Clinical trial NCT02376257
Conditions: Major Depressive Disorder
Keywords: Cognitive behavior therapy (CBT) d-cycloserine (DCS) Modafinil
Sponsor: Boston University Charles River Campus
Start date: 2014-09-16; Completion date: 2017-05-01
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Despite advances in both pharmacotherapy and psychotherapy for major depression, non-response and partial-response remain relatively common outcomes, motivating the search for new treatments. This study is concerned with the development of one such novel treatment, the augmentation of exposure-based cognitive-behavior therapy (CBT) with d-cycloserine (DCS).

Detailed description:
Investigators will study the efficacy of DCS for augmenting therapeutic learning relevant for the treatment of depression (i.e., outside the extinction learning where DCS has been shown to have success). Specifically, the study investigates the role of DCS in enhancing declarative memory in depressed individuals, as evaluated by standardized tests and the retention of cognitive therapy session material. Investigators will also study an active comparison agent, modafinil, which appears to offer cognitive enhancing effects among both sleep-deprived and non-sleep-deprived individuals, but also appears to have drug-state (e.g., mood and side) effects that are not characteristic of DCS augmentation. Therefore, drug-context effects may affect memory retention over time. Hence, the study will evaluate memory enhancement effects both during the period of drug action as well as one week later when no drug is taken. Overall, investigators will examine cognitive function and memory performance over 4 study sessions in 96 men and women with major depression, who, in a double-blind fashion, will be randomly assigned to either: (1) 250mg DCS, (2) 100mg modafinil, or (3) placebo administered on Study Weeks 2 and 3. The memory tests include both items unique to a given study week and memory tasks that are repeated over time that allow assessment of memory and retention effects across one-week periods.

Arms: arm 1: Baseline assessment (week 1), two weekly sessions when 250mg DCS is administered, and final week (week 4) when retention is assessed. arm 2: Baseline assessment (week 1), two weekly sessions when 100 mg modafinil is administered, and final week (week 4) when retention is assessed. arm 3: Baseline assessment (week 1), two weekly sessions when placebo is administered, and final week (week 4) when retention is assessed.
Interventions: intervention 1: 250 mg DCS intervention 2: 100 mg Modafinil intervention 3: Placebo
Intervention descriptions: intervention 1: Drug intervention 2: Drug intervention 3: Drug

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
for 
 
Improving Therapeutic Learning in Depression: Proof of Concept 
NCT02376257 
Date of Document: November 15, 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


