaluation and 
baseline visits for a subject to participate. If a participant plans to participate by telehealth only, 
participants with predictable lack of access to audio and visual means of communication will not be 
enrolled in the study.  
All telehealth study visits and study procedures (excluding informed consent procedures) will 
be conducted via the MGH telemedicine platform, TeleHealth, which is maintained by Partners 
HealthCare. In the event that TeleHealth malfunctions or the participant does not have access to a 
device compatible with the TeleHealth platform, the study visit will be completed via secure Zoom 
web interface, or if not possible, by telephone call. If at any point during a telemedicine study visit, the 
participant endorses any safety concerns or any acute clinical issues emerge, the study clinician will 
take the necessary steps to ensure the participant receives the appropriate follow-up clinical care.   
 
3. Clinician Assessments and Rating Scales 


 
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As demonstrated by the prior incorporation of telemedicine study visits in studies conducted by 
our research unit, clinician assessments and rating scales can safely and effectively be completed 
remotely. The study clinician will enter data into REDCap for televisits, a secure, HIPAA compliant 
web-based application hosted by Partners HealthCare Research Computing, Enterprise Research 
Infrastructure and Services (ERIS). 
 
4. Informant Assessments and Rating Scales 
Informant assessments and rating scales can safely and effectively be completed remotely via 
REDCap as well. The study coordinator will provide the participant with an online link and access 
code to these REDCap questionnaires via (un)encrypted email.  
 
5. Safety Measures  
Urine Pregnancy Screen 
Women of child-bearing potential will complete a urine pregnancy test as part of the evaluation 
study visit and Week 6/drop study visits. Study staff will order a urine pregnancy test online and ship it 
directly to the participant’s home address. The test will be ordered and shipped in advance to ensure 
delivery prior to the applicable study visit.  On the day of the visit, the participant will complete the test 
after the study coordinator or a study clinician has reviewed the proper procedure for completing the 
test. In addition, the participant will provide the study coordinator with visual confirmation of the result 
via TeleHealth video system or image sent by (un)encrypted email. 
 
Vital Signs 
The study coordinator will ship a blood pressure and heart rate monitor to each participant, and 
ask the participant to self-report the vital signs on the same day as the study visit via telephone call or 
image sent by (un)encrypted email. The study coordinator will note that these data points were 
provided by study subject report, rather than study staff measurement.  
 
 
III. Remote Study Medication Dispensation 
Study medication will be stored at, ordered from, and dispensed by the MGH Clinical Trials 
Pharmacy (CTP). Study staff will pick the study medication that is assigned to each participant from 
the MGH CTP, remaining blinded to whether it is active or placebo product, and send it via courier 
mail service directly to the participant’s home address. Staff will be trained to follow all guidelines 
elaborated by the MGH CTP and Drug Enforcement Agency in this process. The study medication will 
be ordered and shipped in advance to ensure delivery prior to the baseline study visit, with sufficient 
supply to cover partipation throughout the study. Participants will be given 75 mg strength size 
active/placebo pills, such that they can take one or two to make up 75 mg or 150 mg per daily dose.  
Individuals will be given clear instructions to adhere to the agreed-upon dosing schedule between 
study visits, must keep the study agent in a safe place where other’s would not take it in error, must 
not divert any study agent, and must return study agent to the investigators at the end of the study.  
Returns will be done either in person at end of study visit or by same-day courier pickup. Where 
possible, study medication orders for participants from this and other studies within this department 
will be coordinated so that they can be picked up and mailed in bulk. The study coordinator retrieving 
study medication orders will be listed as a member of study staff on all applicable studies. Per 
standard research procedure, the study clinician will record reported medication compliance in the 
applicable Chart Note. After the completion of study participation, the participant will send the leftover 
study medication and bottles to the study coordinator via mail courier service. The study coordinator 
will complete a thorough capsule count at that time and maintain the study medication until it can be 
returned to MGH and discarded in a biohazard container. 
 


 
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