Clinical trial NCT02039908
Conditions: Attention-deficit/Hyperactivity Disorder
Keywords: Tolerance to stimulant medication
Sponsor: Florida International University
Start date: 2013-04-01; Completion date: 2020-03-01
Enrollment: 267 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Although stimulant medication is a well-established treatment for ADHD, it is often necessary for doctors to increase the dose over time to maintain the benefits of the medication. While medication can be very effective for improving symptoms of ADHD during the first year of use, it has not been found to significantly improve the long term course of children with ADHD. For example, in large research studies, groups of children who take medication for ten years do not have consistently better academic grades than groups of children who never used medication (individual results will vary from child to child).

In order to help children with ADHD achieve the best possible outcomes, it is important for doctors to study why this happens. One possible reason is development of tolerance to the medication. Tolerance means that a drug's effects decrease when it is taken consistently over time, so that an increased dose is needed to continue showing effects. Some doctors believe that children who take stimulant medication for ADHD develop tolerance to it which would explain why benefits may not persist over time, but no research studies have been done to measure whether this occurs. This study aims to see if children show a tolerance effect to stimulant medication and whether that tolerance can be prevented by taking short breaks from the medication called medication holidays.

Detailed description:
This is an innovative evaluation of tolerance using an objective measure in an analog classroom. Each subject will complete the a 10-minute math test twice a day for three weeks on optimal dose or placebo, and then be crossed over to the other condition. Within-subject drug/placebo differences will be compared over the three weeks of exposure to assess tolerance in the analog setting.

When school commences, 50% of the sample will be randomized to 7-day-a-week (continuous) dosing and 50% to 5-day-a- week (weekend holidays) dosing to examine the efficacy of prescribed weekend drug holidays for combatting need for dose escalations (tolerance) during the school year.

Participants will be assessed monthly to detect deteriorating functioning. Using a standardized protocol, study physicians will increase dose for subjects in either arm who meet defined impairment thresholds. The difference between the two dosing conditions will inform regarding how best to deal with tolerance in clinical application.

Arms: arm 1: During the school year, children in this arm will receive 7-day dosing of medication. arm 2: During the school year phase, these children will receive 5-day dosing with weekend holidays.
Interventions: intervention 1: Methylphenidate
Intervention descriptions: intervention 1: Children will receive a double-blind assessment to determine their optimal starting dose of Concerta. Doses will be adjusted over the course of the school year and inceased if tolerance to the medication is detected.

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Examining Tolerance to CNS Stimulants in ADHD 
 
NCT 02039908 
 
1/22/2013 
 


 
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Importance  
ADHD is one of the most recognized and treated psychiatric disorders of childhood (ADHD). A 
population survey in 2007-2008 of 4-17 year old children in the USA estimated that 9.5% (about 5.4 million) 
had received a diagnosis of ADHD and 4.8% (2.7 million) were in current treatment with stimulant medications, 
typically methylphenidate and amphetamine (Vissers et al., 2010).  A massive literature exists on the short-
term effects of stimulant medication (see Swanson et al., 1993 for an early “review of reviews”, and an update 
provide a decade later by Conner, 2003). Despite the widespread use of stimulant medications that have 
robust acute effects, the long-term outcomes for many ADHD are disappointing at best. This point is 
emphasized in the recently released AAP guidelines for ADHD that state the ability to “achieve long term 
successful outcomes still remain a challenge” (AAP, 2011 pg 13). While, the literature on long-term effects is 
sparse, that which exists routinely fails to detect appreciable effects of treatment (Barberesi et al., 2007 Marcus 
et al., 2007 Scheffler et al., 2009). A recent review on the long term effects of stimulant medication concluded 
that the existing studies fail to clearly demonstrate long term benefits (Hazell, 2011). The Multimodal Treatment 
Study of ADHD (MTA), which is the largest and most widely cited longitudinal treatment study of ADHD to date 
(MTA, 1999), provides a painfully clear illustration of this effect. In it, state-of-the-art treatment with or without 
stimulant medication was provided at a relatively young age (7 to 9 years). At the end of a 14-month treatment-
by-protocol phase, all of the assigned treatment groups showed substantial improvement, but the assigned 
treatment conditions with stimulant medication as a component (Med and Comb) were superior to the 
treatment condition without stimulant medication as a component (Beh). However, during the naturalistic 
follow-up phase of the MTA, the relative superiority of assigned pharmacological over non-pharmacological 
treatment dissipated by 50% by the 24-month assessment (MTA Group, 2004) and completely by the 36-
month assessment (see Jensen et al., 2007). Even MTA subjects with a decade of medication usage did not 
exhibit improved long term outcomes, suggesting that nonadherence, while common (Marcus, 2005, 2011), is 
not the primary cause of the lack of sustained benefit (Molina et al., 2009). 
Another possible explanation for the failure of chronic medication usage to alter long term outcomes is 
the development of tolerance. Tolerance is defined as a state of adaptation in which exposure to a drug 
induces changes that result in a decrease of the drug's effects over time (Dupen, Shen & Esrek 2007). There 
are two ways to maintain full effects despite the presence of tolerance: (1) escalating dose of the drug over 
time as tolerance emerges (2) interrupting dosing to allow tolerance to dissipate before given the next dose.  
Concerns about possible tolerance to the therapeutic effects of stimulants data back over 30 years. For 
example in 1975, Safer and Allen reported diminishing behavioral responses after the first year of treatment 
with methylphenidate. Similar results have been reported for the cognitive effects of methylphenidate 
(Richardson, 1988) with decaying efficacy noticed within three months of use. The hypothesis of long-term 
tolerance (defined here as occurring after the medication has cleared the body to distinguish from acute 
tolerance or tachyphylaxis) was formally proposed by Swanson 25 years ago (Swanson, 1986). Here, it was 
observed in a clinical practice setting, that aggressive escalation of dose of MPH to extremely high doses (e.g., 
100 mg 4 times a day) was required to maintain full therapeutic effect. Surprisingly, no appreciable worsening 
in acute tolerability was noted.  More recently, in the NIH funded Preschool ADHD Treatment Study (PATS) 
Wigal et al (2007) documented the dissipation of some side effects even when dose increases occur. 
Tolerance has been demonstrated to occur in a variety of other CNS agents from analgesics to 
anticonvulsants (Abou-Khalil & Lazenby 2003; Ossipov et al., 2005). It is not uncommon to have to switch to an 
alternate anticonvulsants or opioids after chronic exposure in order to recapture lost effect (Kloke et al., 2000; 
Zhang et al., 2003). In fact, tolerance to opioid based analgesics is an extremely well documented phenomena 
that has been the source of extensive research (Dupen, Shen & Esrek 2007). The presence of tolerance 
across multiple classes of drugs suggests that tolerance may be more related to properties of the medications 
themselves then the diseases they target.  Therefore, it is difficult to understand why tolerance would not occur 
to stimulants in the clinical treatment of ADHD.  
Investigations into one aspect of tolerance to CNS stimulants has already led to a dramatic shift in the 
treatment paradigms for ADHD. Before the innovative concept of acute tolerance (or tachyphylaxis) was 
tested, the consensus was that a flat or descending PK profile is desirable for stimulant medication.  This effect 
was routinely achieved by using lower afternoon than morning doses of an immediate release (IR) stimulant, 
including in the MTA (Greenhill, 2001). However, this practice assumes that tachyphylaxis does not occur, so 
that a constant drug level would maintain full effect. Based on the principles of pharmacology and the 
pharmacokinetic/pharmacodynamics (PK/PD) properties of stimulant drugs, a translational approach was taken 
to gain theoretical understanding of the reduced efficacy of first-generation controlled-release formulations of 