D. RESEARCH DESIGN AND METHODS 
We propose to study cognitive function and memory performance over 4 study sessions in 77 men and 
women with major depression, who, in a double-blind fashion, will be randomly assigned to either: (1) 250mg 
DCS, (2) 100mg modafinil, or (3) placebo administered on Study Weeks 2 and 3. The design calls for baseline 
assessment (Week 1), followed by two weekly sessions when randomized study drug is administered, and a 
final week (Week 4) when retention is assessed under the conditions of no study drug. The drugs under study 
may have differential effects on immediate recall at the time the drug is taken vs. retention effects one week 
later.  As such, the memory tests include both items unique to a given study week (i.e., the ICAT, digits 
backward, and HVLT), and memory tasks that are repeated over time (i.e., narrative memory tasks and the 
cognitive therapy content). Primary outcomes will be cognitive therapy content and retention of logical memory 
(with exploratory examination of CBT skill use). 
Design Considerations 
Why Investigate Baseline Cognitive Impairment?  Cognitive (including verbal memory) impairments have 
been documented in unipolar depression (e.g., Castaneda et al., 2008; Otto et al., 1994), with poorer 
neuropsychological functioning predicting poorer antidepressant (e.g., Dunkin et al., 2000; Kampf-Sherf et al., 
2004; Withall et al., 2009) as well as CBT response (Dobkin et al., 2012; see also Caudle et al., 2007).  
Because there is a potential for stronger cognitive enhancement effects among individuals with greater 
cognitive dysfunction (e.g., such effects have been reported for modafinil administration in healthy participants; 
Finke et al., 2010), baseline cognitive functioning will be examined as a potential moderator of augmentation 
effects in the present study.  In addition, these baseline measures will serve as covariates, providing potentially 
greater power for detection of drug effects.   
Why Utilize 2 Drug Administration Visits and A Follow-Up Visit? As noted in the “Context...” section 
above, this study examines the effects of study drugs on the day of administration and during subsequent 
weeks.  By keeping the final visit drug-free, we will be able to examine retention of memory when individuals 
are drug-free (across drug-cue contexts).  Use of two isolated administrations of study drug matches the 
original and subsequent applications of DCS for specific phobia (Ressler et al., 2004; Smits et al., in press).   
Why Assess Mood and Fatigue During the Trial and Include SSRI Use? Given evidence that modafinil 
may interact with antidepressants to enhance mood effects (see “Modafinil” section above) we carefully 
considered the inclusion of individuals on antidepressants in the trial.  In clinical practice, patients taking 
antidepressants are frequently referred for CBT; hence, to exclude this cohort would limit the generalizability. 
Including patients on antidepressants raises the possibility of mood interactions with modafinil (previous DCS 
studies have not noted significant differences among those taking and not taking antidepressants with single 
dose DCS administrations; e.g., Otto et al., 2010a; but see Poleszak et al., 2011), but this possible effect is 
targeted in the analysis plan.  We will examine the link between any mood changes occurring during the trial 
(as assessed by the BDI and POMS) and cognitive enhancement effects.  We will also examine whether 
cognitive modafinil effects are specific to (moderated by) the fatigue that can co-occur with depression. 
Why Utilize the Specific Cognitive Tests And CBT Skill Assessments Proposed Below? The frequency and 
quality of CBT skill use is a predictor of response to CBT for depression and protection from relapse (see 
Hundt et al., 2013; Strunk et al., 2007). Given that retention of session material is a logical prerequisite to recall 
and application of this material, our assessment of recall of session material with the CTAS is fully in line with 
the goal of assessing a core mechanism behind CBT – recall of CBT concepts. We also now use the SoCT 
(Jarrett et al., 2011) to provide a broader assessment relevant to CBT skill use (e.g., restructuring negative 
cognitions); such assessment would be most appropriate to a treatment outcome study (which this proof-of-
concept study is not), but nonetheless, spontaneous application of CBT principles from the computerized 
program is of interest as an exploratory outcome.  Also, the standardized cognitive tests administered across 
weeks represent many of those utilized in our previous study of verbal memory enhancement in response to 
50mg DCS (Otto et al., 2009a) as well as the core test used by Onur et al. (2010), as well as select tests 
shown to be sensitive to modafinil use. The test battery is not designed to be a comprehensive assessment, 
but to hone in on the sort of cognitive functions that may affect retention of CBT.  
Randomization and Study Drugs 
Participants will be block randomized (by sex and SSRI use) to one of the 3 drug conditions. Study drugs 
will be provided in identical capsules. Patients will receive one capsule of their randomized drug on Study Visit 
2 and one capsule on Study Visit 3.  At these visits, study capsule administration will be observed and precede 
cognitive testing by 90 minutes. Similar timing has been the standard in our studies of DCS augmentation; and 
is appropriate to the absorption and half-life of modafinil (Darwish et al., 2010). 
Study Participants 