 
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stimulant medications (i.e., Ritalin SR® ). The key to these proof-of-concept studies was the use of a sensitive 
surrogate measure of the pharmacodynamic (PD) response in an analog classroom setting, namely the 10 
minute timed math test (MMT). The 10-MMT has been widely used to document the efficacy of novel stimulant 
formulations (Greenhill et al., 2003; McCracken et al., 2003; Swanson et al., 2004) and is accepted by the FDA 
as a surrogate measure of magnitude of efficacy (Swanson, 2002). The effect size in the above studies for the 
objective the 10-minute math test has been large (e.g., about 1.0) and equal to or larger than that for more 
subjective parent and teacher completed rating scales.  The results – loss of full effect with a flat profile and 
achievement of full effect with an ascending profile -- led to the use of ascending profiles in the design of 
second generation controlled-release formulations (OROS MPH: Pelham et al., 2001 Swanson et al., 
2000/2003)) and amphetamine (Adderall XR®: Greenhill et al., 2003; McCracken et al., 2005; McGough et al., 
2003).  These new products were almost immediately adopted and have remained the standard of care for 
ADHD (Pliszka, 2007).  
In addition to clinical experience with stimulants, recent advancements in neuroscience surrounding the 
proposed therapeutic mechanisms of these agents for ADHD suggest that long-term tolerance may in fact 
occur with therapeutic use of stimulants. The primary neural target of methylphenidate is the dopamine 
transporter (DAT), which has a high density in the striatal brain regions. Wang et al (2009) and Volkow et al 
(2009) documented increased density of DAT after a year of clinical treatment. A recent meta-analysis found a 
strong association between prior stimulant exposure and DAT density (Fusar-Poli, et al., 2011). Based on this 
finding, the authors theorized that increasing DAT density may be an adaptive CNS response to long term 
stimulant usage that could explain the limited capacity of stimulants to impact the long term functioning of 
patients with ADHD. Hence, there is now a data driven model supporting the development of tolerance to the 
therapeutic effects CNS stimulants on ADHD symptoms.  
The few studies that have discounted the existence of examined long term tolerance were essentially 
naturalistic follow-up studies with significant methodological limitations. For example, Safer and Allen (1989) 
examined tolerance using a chart review of youth who had experienced a 50% or greater reduction in 
symptoms during the first three years of treatment. They focused on the subsequent two years of treatment 
(years 4 and 5), assuming that tolerance would be most likely to occur years after optimal dose was achieved.  
Since no significant increase in dose was seen in years 4 and 5, it was concluded that tolerance did not occur. 
However, subjects who could not be maintained on a stable dose for more than two years were excluded, yet 
this would be the group most likely to be experiencing tolerance. Moreover, the vast majority of these youth 
were taking short acting MPH on school days only, so the naturally occurring drug holidays on weekends and 
summer vacations may have precluded the development of tolerance. Hence, this study established ONLY that 
tolerance does not routinely occur years after the dose is optimized, suggesting that examinations of tolerance 
should occur earlier in the treatment course.  
The report detailing the results of the 14-month medication algorithm of the MTA also raises the 
possibility of tolerance to clinical doses of stimulants over a school year (Vitiello et al, 2001). There were 
appreciable changes in dose that are consistent with the development of tolerance. An initial placebo-
controlled, double-blind, dose-response 30-day trial on methylphenidate (MPH) documented large initial 
beneficial effects of MPH (Greenhill, 2001). This phase was followed by 13 months of systematic, study-based 
medication monitoring. In monthly clinic visits, protocol-driven dose adjustments were made to maintain full 
effectiveness based on review of collected efficacy (teacher, parent, therapist) and safety (side effect) ratings. 
The dosing patterns of the Medication Only group may be most relevant as the concomitant provision of 
intensive behavioral services has been found to reduce the need for dose adjustments (Pelham et al., 2005; 
Vitiello et al., 2001). In the MTA maintenance phase, a dose increase was required in 54% of the participants 
in the medication only arm. The mean dose in the Med group increased 18% from 32.2mg to 38.1mg, while the 
mg dose per kg of body weight increased 19% from 1mg/kg/day to 1.19mg/kg. By the end of randomized 
treatment phase the Med group had a higher absolute dose (p<.001) and weight based dose (p<.01) than the 
Comb group despite starting out a comparable doses (Vitiello et al., 2001; Fig. 2 below). The mean time to first 
change was 4.1 months with average of 2.76 changes over the duration of the randomized treatment phase. 
The presence of ODD/CD or other allowable comorbidities did not impact mean dose or time to dose change. 
Gender impacted mean dose but not time to dose change. As there were 13 opportunities to change dose over 
the RCT phase, this means that a dose change occurred at 21% of the possible times. This estimate is 
conservative as not all outcome assessments were available at each visit nor did every visit occur as 
scheduled, so the absence of a symptom change was likely interpreted as sustained efficacy. Hence, even 
though medication led to sustained effects over the first year of treatment in the MTA, it was achieved by 


 
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incrementally increasing the dose, an increase in which was needed per repeated assessment, even though 
the optimal dose had been previously determined under placebo controlled settings. The regression line in 
figure 2 suggests that the dose of stimulant will have to be increased by 18% per year to maintain the initial 
effect.  Although we cannot be certain that tolerance is responsible for this need for increasing dose and there 
are alternative explanations (Vitiello et al, 2001), tolerance is a parsimonious explanation that warrants further 
research. If the increases in dose over time in a natural setting could be linked to laboratory-based, controlled 
evaluations of tolerance, a stronger argument that tolerance might explain the dose escalations needed in the 
natural environment. 
One obvious argument against tolerance is that dose increases over time may be associated with the 
physical growth in developing children. In the medication only group the dose increased from 32.2 to 38.1 
mg/day for one year increase of 5.9mg. Over 
this time period, the med group gained 1.91 
kilos for a ratio of 3.1 mg of medication for 
every kilo of body weight gained which is well 
above standard dosing norms of 1mg/kg/day of 
body weight (Greenhill, 2003). Moreover, Safer 
& Allen (1989) found that using mg of MPH/kg of 
body weight overestimates the predicted dose 
increase needed to correct for growth; therefore, 
the observed discrepancy between actual dose 
increase and expected dose increase due to 
growth is likely larger than what was observed.  
Furthermore, Swanson et al (1978) reported that 
in children, a 6-fold difference exists between 
clinically optimal dosages across individuals that 
was unrelated to weight.  Hence, there is not 
always a need to increase dose simply based on 
increased body mass.  
These findings are not unique to the MTA. Numerous other extended follow-up studies of stimulant 
medication in children have observed a similar need to increase dose over time. In most studies with a long-
term follow-up component, a 25% increase over the first year of treatment is typically seen. For example, the 
PATS protocol included a one year maintenance phase using the MTA algorithm to make changes in dose of 
medication over time.  In this study, the average dose increased from 14 to 21 mg/day during this maintenance 
despite a month long double-blinded titration phase prior to the maintenance period.  The same phenomenon 
has been observed in extension studies of once a day stimulants. For example, in the two year extension study 
of OROS-MPH (Concerta®), dose increased by 26% (on the average from 35 to 42 mg/day) even though 
subjects had been previously titrated to optimal dose (Wilens et al., 2005). These data do not include the 
additional 9% of subjects who dropped out specifically due to loss of effect even on the maximum dose of 
OROS-MPH. The mg/kg dose increased by 13 to 15%, suggesting dose adjustments were not primarily due to 
increasing body mass. The vast majority of this increase occurred in the first year of treatment even though 
efficacy assessments occurred only every 3 months. The fact that dose changed little in the second year was 
likely due to the high attrition rate in year two (nearly half the sample stopped prematurely) and that many 
subjects were at the maximum dose allowed in the study. Hence, the leveling off of dose was likely due to 
methodological factors rather than to the lack of tolerance to OROS-MPH. Similar results were found in 
extension study for AMP (Adderall XR®) (McGough, et al., 2005). After a weekly titration to define optimal 
dose, the mean dose was 16 mg/day.  It increased by over a third to 20.2 mg at 6 months. Little incremental 
change was seen over the next year and a half.  
Another possible mechanism driving the need to increase dose could be that parents adapt their 
expectations to their child’s recent functioning. As stimulants typically do not resolve all ADHD symptoms 
(Jensen et al., 2007; MTA, 1999), parents may rate persistent, residual symptoms more severely as time 
passes. The increase in parent reported severity would then translate into increased dose. If parental 
adaptation of ratings was the primary source of the dose increase, then placebo replacement of medication 
should lead to immediate worsening of parental report. However, Martins found that placebo substitution on 
weekends did not lead to acute worsening in parent ratings of weekend behavior or teacher ratings of behavior 
during the subsequent week (2004). Likewise, Sleator found that the majority of youth on a stable stimulant 
(Vitiello et al., 2001) 


 
5 
regimen for a year or more did not experience an acute worsening in symptoms ratings with transition to 
placebo (1974). However, no prior work has examined the impact of interrupted dosing on long term efficacy.  
In summation, the literature reviewed above suggests that an appreciable dose increase is often 
needed for ADHD children to maintain full effect over the first year of treatment with stimulants. Dose increases 
are needed even when the dose has been systematically titrated, suggesting it is not due to initial under-
dosing. Observed dose increases are greater than predicted by change in body weight alone, so it appears 
that children are not simply outgrowing their dose. This pattern occurs across stimulant classes and 
formulations, suggesting that tolerance may occur with any stimulant medication. Dose increases are an 
effective strategy to overcome this loss, at least in the first one or two years of treatment. However, if the need 
for dose escalation remained constant, untenable doses of stimulants might be required within a few years and 
dose escalations may not be a viable long-term strategy for the majority of ADHD youth prescribed CNS 
stimulants.  In the MTA, only a third of the participants receiving medication demonstrated ongoing treatment 
benefit after two years, leading the authors to question the advisability of continuing medication in the majority 
of participants (Swanson et al., 2007). Long term outcomes were no better for medication adherent youth 
(Molina et al., 2009). Most longitudinal assessments have reached similarly disappointing conclusions about 
the observed long term benefits of stimulant medications (Hazell, et al. 2011). While alternate mechanisms 
may be responsible for the inability to detect long term benefits of stimulant medications, based on the 
collected evidence summarize above, it appears unwise to rule out tolerance to the therapeutic effects of 
stimulants as a contributing factor.  
It is clear that the field needs to identify additional ways to sustain the initial, large clinical effects of 
stimulant medication. Fortunately, efficacious treatments for the management of tolerance have been 
developed for other diseases. Therefore, it seems prudent to prioritize assessing the role of tolerance in the 
long term management of ADHD over other possible mechanism for which we have no current treatments. 
One possible treatment is the use of prescribed drug holidays. They have been found to be efficacious for 
recovering lost effect in trials of anticonvulsants and opioid analgesics (Azar et al., 2010; Ho, Gan & Habib, 
2006; White 2005). School day dosing was once the standard practice with many parents still preferring to 
dose primarily on school days (Pliszka 2007; Sleator, Newman & Sprrague, 1974). Drug holidays have even 
been prescribed as a means of preventing stimulant induced growth suppression (Faraone 2008). Evidence 
based behavioral treatment options exist (Fabiano et al., 2009; Pelham & Fabiano, 2008) that can be 
employed on days off medication to provide symptom relief. As reported above, Safer and Allen (1998) found 
that the vast majority of youth achieving a 50% symptom response were able to sustain this effect for 3 years 
or more. Interestingly, 85% of their sample used medication only on school days. Martins found that over 4 
weeks, substitution of placebo for IR MPH on weekends produced little reduction in symptom control on 
weekends (2004). Hence, the increased morbidity from drug holidays for ADHD medication is likely less 
impairing than that for opioid analgesics where drug holidays are recommended to enhance therapeutic 
response (Dupen, Shen & Esrek 2007; White 2005). These results suggest that prescribed drug holidays are 
feasible and merit exploration as a means of combating tolerance.  
An extended, controlled clinical trial that evaluates children in their naturalistic settings, similar to the 
MTA, would be the preferred design for examining the efficacy of prescribed drug holidays to reduce the need 
for recurrent dose increases and to improve long term symptom control. However, they are not ideal for the 
precise determination of pharmacodynamic response that may be necessary to identify drug tolerance. In 
these trials, dose adjustments can be caused by many factors that may have little to do with drug efficacy, 
such as parental preference or treatment adherence. Moreover, the commonly employed outcome measures 
of parent and teacher ratings are prone to rater expectancy bias (Waschbusch, Pelham, & Waxmonsky, 2009) 
that may further reduce the ability to identify changes in therapeutic efficacy. Analog classroom designs 
employing objective outcome measures are the preferred modality for detecting changes in efficacy at specific 
time points or for detecting subtle differences between agents with established efficacy (e.g., Pelham et al., 
1999 for comparisons of Adderall and Ritalin). This paradigm (see Swanson et al., 2002) has been employed 
to aid the development of several stimulant formulations (e.g., Metadate CD: Swanson et al., 2004), and the 
concept of tachyphylaxis was first identified in the analog classroom setting. The most commonly used 
measure to detect incremental changes in efficacy is the 10 minute timed math test (MMT—dozens of 
studies—see below) where subjects are scored on the number of problems completed as well as the 
percentage completed correctly. Studies of extended release stimulants in analog classroom settings done by 
this investigative team have already suggested the capacity of CNS stimulants to impact next day behavior 


 
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even after they have cleared the body, presumably through producing an adaptation in the CNS (see prelim 
studies).  
Preliminary Studies: Analog classroom measures have been widely used to evaluate the efficacy and 
time course of CNS stimulants (McCracken et al., 2003; Swanson et al., 1999/2005). The sensitivity of these 
lab school protocols have made it possible to document statistically significant differences related to subtle 
differences in dose and time of evaluation of medication. Even though neither was designed to assess 
tolerance, two such studies mention an unexpected finding suggesting carry-over tolerance. 
  
Results from these published studies can be used to obtain an estimate of an effect size for long-term 
tolerance.  In these designs, each medication condition is typically started 6 days before the analog classroom 
day, which consisted of 8 tests spread out across the day at 1.5 hour intervals. Hence, by the time subjects 
arrive in the analog classroom they have already been treated with a fixed dose of medication for almost a 
week. By comparing the performance on the initial test after 6 days of placebo to 6 days of active drug, we can 
estimate the carry-over tolerance from the prior exposure. For example, Swanson et al (2005) noted large 
positive effects on attention and behavior for Concerta® and Metadate CD® on the 10 minute math test (10-
MMT) administered in the analog classroom 1.5 and 3.0 hours after dosing. However, on the preceding test 
administered immediately after the morning dose (before expected onset of effect), the effect sizes were 
moderately negative (for Concerta®, -0.33 for 18 mg, -0.25 for 36 mg, and -0.43 for 54 mg). The authors 
interpreted the temporary superiority of the placebo over the medication conditions results as possible 
evidence of tolerance. McCracken, Biederman, Greenhill, Swanson et al. (2003) also reported this initial 
temporary superiority of the placebo condition in a study of Adderall® and Adderall XR® but effect sizes were 
not reported.  We will provide an effect size analysis of the Adderall® 10 mg and the Adderall XR® 10 mg 
(equivalent to Adderall 5 mg BID) conditions to show the magnitude of this effect the 10-MMT measure of 
performance (number of problems worked correctly).  After the 6-day placebo exposure, performance was 
associated with better performance (86.7 problems) than after 6 days of drug exposure conditions (e.g., 56.2 
problems for the 10 mg Adderall and 60.9 problems for 10 mg Adderall XR). The differences divided by the SD 
of the placebo condition (56.1) provides an estimate of effect size: (56.20 – 86.77)/56.1 = - 0.545 for Adderall 
and (60.95 – 86.77)/56.1 = -0.46 for Adderall XR. The test 1.5 hours later provides some indication of how this 
carry-over tolerance effect is overcome by the dose of medication on day 7. Based on these preliminary 
analyses of performance in lab school studies, we provide evidence that the build-up of tolerance over a 1-
week period, has an effect size of about 0.4 for the 10-MMT measure for a standard dose of stimulant 
medication.    
These results document that repeated exposure to CNS stimulants impacts objectively measured 
performance the day after the therapeutic effects of the medication have stopped, presumably through 
producing an adaptation in the CNS. This effect can be detected within the first week of medication use in 
analog settings. If declining performance on the MMT (administered when medication is active in contrast to 
the above studies) within a given subject tested repeatedly across days on a fixed, therapeutic dose of a CNS 
stimulant can be demonstrated, then tolerance to CNS stimulants has been demonstrated according to current 
definitions of the concept (Dupen, Shen & Esrek 2007). No prior study has attempted to do this task. These 
results also support that tolerance may occur within one week of dosing and that analog classrooms can 
measure performance with the necessary precision to detect tolerance. 
Innovation 
Numerous studies have documented the impressive capacity of CNS stimulants to reduce symptoms of ADHD 
over the course of weeks to months. In contrast, the MTA (Molina et al., 2009) and most other longitudinal 
studies (Barberesi et al., 2007, Marcus & Durkin 2011, Scheffler, et al., 2009) have failed to find that these 
short term benefits translate to appreciable long term advantages, even for those adherent to the medication. 
This great divide between the acute vs. chronic effects of treatment is one of the most vexing clinical dilemmas 
in the field today- How can a treatment that works so well at one time point not translate to sustained 
improvements over time? However, the phenomenon of diminishing effects over time is not unique to the 
treatment of ADHD.  Multiple classes of medications exhibit reduced efficacy over time when used daily for 
extended durations, such as opioid analgesics (DuPen, Shren & Esrek 2007) and the anticonvulsants (Azar et 
al., 2010). This is in essence the definition of tolerance. For opioids, the concept of tolerance (i.e., repeated 
exposure decreasing the drug's effects over time) is well established as the need to increase dose to maintain 
effect is widely observed (Mao, 2002). Yet, despite similar observations for ADHD, tolerance to stimulant 
medications is thought by some leading researchers to not occur (Safer & Allen 1988; Vitiello et al., 2001). 
However, as we discussed above, the MTA and most other extended trials of CNS stimulants clearly document 


 
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a need to increase dose by 25% or more over the first year of treatment to maintain therapeutic effect 
(Greenhill et al., 2007; McCracken et al., 2003; Vitiello et al., 2001; Wilens et al., 2005). These dose increases 
surpass what would be expected by growth alone. Imaging data support the occurrence of changes in receptor 
density with repeated use of CNS stimulants (Volkow et al., 2012), which has been proposed as a possible 
neurobiological mechanism for the development of tolerance (DuPen, Shen & Esrek, 2007). Moreover, short 
term tolerance, or tachyphylaxis, has been established to occur within the day for CNS stimulants (Swanson et 
al., 1999). This discovery led to the development of truly effective extended release stimulants that have been 
one of the greatest revolutions in ADHD pharmacology over the last two decades (Pliszka, 2007; ACNP, 2011). 
These combined observations suggest that tolerance merits exploration as the mechanism underlying the 
disconnect between short and long term efficacy for CNS stimulants. If tolerance is identified with routine use 
of these agents for treatment of ADHD, then manipulations such as drug holidays that have successfully 
minimized tolerance for other CNS agents could prove efficacious for enhancing long term outcomes in ADHD.  
There have been no controlled studies designed specifically to ascertain the occurrence of tolerance.  
Existing studies of stimulants and ADHD are comprised of large scale clinical outcome studies that measure 
effect primarily from monthly parent and teacher ratings in natural settings (MTA, 1999; Vitiello et al., 2001). 
These designs are ideal for documenting and comparing the efficacy and feasibility of prescribed treatments. 
However, limitations of symptom ratings of ADHD as well as the occurrence of multiple confounders that arise 
in extended clinical trials (nonadherence, missing ratings, selective dropout, parental treatment preferences, 
etc.) make it extremely difficult to determine if tolerance is the primary causal mechanism for the observed 
pattern of dose increases seen over time in clinical trials in natural settings with CNS stimulants.  Moreover, 
only a subset of youth with ADHD require chronically escalating doses to maintain effect, suggesting that a 
within-subject design may be more appropriate to detect tolerance rather than large-scale, between-group 
studies where effects in a subset of participants could be missed. Therefore, we propose to use the same 
methods used to discover tachyphylaxis (within-day tolerance) in a within-subject design under tightly 
controlled conditions to ascertain if tolerance occurs across dosing days. Specifically, we will employ the 10 
minute math test (10-MMT) in the analog classroom setting using a within-subjects, crossover design to 
compare drug response after 3 weeks of continuous OROS MPH treatment vs. 3 weeks of placebo with 
drug/placebo probes after each 3-week block. In addition, we propose to test under randomized conditions in 
the regular school year and home settings, whether 5-day-a-week (prescribed weekend drug holidays) dosing 
reduce the need for subsequent dose increases while sustaining initial medication effects compared to 7-day-a 
week (continuous) dosing. This study will be the first trial to examine if dosing schedule impacts total the need 
for dose adjustments, total daily dosage, and the level of symptom control.  
Consistent with the NIH’s desire to promote translational research, we have elected to unite the 
laboratory assessment of tolerance with the randomized clinical trial of weekly drug holidays vs. continuous 
dosing.  The detection of tolerance in analog settings is of limited import if it does not alter outcomes in real 
world settings. By testing every subject on multiple days of OROS-MPH and placebo treatment and by 
including a drug-placebo probe following 3 weeks of OROS or placebo, we can create individualized tolerance 
indices in a controlled setting as well as as predictors of the need for dose adjustments in the natural setting.  
This will allow us to determine if subjects who manifest a diminishing response across days in the analog 
classroom are more likely to display worsening ADHD symptoms over the course of the school year despite 
being medicated and subsequently need to have their previously optimized dose further increased. This 
method maximizes precision by using the same subjects in both phases and cost-effectiveness by sharing 
staff, resources and recruitment efforts. Most importantly, it allows us to correlate the need for dose changes in 
real world settings with the occurrence of tolerance in the laboratory, thereby linking the mechanism (tolerance) 
and outcome (dose increase) of interest. The observed association between these two stages is critical to the 
identification of tolerance as a causal factor for the need for dose increases so commonly observed in research 
and clinical work with ADHD children. If our translational study of the concept of tolerance is successful and 
our proposed intervention—weekend drug holidays—are effective, then a dramatic change many once again 
occur in long-term treatment of a disease impacting millions of children.   
In summary, the proposed research is of high import and innovation because it addresses one of the 
most recognized and treated psychiatric disorders of childhood (ADHD). It uses the established principles and 
techniques of pharmacology to identify a possible mechanism (long-term tolerance) for one of the most 
significant unanswered questions in the field to date, the unexplained loss of efficacy with long-term use of 
stimulant medication. Our work is both novel and innovative as it proposes to evaluate one potential solution to 
this dilemma while challenging the prevailing belief, in the absence of data, that long-term tolerance does not 