We plan to recruit 77 male and female participants between the ages of 18 and 65, willing and able to 
provide informed consent, attend all study visits, and comply with the protocol. Participants must have a DSM 
diagnosis of major depression as determined by structured diagnostic interview (SCID), must be free of 
psychotropic medications other than SSRIs for at least 2 weeks, and have no current suicidal ideation. 
Additional exclusion criteria include: (1) DSM diagnosis of dementia, neurodegenerative disease, or other 
organic mental disorder; substance use disorder other than nicotine or caffeine in the last 3 months; bulimia or 
anorexia within the last 3 months; lifetime history of psychotic disorder, bipolar disorder , or developmental 
disorder; medical illness including hypertension, cardiac disease, liver disease, pulmonary diseases, central 
nervous system disease, and epilepsy; (2) recent (1 year) suicidal attempts; (3) for women, currently pregnant, 
plans to be pregnant in the next 2 months, or currently breastfeeding; (4) treatment with phenytoin, isoniazid, 
or propranolol or known sensitivity to modafinil or cycloserine; (5) history of head trauma causing loss of 
consciousness, seizure or ongoing cognitive impairment; (6) use of psychotropic medication other than SSRIs; 
(6) CBT in the last 5 years; or (7) insufficient command of the English language (i.e., cannot carry on a 
conversation with an interviewer in the English language or read associated text).  
Recruitment and Feasibility 
Recruitment. Recruitment strategies will be based upon those employed in our previous studies of 
depressed individuals in the Boston University catchment area, including referrals directly from the Center for 
Anxiety and Related Disorders at BU and the BU Medical Center (BUMC).  Our recruitment strategies will 
include area advertisements as well as advertisements/direct referrals from these treatment centers. Across all 
assessments and study procedures, participants will be compensated a total of $200 for complete adherence. 
Feasibility:  Dr. Otto has evidence of adequate recruitment rates of depressed individuals for 
augmentation studies. For example, Dr. Otto’s team recruited 48 non-treatment-seeking depressed adults over 
a 17-month period (Calkins et al., 2013).  Likewise, using strategies similar to those proposed here, in 2.5 
months his team has recruited 12 individuals for participation in a study combining cognitive control training for 
depression with brief behavioral activation treatment. The study team also has the added resource of being 
able to study patients during their waiting period for treatment (often 8 weeks) at the Center for Anxiety and 
Related Disorders, or from patients at BUMC. Hence, given our recent recruitment history, we anticipate no 
difficulties meeting our recruitment goals 
Procedures 
 Visit 1: Screening and Baseline Assessment:  Following phone screening, patients will be scheduled for an 
evaluation session where informed consent will be obtained. The psychiatric evaluation begins with the 
Structured Clinical Interview (SCID) to evaluate the presence of psychiatric inclusion and exclusion criteria. 
Patients will also complete a medical history form and interview with the study physician. If inclusion criteria 
are met, baseline questionnaires and cognitive assessment :administration of the WMS--Logical Memory 
(Story A), Digit Span,  Hopkins Verbal Learning Test, Trails A and B, and the Controlled Oral Word 
Association Test (see below). Participants will then be scheduled for 3 subsequent weekly assessment 
sessions, with randomization in a double-blind fashion using a random number list to receive one of the 4 
study conditions. Randomizations will be blocked by sex and SSRI use and will occur at week 2. 
 Visit 2: Study Drug Administration and Assessment. At this visit, patients will first complete the BDI and FSS 
followed by administration of the randomized study capsule 90 minutes before initiation of cognitive testing 
procedures. During the waiting period, magazines and television videotapes will be provided. Drug adverse 
effects will be queried at the end of this waiting period for symptoms over the last hour as well as emergent 
symptoms occurring after the last study session. For cognitive testing, participants will listen to the WMS 
Logical Memory story B, followed by immediate recall.  Similar procedures will then be followed for the 
Emotional Logical Memory Task. Participants will then complete unique versions (to the study week) of Digit 
Span-Backwards, HVLT, and ICAT. Finally, participants will complete a 45min portion of computerized CBT 
providing an overview of cognitive therapy and experience with cognitive errors. 
 Visit 3: Study Drug Administration and Assessment. Study drug administration and assessment procedures 
match Visit 2, but with the addition of one-week delayed recall of both the WMS Logical Memory story B and 
the Emotional Logical Memory Task.  CTAS and SoCT are specific to the previous week’s content, and a 
novel 45min portion of computerized CBT (cognitive schema work) is presented. 
 Visit 4: Final Assessment. No study drug is administered. Participants will first complete the BDI and FSS 
followed by one-week delayed recall of the WMS Logical Memory story B, followed by one week delayed 
recall of the Emotional Logical Memory Task. Then, in turn, each story will be retold, and followed by an 
immediate recall session. Participants will then complete the Cognitive Therapy Awareness Scale (for the 
previous weeks CBT content) and SoCT followed by a unique Digit Span-Backwards, HVLT, and ICAT.  