 
8 
occur. The same approach has been used to identify the occurrence of acute tolerance, which led to the 
development of the new generation of long-acting stimulants and a dramatic shift in prescribing practices. This 
application is derived directly from those experiences and integrates the experience, skills and knowledge of 
experts on the neuroscience of CNS stimulants and clinical outcomes in ADHD. 
Approach 
Participants. Two-hundred and fifty children with ADHD between the ages of 6-12 will be recruited in 4 
cohorts (N =63 per cohort) during Y01 to 04 of the project.  Recruitment will occur between January and June 
of each year. Each year, the cohort of participants will be recruited from among those families seeking to enroll 
their child in the Summer Treatment Program (STP) for Children with ADHD at Florida International University. 
The STP is an intensive 8 week summer camp for children with ADHD that was the model for the summer 
program employed in the MTA (MTA, 1999) and has received national recognition as a model clinical treatment 
program. All study participants will also be enrolled in the Summer Treatment Program (STP), as this is the 
setting for the analog classroom component of the study.  
Based on prior experience, the participants are expected to be approximately 25% female and 75% 
male as these gender rates are representative of epidemiological prevalence estimates of ADHD in children 
(American Psychiatric Association, 2000; Visser et al, 2010). The combined population of Broward and Miami 
Dade Counties is approximately 57% Hispanic, 25% Caucasian, and 18% African American. Based on the 
local demographics and our previous trials in South Florida, We expect at least 50% minority enrollees (see 
targeted enrollment chart), surpassing the percentage in the MTA (MTA, 1999).  
Recruitment. Participants will be recruited from applicants for the STP. In 2012, the STP enrolled 240 
ADHD children and at least that number is expected annually. Our center has an extensive history of running 
large-scale, ADHD clinical trials, several of which have been set at the STP. Over the past 10 years, we have 
recruited more than 1000 ADHD children for a variety of federally-funded projects and STPs, including more 
than 500 since the CCF relocated to FIU in 2010.  
Inclusion/Exclusion. Inclusion criteria will include a DSM-IV-TR diagnosis of ADHD, and a Full Scale 
IQ above 80. Exclusion criteria will include: currently or in the past 6 months receiving psychotropic medication 
for conditions other than ADHD or active medical or psychiatric conditions that could be worsened by 
stimulants (seizures, pregnancy, arrhythmias, hypertension, Tourette’s Disorder, psychoses, mania etc.,). 
Youth who meet full DSM IV criteria for Autism or Asperger’s Disorder will be excluded as stimulants have 
been found to have reduced efficacy and tolerability in this population (Rupp Treatment Team, 2005). Youth 
with a documented intolerance to methylphenidate medications or a failed trial of OROS MPH at full 
therapeutic doses will not be enrolled. Youth with comorbid ODD, CD or a mood or anxiety disorder not 
requiring psychotropic medication will be allowed to enroll as long as they do not need emergent treatment 
(mania, active suicidal ideation) as their conditions did not predict stimulant dose during the 13 months of 
randomized treatment in the MTA (Vitiello et al., 2001). Participants will be permitted to engage in community 
based psychosocial treatments but cannot start new psychotropic medication. The type and intensity of 
community based treatments with be measured using the Services for Children and Adolescents-Parent 
Interview that was used in the MTA (Jensen et al., 2004), and analyzed as a covariate. 
Initial Assessment, Diagnosis, and Measures. At an intake assessment, informed parental consent 
and youth assent will be obtained. During this assessment, diagnosis of ADHD will be assessed through a 
combination of parent structured interview (NIMH Diagnostic Interview Schedule for Children IV, computerized 
version: Shaffer et al., 2000) and parent and teacher rating scales, as is the standard and recommended 
practice in the field including for adolescents (Pelham, Fabiano & Massetti, 2005; Wolraich et al., 2005). A dual 
clinician review procedure will be used to determine diagnostic status and where disagreement occurs, a third 
clinician will be consulted. Additionally, a clinician will administer to the child a brief intelligence test (WASI-II; 
Wechsler, 2011) and achievement testing (WIAT-III; Wechsler, 2011). Teacher ratings (Disruptive Behavior 
Disorders Rating Scale, Pelham et al., 1992; Impairment Rating Scale (IRS), Fabiano et al., 2006; Academic 
Performance Rating Scale (APRS); DuPaul et al., 1991) will also be obtained. As part of the Pittsburgh 
Modified Conners Rating Scale, Parents and teachers will rate children’s peer relationships from the SNAP 
rating scale on the (Atkins et al., 1985; Pelham et al., 2001).  The APRS and peer relationship itsms will be 
repeated at study endpoint as measures of functional social and academic outcomes. Similarly, the Disruptive 
Behavior Disorders Rating Scale (Pelham et al., 1992) will be completed at baseline and endpoint by parents 
and teachers, as it rates all DSM IV symptoms of ODD, CD and ADHD. These measureshave been employed 
in multiple pharmacological trials for pediatric ADHD (Waxmonsky et al., 2010). The Coddington Life Events 
List (Coddington,1972) will also be administered at baseline to assess the degree of familial stressors. Life 


 
9 
stressors will be analyzed as a covariate. The CBCL (parent version) will be used to assess for psychiatric 
comorbidity (Achenbach, 2009). If any subject scores in the borderline or clinical ranges on the 
anxious/depressed, withdrawn/depressed, social problem or thought problems subscales, parents will then 
complete all modules of the C-DISC. It has been used in numerous clinical trials as well as in epidemiological 
studies of pediatric mental illness (Costello, Egger & Angold, 2005). All DISC diagnoses will be reviewed by a 
MD/PhD level clinician prior to a formal decision on subject eligibility. Study physicians will also gather medical 
history and collect vital signs (resting pulse and BP, weight, height) to ensure it is medically appropriate for 
subjects to be prescribed stimulants. Study physicians will conduct their own exam or consult with the primary 
care provider if review of the medical history indicates the possibility of additional risk.  
 
Phase 1: To assess for the development of tolerance to the therapeutic effects of stimulant medication in a 
controlled summer program setting.  
The Lab School Protocol uses highly controlled settings and a surrogate measure of efficacy -- the 10-
Minute Math Test (10-MMT) -- to gain precision.  We will use these procedures for the evaluation of long-term 
tolerance during an 8-week Summer Treatment Program (STP.  As an operational definition, we consider long-
term tolerance to be reduced response to medication a day or more after prior exposure to medication.  In 
contrast, we consider short-term tolerance (tachyphylaxis) to be the effects manifested to a given dose before 
the medication has cleared the body. In the 8-week STP, we can establish the classic conditions to test for 
tolerance by varying long-term exposure (e.g., two weeks or more) to stimulant medication that precedes a 
standard test on the optimal dose.  Medication will be provided weekly to parents in the form of blister packs 
with each dose marked with day of the week it is to be given. Upon arrival to the STP, camp staff will verify that 
the participant took the scheduled dose of medication for that day. As part of the daily STP schedule, there are 
classroom periods in the midmorning (no earlier than 9:45 AM) and midafternoon (no later than 2:45 PM).  The 
10- MMT will be administered as part of each classroom period to provide a daily measure of academic 
productivity (averaged across the two classroom periods per day) that can be used as a measure of 
pharmacodynamic response to medication.   
As part of the assessment for entering the STP, the baseline 10-MMT will be administered, which 
consists of 6 separate pages of math problems, each with a different level of difficulty (i.e., 1-digit addition, 1 
digit addition or subtraction, 2-digit addition, 2-digit addition and subtraction, 3-digit addition, 3-digit addition 
and subtraction).  This will be repeated twice, and on the second test the difficulty level that most closely 
approximates the target productivity rate of 10 problems per minute will be selected as the difficulty level for 
that child for all future tests. In this way, the difficulty level will be individualized and then held constant across 
the 8 week STP. Similar procedures have been used in summer programs and lab schools to precisely assess 
therapeutic effects of stimulant preparations (e.g., Pelham et al., 1987; 1990, 1999a,b, 2001; Swanson et al., 
1998, 1999, 2002, 2003, 2005). We will use OROS®MPH, which achieves a constant effect from 1.5 to 10+ 
hours after administration (Pelham et al., 2001; Swanson et al, 2001; Swanson et al, 2003). 
During the first two weeks of the STP, placebo-controlled assessments of up to four different OROS 
methylphenidate doses (18mg, 27mg, 36mg, 54mg,--max dose not to exceed 2mg/kg/day) will be conducted to 
establish each child’s optimal dose. These doses cover the entire range of commercially available FDA 
approved doses for children ages 6-12. Study investigators will review teachers and counselor measures of 
efficacy (frequency counts of problem behaviors, percentage of academic seatwork assignments completed 
correctly, ratings of behavior during the camp day) and parent and counselor ratings of tolerability to establish 
each child’s individual optimal dose (Pelham et al, 1985; Pelham & Hoza, 1987; Pelham et al, 1987, 1990, 
1999a,b, 2005). Tolerability will be assessed using the Pittsburgh Side Effect Rating Scale (Pelham, 1993). 
Similar scales were used by the MTA during the month long medication titration phase (Greenhill et al 2001) 
and have been used in dozens of medication studies in the STP (see references above). Medication will not be 
administered on weekends during the titration period to give parents experience at applying learned behavioral 
treatments (that are part of the STP) when children are unmedicated, as they need to be prepared for weekend 
drug holidays that may be prescribed in the longitudinal follow-up phase.  
Over the next 6 weeks, exposure differences will be established by a cross-over of 3-week treatments 
with optimal dose vs. placebo. Twice-daily assessments will be performed with the 10-MMT administered in 
each classroom period to establish a sensitive and reliable surrogate measure of efficacy as the 10-MMT has 
been the primary objective measure of treatment response used in analog classroom studies (Swanson, 2002).  
Before each condition, a 2-day (Saturday and Sunday) placebo washout will be imposed. During each 
exposure conditions, children will receive the same condition on weekends to extend the continuous exposure 


 
10 
period to 19 days for each condition.  At the end (day 18 or 19) of each 3-week condition, a probe will be 
administered to create a drug-placebo contrast.  Order of placebo or drug will be counterbalanced across 
participants on these two days. For the Placebo Exposure, the optimal dose will be inserted under double-blind 
conditions on day 18 or day 19, and for the Drug Exposure condition, a placebo will be inserted.  This is shown 
schematically in Table 1. These probes will provide a drug-placebo difference balanced for other effects that 
may occur over time in the STP.  Order of drug and placebo will be counterbalanced across participants such 
that half receive active medication first and half receive placebo first.   
Behavioral interventions will not be employed in the classroom context when the MMT assessments 
are being gathered so as not to confound the behavioral and pharmacological effects and perhaps minimize 
the effect of medication.  We have used this approach in multiple prior STP studies and have shown that it 
eliminates the potential confound (e.g., Carlson et al, 1992; Pelham et al, 1985,1993). 
*One group order is shown; drug and placebo will be administered in reverse order for half of the participants. Within each condition, 
there are two orders for drug vs. placebo testing with each subject getting the opposite assigned treatment on days 18 or 19 ensuring 
17-18 days of constant exposure. 
Dependent measures. The six weeks of the RCT phase will provide comparisons for proof-of-concept 
tests of the hypothesis of long-term tolerance.  The efficacy measure (academic productivity on the 10-MMT) 
will be obtained twice a day for 15 STP school days. The drug-placebo difference for each of the 13 matched 
weekdays prior to the probe days will provide within-subject estimates of effect size with different histories of 
exposure for the preceding days. Based on experience, the initial effect size (estimated from the drug-placebo 
contrast on day 1 and 2) is expected to be large (e.g., ES ~ 1.0).  If long-term tolerance emerges, the effect 
size derived from the individual drug-placebo differences should decrease over the 3 weeks; individual slopes 
will be calculated to determine these differences and analyzed as described below for study Aim 1.  Since we 
have multiple tests administered each day, we will be able to obtain precise and stable measures of 
performance on the 10-MMT and an effect size for each individual. The placebo/drug probe at the end of each 
3-week exposure will provide a second index of possible tolerance such that the effect size following 3 weeks 
of medication exposure is expected to be smaller than the effect size following placebo exposure. This second 
index of tolerance will be used to examine the relationship between the controlled measure of tolerance in the 
summer and the need for dose escalation during the following school year (Phase 2) in Specific Aim 2.  
 
Phase 2: random assignment to continuous dosing regimen or weekend holidays for the school year. Monitor 
medication effectiveness and standardized need for dose escalation with monthly clinical visits modeled after 
the MTA protocol in which full effectiveness waned and was maintained by increases in dose. 
 
At the end of the STP, participants will be randomly assigned to either 7 day-a-week (continuous) or 5-
day-a-week (weekend drug holidays) dosing for the duration of the academic year (50% chance for each) to 
evaluate the impact of drug holidays on dosage requirements. Children will stay in their assigned groups (5 
vs.7 day a week dosing during extended school breaks such as winter and spring break. Children will begin the 
school year on their established, optimal dose of OROS from Phase 1 of the study.  Two prior placebo-
controlled trials have found that a dose of stimulant in the STP/analogue classroom settings was comparably 
effective during the child’s regular school setting (Pelham et al., 2001, 2002), so the transition from STP to 
school does not necessitate dose adjustments.  
Procedures modeled after the MTA medication maintenance phase will be followed to collect monthly 
assessments of medication effectiveness and to determine the need for dose escalation (Vitiello et al., 2001).  
Initial treatment will remain stable for the first 4 weeks of the school year to allow for adjustment to the school 
setting and for the teacher to become familiar with the child. After 4 weeks, parents and children will attend 
monthly medication visits, where physicians will measure heart rate and blood pressure and will conduct a 
review of monthly ratings from teachers and parents.  Prior to these visits, teachers and parents will complete 
 
Week/day 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Titration 
1 
Placebo 
18 mg 
27 mg 
36 mg 
54 mg 
Titration 
2 
18 mg 
27 mg 
36 mg 
54 mg 
Placebo 
Condition 1* 
3 
Med -1 
Med -2 
Med-3 
Med-4 
Med-5 
Condition 1 
4 
Med-8 
Med-9 
Med-10 
Med-11 
Med-12 
Condition 1 
5 
Med-15 
Med-16 
Med -17 
Med or Pla-18 
Med or Pla-19 
Condition 2 
6 
Pla-1 
Pla -2 
Pla-3 
Pla-4 
Pla-5 
Condition 2 
7 
Pla-8 
Pla-9 
Pla-10 
Pla-11 
Pla-12 
Condition 2 
8 
Pla-15 
Pla-16 
Pla-17 
Pla or Med-18 
Pla or Med-19 


 
11 
ratings of medication effects. Parent and teacher ratings of symptoms and impairment (see measures below) 
will be evaluated by the investigators to determine need for medication dose escalation.  In both arms, children 
whose teachers or parents indicate continued efficacy of medication will remain on their current dose. If it is 
documented by the parent or teacher and affirmed by the physician investigators (see algorithm below) that 
symptoms have worsened, OROS MPH will be increased to next available dose (e.g. if at 36mg increase to 
54mg) for participants in either arm. Functioning will be monitored for the following month, and the assessment 
will be repeated for the next visit. 
Dose can be increased up to FDA-recommended daily maximum dose for the age, unless there are 
safety concerns or emergent adverse effects. Dosages may be lowered at any time. If a participant is still 
impaired on the maximum FDA dose, than they can be switched to amphetamine based medication such as 
mixed amphetamine salts XR. Switching stimulant classes is the recommended treatment when an initial 
stimulant trial is not successful (Pliszka, 2007). The timing of and the rationale for the switch will be 
documented. A switch in medication class was uncommon in the MTA (12%), but nonetheless the percentage 
of subjects reaching maximum approved OROS dose and then percentage crossing over to alternate 
medication will be evaluated as a exploratory outcome if the N is sufficient (MTA, 1999). 
Measures and adjustment algorithm. IOWA Conners and the Impairment Rating Scale are employed 
because they are brief and therefore more likely to be completed by teachers without complaint than more 
lengthy measures. They have been found to as reliable for detecting treatment change as longer scales 
(Pelham, Fabiano & Massetti, 2005). We have employed these measures and this approach to detecting need 
for dose escalation in the MTA and several previous NIH-and IES-funded studies (NIMH: MH0629046; IES: 
R324B060045). The IRS evaluates the child’s functioning in developmentally important area of peer 
relationships, adult-child relationships, academic performance and classroom behavior. For this study, raters 
will be instructed on the IRS to rate the past month and compare it to the month prior in order to aide detection 
of tolerance. The IOWA Conners assesses the spectrum of ADHD and ODD symptoms. Both measures have 
been found to be a sensitive marker of medication effects (Fabiano, et al., 2006; Goyette et al., 1978). Parents 
will be specifically instructed to rate only school days when all subjects are medicated, so that symptom 
exacerbations on weekends in the drug holiday arm will not trigger a dose increase.  
The study physicians will review all of the collected ratings to evaluate each child’s functioning and 
response to the current dose of medication. As classroom performance and behavior will be used to determine 
optimal dose in the STP, teacher ratings will be the primary determinant of dose. If ratings indicate that 
children’s response is worse than the previous month, study staff members will contact the rater to rule out 
factors other than reduced response to medication (e.g., learning problems, external family stressors). If 
reduced responsiveness is determined, a dose increase will be recommended. Similar assessment measures 
and titration thresholds in multiple medication studies (Vitiello et al., 2001, Pelham et al., in preparation). 
Parents in both arms will also rate symptom levels specifically on weekends for the weekend before the visit to 
assess symptom levels during possible times off medication. A similar assessment protocol has been 
successfully employed in a current study by Dr. Waxmonsky assessing the effects of stimulants on growth 
(MH083692). Parents will also complete the Pittsburgh Side Effect Rating Scale (PSERS) monthly to evaluate 
adverse events.  
 