Core Cognitive Assessments – Delayed Recall 
 Cognitive Therapy Awareness Scale (CTAS; Wright et al., 2002). A modified CTAS will be used to assess 
delayed memory for cognitive therapy content from the computerized CBT.  The CTAS will be modified to 
enhance specific content from the computerized CBT and to delete extraneous content. We have 
successfully used the CTA in previous study of computerized CBT (Wright et al., 2005).  
 Skills of Cognitive Therapy (SoCT; Jarrett et al., 2011) at the same assessment points as the CTAS, to 
provide a broader assessment relevant to CBT skill use (e.g., restructuring negative cognitions).   
 WMS-Logical Memory Test. For the assessment of therapy-relevant learning of verbal material, the Wechsler 
Memory Scale––Revised Logical Memory paragraphs will be used as per Otto et al. (2009a). This test 
assesses memory for a brief story passage; two stories are available (forms A and B of the test). For 
baseline assessment, Form A of the story will be used for immediate and 30 min delayed recall. Form B will 
be subsequently administered, with assessment of 1-week delayed recall at Weeks 3 & 4).  
 Emotional Logical Memory Test. For the assessment of “therapy-relevant” learning of emotional verbal 
material the Wechsler Memory Scale––Revised Logical Memory paragraphs) will be used. This test 
assesses memory for a brief emotional story passage; the study team has constructed a scoring method 
similar to that used by the WMS Logical Memory Test.  
Covariates and Weekly Immediate Memory Assessment Tasks 
 
Digit Span Test.  The Digit Span test is the most commonly used measure of immediate/working verbal 
recall.  Scores for Digits Forward and Digits Backward will be used as a baseline covariate and digits 
backwards will be used as a unique weekly memory task. 
 
Hopkins Verbal Learning Test (HVLT).  The HVLT is a test of verbal memory.  Participants receive three 
consecutive trials of the presentation of a list of 12 nouns, each followed by a free-recall test. Each 
participant will receive a different list for each subsequent weekly session. 
 
Item-Category Association Task. This task identified differences between 250mg DCS and placebo in the 
study by Onur et al., For the task participants will make computer key press responses to judge the 
category membership (A or B) of three-digit numbers presented repeatedly on screen. Visual feedback is 
provided for correct and incorrect categorizations, allowing participants to improve across trials. 
 
Controlled Oral Word Association Test (COWAT).  The COWAT is one of the most commonly used 
measures of verbal fluency. The task employs a word-list generation procedure during which subjects are 
asked to produce a list of words according to some linguistic rule or category in a limited amount of time. 
The total number of correctly generated words will serve as a covariate.  
 
Trail Making Test (TMT) (Trails A and B).  This task consists of Part A and Part B of the paper/pencil trail-
making test of the Halstead–Reitan Neuropsychological Test Battery. It is a measure of psychomotor 
speed and mental flexibility. Trails B will be used as a covariate indexing executive functioning.  
Adverse Events. The assessment of adverse events will occur at Weeks 2 and 3, and retrospectively at 4. 
Mood and Fatigue. Depressed mood will be assessed with the BDI-II (Beck et al., 1996), other moods with the 
POMS (McNair et al., 1971), and fatigue with the Fatigue Survey Schedule (Krupp et al., 1989). 
Quality Control Procedures for Missing Data.  As formalized in Wisniewski et al. (2006), we will follow our 
own recommendations in 7 content areas--documentation, training, monitoring reports, participant contact, 
data entry & management, pilot data, and communication—for reducing missing trial data.  
80 power to detect a medium effect size in all Aims. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
for 
 