 
Weekend medication will be blinded and dispensed in separate blister packs from the unblinded 
weekday medication to ensure that parents and prescribing physician are blind to treatment assignment.  
Families will be given only enough medication for the month and will be asked to track medication 
administration on a daily basis using dosing calendars to maximize adherence. Pill counts and dosing 
calendars will be reviewed at each visit to verify adherence to prescribed medication and drug holidays. To 
assess accuracy of parent report of medication adherence, a MPH saliva assay will be collected at 3 random 
medication visits during the course of the school year. Identical collection policies to that employed in the MTA 
will be used. The assays are sufficiently sensitive that administration of medication the prior morning will not 
produce a positive result the next day, even after repeated dosing (Modi et al., 2000; Papadopoulos, et al., 
2009).  
The ideal duration for a therapeutic stimulant holiday is unknown. Weekend holidays were selected 
because preliminary data suggests that tolerance can onset within days, so the offset may be as rapid. In 
support of this theory, anticonvulsant holidays as short as two days have been associated with improved 
seizure control (Azar et al., 2010). Further, weekend holidays are practical and commonly used in clinical 
practice to address side effect concerns (Pliszka, 2007) and been found to be well tolerated by families whose 
children are already stabilized on a daily medication routine (Martins, et al., 2004).  


 
12 
As part of their participation in the Summer Treatment Program, all parents will complete a behavioral 
parent training course (BPT; 8 group sessions) to give them the skills necessary to manage ADHD symptoms 
at home and to learn how to establish a school-based daily report card (DRC). Monthly group “booster” BPT 
sessions addressing these topics will be held for the remainder of the school year in an effort to maximize 
retention. Similar “low dose” behavioral supports services have been provided to families in several of our 
recent longitudinal treatment studies (e.g., MH062946; IES R324B060045). They have proven helpful in 
increasing retention (mean annual attrition under 5% across three trials totaling 450 children). Provision of 
ongoing behavioral services is particularly relevant for this proposal as racial and ethnic minority families are 
more likely to benefit from and to adhere to combined treatment services for ADHD than medication alone 
(Arnold et al, 2003; Stein et al., 2012). Notably, less than a third of parents access these optional booster 
services with the mean number of sessions attended being less than 1 per year. Hence, it is unlikely that this 
level of behavioral support for parents will influence need for dose escalation based on teacher reports. As 
participants in both arms will have equal access to BPT, the comparison of the two dosing schedules should 
not be impacted.  Behavioral interventions will not be implemented in the children’s regular school settings by 
study staff so as not to influence need for dose increases (cf. the MTA, Vitiello et al., 2001). Instead, study staff 
will be available during the monthly booster sessions to assist parents in establishing a school-based daily 
report card. Teacher-implemented, usual-care classroom interventions will be tracked for analysis as a 
covariate.  ADHD medication will be provided through the study to minimize financial burden to families and to 
maximize treatment adherence. 
Dependent Measures.  The number of dose changes needed per the protocol during the school year 
will be the primary outcome measure. Additional, secondary dosing outcomes will include time to first dose 
increase, mean endpoint total daily dose, and percent reaching maximum OROS dose. The index of tolerance 
manifested in the controlled STP setting (as described above) will be investigated as a predictor of putative 
tolerance (dose escalations) during the school year.  In addition, at the end of the school year, the SSRS, 
APRS, LES, and DBD Rating will be repeated to measure endpoint symptoms (both ADHD and ODD), social 
skills, academic performance, and familial life events (secondary outcomes or covariates for analyses).  
Analytic Plan.  
Aim 1: The critical test of tolerance in the STP will be based on the comparison of the final estimates of effect 
size based on the within-subject probes on Days 18 and 19 of each condition (see Table above). These tests 
will provide within-subject estimates of effect size for the same conditions (i.e., the optimal dose of OROS 
MPH), but with different histories of exposure for the preceding 3 weeks (i.e., either to medication or to 
placebo).  Our operational definition of tolerance will be a smaller Drug/Placebo effect size after the Drug 
exposure than after the Placebo exposure.  This planned t-test will be from the full ANOVA (see below).  
We propose additional planned tests (see below) embedded in an ANOVA that includes other factors to control 
for one between-subject factors (Order, with 2 levels: Drug/Placebo or Placebo/Drug) and one within-subject 
factor (Day, with 13 levels for the 13 weekdays in each condition prior to the placebo probe).  This will provide 
a test of Drug/Placebo differences controlled for exposure on a day-by-day basis.  Each difference will also 
represent an effect size, but the conditions will be offset by 3-weeks in contrast to the main planned 
comparison based on the drug-placebo probes at the end of each Exposure condition (see above).  Using a 
mixed model ANOVA (SAS Proc Mixed), we will test for a differential change in performance (absolute score 
on the 10-MMT) for the Exposure conditions (Drug and Placebo).  With a sample size of 200, the power to 
detect a difference with effect size of .4 is greater than 0.8, so power is clearly adequate with a sample of 250. 
 
One planned test of tolerance will be based on a comparison of the average change in effect size for 
the 2 exposure conditions.  Based on prior studies (see Preliminary Studies section), we expect that the 
tolerance effect in the STP setting will reach an effect size of about 0.4 after a week or more or exposure to 
stimulant medication.  For a sample size of n = 200, and the average effect size of 0.4 for the group, the power 
to detect a difference in the two exposure conditions (Drug, Placebo) will be greater than 0.8.  
 
Since we expect individual differences in tolerance, we will perform a test of the presence or absence of 
tolerance.  We estimate the proportion of cases manifesting a smaller effect size after the Drug Exposure than 
after the Placebo Exposure condition.  For a sample size of n = 200, and for an expected proportion who will 
show tolerance of 0.6, the power to detect a difference in direction of change will be greater than 0.8.  The 
primary index of tolerance (drug/placebo differences on final days of exposure) will be used to address Aim 3.  
Aims 2 and 3: The basic design is a two-arm randomized, double-blind, controlled clinical trial, with 
participating children being allocated 1:1 at the beginning of the school term to either a seven-day continuous 
dosing drug regimen or a five-day weekend-drug-holiday regimen.  The allocation will be done with a permuted 


 
13 
block randomization strategy with block sizes 2 and 4.  The participants will be followed for the full school term. 
The primary outcome will be the number of dose changes required during the entire school year for which will 
compare the two treatment arms using a Poisson regression model (secondary dose-related measures are 
described below).  Number of dose changes was selected as the primary outcome as it is the direct measure 
of tolerance in this protocol. Symptom severity and social/academic impairment will be evaluated descriptively 
as secondary outcomes.  All children are expected to show large improvement on these measures since all will 
be medicated at a therapeutic dose level and actively medicated at endpoint and we do not necessarily expect 
group differences on these variables. If our intervention is successful, outcomes may be similar although the 
doses for the weekend holiday group may be lower than the continuous dosing group. 
We will also investigate the impact of the individual index of tolerance (Aim 3) and other covariates of 
interest (DBD scale ODD/CD symptom severity, gender and stressful familial life events) on the number of 
dose changes by including these terms in the regression model. This will permit useful estimates and tests of 
the impact of these factors on number of dose changes.  
 
The expected number of dose changes for 7-days medication group is 2.76, based on the 13 month 
RCT phase of the MTA (Vitiello, et al., 2001).  A sample size of n=250 (125 per treatment arm) should provide 
95% power to detect at a least 25% decrease in the number of dose changes for the weekend drug holiday 
group, two sided test, α = 0.05 (Aim 2). The power for assessing the impact of the individual index of tolerance 
(Aim 3) on the number of dose changes is above 95%.  We recognize that use of OROS vs. short acting MPH 
(as was done in the MTA) may impact the number of dose changes. However, for a sample size 250, power 
remains above .8 to detect a 25% difference between groups if the average number of dose increases is as 
low as 1.6 in the 7 day a week dosing group. The maximum number of dose increases is four in this study due 
to limits on the maximum prescribed dose of OROS-MPH, which could decrease the power somewhat should 
this occur with sufficient frequency.  However, our sample size of 250 should still provide adequate power.  
Also, should this occur with sufficient frequency, we can compare the proportions of the children in the two 
treatment arms for which dosage reaches the maximum threshold as well as the percentage crossing over to 
an alternate medication, which was 12 % in the MTA (MTA, 1999). We have run numerous longitudinal 
treatment studies including ones that similarly assigned subjects to specified treatment arms for a year’s 
duration. In a current medication study set in South Florida (MH083693), we have experienced only a 5% 
attrition rate after one year. After adjustment for a 12% drug switch and 5% attrition rate--sample size drops to 
208—power is sufficient to detect a 25% difference in the number of doses switches between group if the 7-
day-a-week group averages 1.9 medication switches per year, a third less than what was observed in the MTA 
(Vitiello et al., 2001). We have multiple safeguards in place to maximize adherence as a threat to internal 
validity but results will also be analyzed by reported medication usage as well as by assigned treatment group.  
 
The secondary outcome will be the time-to-change from the initial dose during the school year. We will 
compare the hazard rates for the two treatment arms with a Cox proportional hazard survival regression model. 
We can also investigate the impact of the individual index of tolerance and other covariates on the hazard rate 
ratio by including these terms in the regression model. In the MTA maintenance trial, 54% of the medication 
only group had their dose increased at least once during the 13-month maintenance phase. Therefore, the 
expected hazard rate for 7-days medication group will be 54% during the school year. A sample size of n=250 
(125 per treatment arm) should provide about 80% power to detect a hazard rate ratio of about 1.69 (54% for 7 
days medication from MTA/32% for weekend drug holiday), two sided test at α = 0.05. The power for the test of 
the impact of individual index of tolerance (Aim 3) on the hazard rate ratio is considerably above 80%. Another 
potential outcome of interest is the time to the second dose change. The analysis will be very similar to that for 
the time to first change, but will have less power since the frequency of events will be lower. The difference of 
average final dose between two treatment arms will be compared by using two sample t-tests. Based on the 
results from Vitiello et al (2001), the expected final dose for weekend drug holiday (31.1+/-11.7 mg/day) will be 
lower than 7-days medication (38.1+/- 14.2 mg/day). A sample size 250 (125 per group) will provide 99% 
power to detect a difference at least 7mg/day using a two-sided two-sample t-test at significance level of 0.05. 
Furthermore, we will also investigate the impact of covariates on the average final dose by using a mixed 
model to take into account the possible dependent ratings from the same rater. 
 
 
Protection of Human Subjects 
 
1) 
Risks to the Subjects 


 
14 
 
a) Human Subjects Involvement and Characteristics 
 
We will recruit 250 physically healthy children, ages 6-12 with ADHD who have no documented adverse 
response to stimulants. All human subjects’ research will occur at the Center for Children and Families (CCF), 
an established multidisciplinary site for clinical trials of pediatric psychopathology led by Dr. Pelham. All 
investigators are faculty at the CCF, and Drs. Swanson, Waxmonsky, and Pelham are all well-experienced in 
conduct of NIH- and industry-sponsored clinical trials with stimulants (more than 50 studies among them). All 
assessments, medication visits and therapy sessions will occur at the CCF, the sole clinical site for this study.  
b) Sources of Research Material 
 
Information gathered during the study will be used for research purposes only and includes: (1) parent, 
clinician and teacher ratings of subject’s ADHD symptoms and impairment (e.g., social, academic) at home 
and at school; (2) analog-classroom records of timed-math problems completed correctly; (3) semi-structured 
interview data; (3) physical health histories of the child; (5) saliva assay samples from subjects; and (6) records 
of medication administration. Only the clinical staff performing the assessments, medication visits and therapy 
sessions will have access to subjects’ identities (approximately 10 staff). All information gathered is treated 
under the FIU Human Subjects Review Board guidelines for confidentiality of subject records. All data will be 
encoded and transmitted only in encoded form. Hard copies of data will be stored in a locked data storage 
room at the CCF. The sheet linking study code numbers to individuals will be stored in a separate locked filing 
cabinet. 
c) Potential Study Risks and Protection against Risks 
 
Risk: The primary risk to participants (children or parents) from the assessment sessions will be the 
time commitments and the stress of completing the necessary ratings and visits. Procedure: No invasive 
medical procedures (e.g., MPH sample collected via saliva sample, not blood test) will be performed during the 
study that would present any physical risk to the child subjects. The CCF has an established process for timely 
collection of these data that minimizes the burden on family and other raters (teachers). All raters will be 
trained using a manualized procedure for collection of data. The same treating clinician will meet with the 
subject and parents each time to minimize subject anxiety and provide continuity of care, similar to treatment at 
the subject’s pediatrician.  
Risk: Randomization to possibly undesirable treatment arm. Procedure: This minimal risk (neither treatment 
arm is undesirable, as both are standard stimulant treatment regiments) will be addressed through the 
informed consent/assent process, where parents and children will agree to be assigned to either group. 
Subjects will still have their dose optimized during summer analog classroom and all parents will be offered 8 
sessions of group parent training during the summer and monthly group booster sessions during the school 
year to address symptoms accruing when medication is not active or not effective. In the revised treatment 
protocol, all subjects will be randomized to either 5 day a week (drug holidays) or 7 day a week dosing.  
Weekend medication will be administered in double blind fashion so participants will not know the difference 
between conditions. Dose increases will be standardized in both arms. Therefore, all subjects will be able to 
have their medication dose adjusted to address worsening symptoms.  Finally, parents and children are free to 
withdraw from the study at any time and are not obligated to participate in a group they are assigned to. 
Withdrawing from this study will not affect any future interactions or their participation in any future clinical 
services or studies at the CCF.   
Risk: Some children may experience symptom exacerbations during assigned weekend drug holidays. 
Procedure: Weekend drug holidays are a common clinical occurrence and have been found to be tolerable in 
research studies (Martins et al., 2004). In fact, a substantial number of ADHD children are treated clinically with 
medication on school days only, depending on physician and parent decision.  Therefore, this risk would not be 
greater than that of routine clinical care. Medication will never be withdrawn on school days unless medically 
necessary. All families will participate in an 8 week course of parent training intervention to give them the basic 
therapeutic tools necessary to manage ADHD symptoms at home. Monthly behavior therapy booster sessions 
with experienced clinicians will also be available to families in both groups for the duration of the study so they 
will have access to professional guidance when they need it. In addition, all families are allowed to participate 
in community-based psychosocial treatments which should further decrease the risk of significant symptom 
exacerbations.  
Risk: Financial costs of medication. Procedure: All subjects will be provided with medication free of cost for the 
duration of the study, providing a significant financial savings to families and assisting in recruitment efforts. 


 
15 
Subjects will not endure any costs from participation in the study other than the cost of transportation to the 
study site.  
Risk: Blinding of weekend medication: This risk will be reviewed in the consent form. Parents will know that it is 
either their optimal dose or placebo. Study physicians will also be blinded.  Unblinded medication will be used 
during weekdays (including any school days). The study pharmacist and data coordinator (who is available on 
weekends) will have access to blinding codes, so weekend medication status can be determined emergently if 
needed.  
Risk: Side effects of stimulant therapy: irritability, appetite loss and insomnia are the most common adverse 
reactions to stimulant drug treatment. Other reactions that can occur in varying frequency include nausea, 
dizziness, stomachaches, headaches, tachycardia, skin rashes, drowsiness, motor movements (particularly of 
the mouth, jaw, and tongue) cognitive blunting, social withdrawal and other adverse emotional responses. 
Procedure: Many of these symptoms are transient and will disappear within a few days. The dosage range 
employed herein (.3-2mg/kg/day of MPH) is within the clinical standards. Because all of the participants in the 
proposed research will undergo structured medication assessments with gradually increasing dosages and 
because side effects often diminish with repeated exposures to stimulants, the likelihood of impairing side 
effects will be minimal. Side effects ratings will be collected for the duration of the study. In the event of side 
effects that need immediate attention, a study physician is on-call at all times. Dosage reduction often 
eliminates stimulant induced side effects and will be allowed during all phases of the study. In more severe 
cases, termination of treatment alleviates the symptoms. Standard procedures are used in case of any medical 
emergency. To ensure the safety of all subjects, Dr. Waxmonsky (a board certified child psychiatrist) or Dr. 
Humphery (child psychiatrist who speaks fluent Spanish) will be available by pager 24 hours a day during all 
phases of the trial. As part of the screening intake, all subjects will undergo a routine medical history by one of 
the study physicians to detect any health conditions that could be negatively affected by stimulants. If any 
abnormalities are detected, the child’s pediatrician will be contacted to determine if stimulants would be 
medically advisable. Laboratory testing will be obtained if clinically indicated. Any child with health problems 
that could be predictably worsened by stimulant exposure will be excluded. As it is not standard practice to 
collect laboratory tests in healthy children taking stimulants, they will not be collected during the study unless 
clinically indicated.  
Risk: Medical or professional intervention may be required in the event of side effects that need immediate 
attention. Procedure: A study physician is on-call at all times. Standard procedures approved by the governing 
IRB are used in case of any medical emergency.  
Risk: There is some clinical evidence that stimulants lower the seizure threshold in children with a prior history 
of seizures or children with abnormal EEGs without seizure activity (Aldenkamp et al., 2006). Safe concomitant 
use of anticonvulsants and MPH has not been established. Procedure: Children with a history of seizure 
episodes requiring treatment (not including febrile seizures), or taking medication to control seizures will not be 
included in the study. 
Risk: There are concerns about serious cardiovascular events in children treated with stimulants (Vetter, et al., 
2008). Procedure: Children with hypertension, significant arrhythmias or other serious cardiovascular problems 
will not be enrolled in the study. A medical exam and physical exam will be performed by one of the study 
physicians prior to prescription of any medication. Based on the current AACAP and the American Academy of 
Pediatrics guidelines for stimulant usage, baseline EKGS will be performed only on subjects identified as 
having cardiac risk factors on the initial history and exam. The AHA recommendations regarding use of 
stimulant medication will be reviewed with all families and they will be offered EKG testing of their child. 
However, in accordance with AACAP’s policy, only those children with identified risk factors will be required to 
undergo EKG testing prior to study entry. Results will be reviewed with the child’s primary medical doctor 
before a decision on study enrollment is made. Risk factors would include pre-existing heart disease, 
symptoms suggesting significant cardiovascular disease, such as elevated blood pressure, or a family history 
of early onset cardiac events. Any child with documented, significant EKG abnormalities will be excluded. 
Blood pressure and pulse will be monitored regularly throughout the study. Resting blood pressure and pulse 
will be monitored at each visit to detect any clinically significant elevations in these parameters.  
Risk: Parents may dislike some of the rating forms or answering some of the questions on the forms. 
Procedure: To address this risk, parents are not obligated to answer any question on the rating forms. They 
may skip any item they choose not to answer. Most parent rating forms are short, each taking less than 5 
minutes to finish and none more than 20 minutes. For parents who wish, ratings will be read to them, and they 
will be permitted to answer orally. This will be offered as a standard option to all parents, so that any with 