Improving Therapeutic Learning in Depression: Proof of Concept 
NCT02376257 
Date of Document: November 15, 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Otto et al. DCS, Modafinil, PBO: Data Analysis   
Analyses for outliers, non-normal distributions, nonlinear relations, and influence statistics 
will be conducted; data transformations will be considered where appropriate. We will perform 
repeated-measures ANOVAs using mixed-effects regression models (MRMs) in SPSS 20.0 to 
analyze the data. The MRM approach to repeated measures ANCOVA allows inclusion of all 
participants regardless of missing data (which improves power and generalizability), can model 
the covariance matrix of the repeated measures more flexibly than ANCOVA, and is the 
recommended method for longitudinal data analysis (Hamer & Simpson, 2009). The ANCOVA 
will consist of 3 levels of the between-subjects IV (Treatment Condition) and 2 (or 3) levels of 
the within-subjects IV (Time).  For delayed recall memory, Time will represent weeks 3 and 4, 
when recall for information presented at the previous session will be assessed. Three separate 
analyses will be performed, one for each of the 3 measures of delayed recall memory; retention 
of 1) cognitive therapy principles,  2) emotional narrative, and 3) WMS Story B (exploratory 
analyses will also examine cognitive therapy skill use, following this analytic approach). For 
immediate memory, Time will represent weeks 2 & 3, the time points of primary interest for the 
immediate memory tests (digit span, HVLT, ICAT). Scores on the baseline memory 
assessments (week 1) and baseline antidepressant use will be included as covariates in all 
analyses. Since the relation between the covariates and outcome may be different among 
treatment conditions (e.g., the relation between baseline memory and drug influenced memory 
may be lower for 250 DCS and 100 modafinil compared to placebo), interaction terms will allow 
these relations to vary across treatment conditions. Similarly, because the relation between the 
covariates and the DVs may be lower at weeks 2 and 3 (with drug ingestion) compared to week 
4 (no drug ingestion), interaction terms will also allow these relations to vary across Time. Non-
significant interaction terms will be dropped.  
Aim 1. A significant main effect for Treatment Condition for “delayed memory” would 
indicate differences between conditions in delayed memory. In particular, we expect that 
pairwise comparisons among the 3 treatment conditions (using the Sidak correction for multiple 
comparisons [this correction is available in SPSS’s mixed effects routine]) will show that 250 
DCS and 100 modafinil significantly enhance delayed memory compared to placebo.  
Aim 2: A significant interaction between Treatment Condition and Time will indicate that 
differences between delayed recall in the “drug context” (week 3) vs. “no-drug context” (week 4) 
are different for different treatment conditions. Dummy variable coding for treatment condition, 
comparing modafinil to each of the 2 other treatment conditions, is expected to show 
significantly greater reduction of recall memory between weeks 3 and 4 for those taking 
modafinil compared to other conditions due to the change in drug context in week 4.  
Aim 3: We hypothesize a Treatment Condition main effect for immediate memory, such 
that pairwise comparisons among the 3 conditions (using the Sidak correction for multiple 
comparisons) will show that 250 DCS and 100 modafinil will significantly enhance immediate 
memory compared to placebo.  
Exploratory Analyses:  We will examine whether baseline antidepressant use, mood 
(BDI-II), fatigue (FSS), attentional/executive function (COWAT,TMT-B), HVLT total score, and/or 
digits backward performance moderates active study drug effects relative to the placebo 
condition.  Examination of associations between performance on immediate memory scores and 
delayed recall (including ICAT performance at Weeks 2-4) will also be examined in each study 
drug condition to help clarify the nature of in-session memory augmentation vs. retention effects 
across the weeks of testing. The effect of treatment condition on BDI will also be examined 
using the same analysis as Aim 1 (including pairwise comparisons among the groups). We 
expect BDI to be enhanced in 100 Modafinil, and explore whether it will also be enhanced in 
250 DCS. We will also examine if improved memory mediates the changes in BDI.  
Power Analysis. We used PinT 2.12 (a program to calculate effect sizes in mixed models) to 
calculate the smallest N necessary to detect a medium effect size (d=.5) with .80 power for the 


specific hypothesized comparisons in Aims 1, 2, and 3. We conservatively assumed that 15 
covariates (including interaction terms between covariates and both Treatment Condition and 
Time) will be included as additional predictors in each analysis (the power is greater if no 
interaction terms are necessary). We also assumed 10% attrition by week 4, although the mixed 
effects models include all participants regardless of missing data. Since there are multiple 
comparison tests, we used the conservative Bonferroni correction and set the p level at 
.05/3=.0167. Aim 1: A total sample size of 77 is necessary to detect a medium effect with .80 
power. Aim 2: A sample size of 59 is necessary to detect a medium effect size for the 
interaction between time and individual treatment contrasts.  Aim 3: Since the analysis in Aim 3 
is identical to that in Aim1, 77 participants are required for Aim 3. Thus, a total sample size of 77 
will give us at least .