 
16 
known or suspected reading difficulties will not feel stigmatized. All forms will be made available in English and 
Spanish so families may complete them in their primary language.  
 
2) Recruitment and Informed Consent 
 
Particiapnts will be drawn from the applicant pool for the STP. The STP serves an ethnically and 
racially diverse population including a large percentage of Hispanic patients. Because of the large Hispanic 
population in South Florida, measures will be taken to make the study accessible to parents and children who 
speak Spanish as their first language. A Spanish speaking physician is named on the grant and the center 
employs numerous research staff fluent in Spanish who can work on the grant. The consent form as well as 
assessment forms will be translated into Spanish.  
 
Splitting the cohort into four 63-member samples, each recruited one year apart, should facilitate timely 
enrollment. We have budgeted a sizable amount for advertising, and the CCF has a marketing director who will 
oversee all recruitment efforts. The CCF is the only academic provider of evidence-based treatment protocols 
for pediatric ADHD in the Greater Miami region and operates a fully-functional outpatient pediatric mental 
health clinic on the FIU campus. This center specializes in the provision of evidence based treatments for 
disruptive behavior disorders. We have several ongoing initiatives with the Miami Dade School District (the 
fourth largest school district in the United States with over 350,000 students) which predominantly serves 
students of minority racial/ethnic status and has a school located on the FIU campus. In our 2 years in Miami, 
we have successfully recruited hundreds of ADHD youth for NIMH, IES and industry funded clinical trials and 
another 370 for summer treatment programs, demonstrating that we in fact can meet the goals for this study. 
For a current RO1(MH083692; PI Waxmonsky) examining the effects of stimulant medication on growth that is 
set here in South Florida, we have enrolled over 180 stimulant naïve children in 18 months for  a medication 
treatment study. The majority of the sample is of Hispanic descent. Hence, we can successfully recruit large 
numbers of local ADHD youth including those of Hispanic ethnicity for medication trials. In this trial, we 
recruitment is divided into 4 annual cohorts so that no more than 63 subjects need to be recruited at any one 
time.  
3) Potential Benefits of the Proposed Research to the Subjects and Others 
 
The foremost benefit to subjects who participate in this project is that they will receive evaluation and 
treatment for their ADHD for one school year, by clinical staff experienced in the management of the disorder. 
Treatment will include regular monitoring of their performance at school and home. The school-year phase of 
the study was designed to mimic routine clinical treatment of ADHD, so both study arms are comprised of 
common clinical medication regimens for pediatric ADHD. The primary difference vs. clinical care is random 
assignment to 5 vs. 7 day a week dosing. Both of these dosing schedules are routinely employed in clinical 
practice so families will not be asked to endure any treatments that would not occur in routine clinical care. Any 
additional risks of study participation parallel those that would occur during routine clinical care (side effects of 
stimulants or the time burdens of behavioral therapy). The primary benefits vs. routine clinical care are 
treatment by expert clinicians in ADHD, frequent assessment and provision of all services at no cost. These 
direct clinical benefits in addition to the knowledge to be gained would seem to significantly outweigh the risks 
of the study.  
4) Importance of the Knowledge to Be Gained 
 
This research will enhance our understanding of the mechanisms of long-term tolerance to stimulant 
medication. It will also evaluate the relative efficacy of drug holidays and dose increases for correcting 
tolerance when it is demonstrated.  
5) Data and Safety Monitoring 
 
All data will be monitored for accuracy as they are collected by senior research staff, who will 
immediately contact raters who do not complete questionnaires thoroughly. Teacher ratings will be obtained 
via secure internet transmission, mail, or phone. Data obtained by phone interview will be recorded on paper 
forms. Medication administration records will be collected along with parent ratings to measure procedural 
integrity. Additional safety and efficacy data will also be collected at each visit. Research assistants will enter 
all of these data points on a rolling basis as the ratings are collected, and check these entries by comparing 
raw data ratings with computer printouts of the data sets, checking for and correcting any discrepancies. The 
data management process will be overseen by Elizabeth Gnagy who has served as our center’s data 
coordinator for 20 years on 6 NIMH-funded clinical medication trials and multiple industry-funded trials. Ms. 
Gnagy will review all data collection procedures with study staff during weekly team meetings.  


 
17 
Study treatments are all derived from evidence based interventions and approved FDA dosing ranges for all 
medications will be employed along with systematic tolerability assessments. All clinician ratings will be 
completed by PhD/MD level clinicians experienced with pediatric ADHD. Medication adverse events will be 
recorded using the Pittsburgh Side Effect Rating Scale (PSERS) during each visit for the duration of the trial, 
and reviewed by Dr. Waxmonsky or Dr. Humphery. The PSERS was the primary side effect scale used in the 
MTA (MTA 1999; Pelham, 1993) and many other studies of stimulant effects. Safety measures to be performed 
at each assessment will include: weight, height, blood pressure and pulse. Additional examination of medical 
and mental health by study physicians will be performed as needed. Any time parents are concerned about 
possible side effects during the trial they may telephone the CCF or directly contact a study physician to speak 
with them about their concerns.  
Any necessary medication adjustments including treatment discontinuation can be made during the 
assessment visits by the study physicians as our on-campus research pharmacy can process medication 
orders within 30 minutes. If a parent reports a tolerability concern between study visits, dose decreases to 
address adverse events may be performed at any time. All calls regarding tolerability concerns will be returned 
that same day as our center has physician on call 24 hours per day. The subject will be contacted (brought 
back to the CCF if necessary) to make any medication changes that may be needed. Any subject discontinuing 
study treatment due to tolerability concerns will be seen by a study physician to assess on treatment needs 
and referred to appropriate clinical programs within our center or in the community for ongoing care.  
Dr. Waxmonsky will review all reports of potential serious adverse events (SAE) within 24 hours. If a serious 
adverse event does occur, the necessary reports will be filed with the governing IRB (Western IRB) by Dr. 
Waxmonsky and his staff within 24hrs. NIH will also be notified of any SAEs in the same timeframe. Regular 
notice of non-serious AEs will be provided on an annual basis to the NIH (yearly progress report), IRB (at each 
renewal) and DSMB (at every semi-annual meeting) unless requested more frequently. Issues regarding 
tolerability of study treatment will also be reviewed at weekly team meetings to ensure all staff are aware of 
current safety procedures and active cases with tolerability concerns.  
 
This protocol is a large scale clinical trial of vulnerable subjects designed to assess loss of treatment 
efficacy over time and now includes some use of blinded medication. Therefore we elected to employ a Data 
Safety and Monitoring Board (DSMB) even though none is required, in order to ensure that study treatments 
(drug holidays) are not adversely impacting efficacy. The Data Safety Monitoring Board will consist of senior 
investigators in the etiology and pharmacological treatment of ADHD experienced in the conduct and analysis 
of large scale treatment studies. Dr. Wigal is Deputy Director of the Child Treatment Center at UC Irvine and 
has conducted numerous analog classrooms studies focusing on the efficacy of the stimulant medications. Dr. 
Arnold has published extensively on the tolerability and efficacy of ADHD medication over the past 40 years 
and currently supervises ADHD clinical services at Ohio State University. Dr. Wigal served as one of the MTA 
site investigators and Dr. Arnold was on the DSMB for the study. Both supervise large clinical treatment 
programs at their prospective sites. Dr. Nigg is a nationally researcher whose works focuses on the underlying 
mechanisms of ADHD as well as its associated neuropsychological impairments. The DSMB will meet via 
phone conference every 6 months to review findings and to determine if any adjustments need to be made to 
the provided treatments or other study methodology. At least one study PI will attend every meeting. Two 
weeks prior to meeting, the members will be provided with collected group level data on treatment efficacy, 
adherence and safety including detailed reports of each SAE that has occurred. If concerns arise about the 
results of a particular treatment group, then the DSMB may request that the study statistician (Dr. Williams) 
perform an interim statistical analysis. The DSMB will have the authority to modify study procedures or 
suspend enrollment if deemed necessary. The first meeting will occur prior to enrollment of any study subjects 
to ensure that all members deem study treatments safe and acceptable. Similar DSMB procedures are 
employed for another larger scale single site treatment study at our center FIU (MH086392).