Conditions: Epilepsy Epilepsy, Temporal Lobe Partial Epilepsy
Keywords: Epilepsy Drug Trial Serotonin Serotonin 1A Receptor Temporal Lobe Epilepsy Partial Epilepsy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: no

Brief summary:
Background:

\- The brain chemical serotonin helps nerve cells communicate. Previous research suggests that serotonin activity may be lower in brain areas where seizures start, and that increasing activity at the serotonin receptor site on nerve cells may help prevent seizures. Researchers are interested in determining whether the experimental medication PRX-00023, which increases the activity of serotonin receptors, can reduce seizure frequency in people whose seizures are not well-controlled on antiseizure medication. PRX-00023 has not previously been studied in people with epilepsy and has not previously been given to people taking antiseizure medication at the same time.

Objectives:

\- To evaluate the effectiveness of PRX-00023 in reducing the frequency of epileptic seizures that start from only one part of the brain.

Eligibility:

\- Individuals between 18 and 65 years of age who have frequent epileptic seizures even after trying at least two different standard anti-seizure medications (either at the same time or one after the other).

Design:

* The study requires 9 outpatient visits to the NIH Clinical Center over a 34-week period. Individuals who choose to participate in additional studies may be an inpatient during some of these visits.
* Participants will be screened with a medical history and physical examination, blood and urine samples, ECG, EEG, neuropsychological studies, imaging studies, including PET and MRI scans
* Participants will have a 6-week observation and evaluation period before starting the study medication. Participants who have at least four seizures during this period will be eligible for the treatment portion of the study.
* All participants will receive either PRX-00023 or a placebo pill twice daily for 12 weeks, and will have regular clinic visits with blood samples and imaging studies.
* After the 12-week period, participants will have a 2- to 3-week washout period without any study medication.
* Participants will then have another study medication period, and will receive the opposite pill (PRX-00023 or placebo) from the one taken in the first treatment phase. Participants will continue to have regular clinic visits with blood samples, ECG, EEG and neuropsychologicalstudies.
* One month after the end of the second study medication phase, participants will have a followup evaluation with a physical examination, blood tests, ECG, EEG, mood and neuropsychological tests.

Outcome measures:

The primary outcome measure for drug efficacy will be:

Mean difference in seizure frequency comparing the active and placebo periods.

Secondary outcome measures for efficacy will be:

Proportion of patients with greater than or equal to 50% lower seizure rate on PRX-00023 than placebo

Hamilton Depression and Anxiety Rating scales

Performance on mood and neuropsychological testing scales

Detailed description:
Introduction:

PRX-00023 is a selective 5HT1A agonist being developed as an oral therapeutic treatment for epilepsy.

Objective:

To initiate a pilot clinical trial assessing the safety, tolerability and efficacy of the 5HT1A receptor agonist PRX-00023 in patients with localization-related epilepsy. PRX-00023 is a 5HT1A receptor agonist that has shown promise in clinical trials of depression. Patients with localization-related epilepsy have reduced 5HT1A receptor binding on 18FCWAY positron emission tomography (PET). Increasing neurotransmitter activity at 5HT1A receptor sites might ameliorate seizures. Moreover, depression is a common co-morbidity in people with epilepsy. Altered 5HT1A receptor binding has been found in depression.

Study Population:

Thirty adults with localization-related epilepsy.

Design:

A randomized, double-blind, placebo-controlled cross-over, phase II clinical trial. Subjects will be screened under protocol 01-N-0139 and will undergo medical and epilepsy history and physical examination, vital signs, ECG, clinical laboratory studies including standard clinical chemistry and hematology studies, urinalysis, pregnancy test for females of childbearing potential, and MRI scan and eo EEG monitoring will be performed if not previously completed successfully, and measurement of plasma AED levels (for those AEDs in which an assay is available at NIH).

The trial will have a baseline phase, which will last up to 6 weeks. Baseline may occur concurrent with screening procedures. The baseline phase will include measurement of seizure frequency (patient will record via seizure calendar). In addition the following will be administered, unless previously completed: Columbia Suicide Severity Rating Scale, neuropsychological and mood evaluations, FCWAY PET (if not already performed), EEG, measurement of plasma AED levels (if assay available), and pregnancy test (for women of child bearing potential), saliva samples will be obtained for genetic testing (if not previously obtained) and blood samples will be obtained during the PET procedure for cortisol and ACTH levels.

Following baseline, patients will begin the treatment phase (consisting of Period 1 and Period 2). Patients will be randomized to PRX-00023 (120mg BID) or matching placebo. After completion of the first treatment period, patients will undergo a washout period after which patients will be crossed over to the alternate treatment period.

Outcome measures:

1. Seizure frequency counts during the 3-month placebo and active treatment phases
2. Neuropsychological and mood indices
3. Safety assessment will include adverse events, vital signs, laboratory signs and physical examination.

Arms:
arm 1: Subjects are administered Placebo x3 months followed by PRX (selective 5HT1A agonist) x3 months arm 2: Subjects are administered PRX (selective 5HT1A agonist) x3 months followed by Placebo x3 months

Interventions: intervention 1: PRX-00023 intervention 2: Placebo
Intervention descriptions: intervention 1: PRX-00023 (Selective 5HT1A agonist) intervention 2: Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
CNS IRB Protocol Template (rev.3.25.10) 
 
 
Title Page 
 
Protocol Title: A Phase II Clinical Trial of PRX-00023 Therapy in localization-
related Epilepsy 
Protocol Number: 11-N-0039 
Date of This Submission/Version: January 12, 2017 / version 10. 
 
Principal Investigator 
William H. 
Theodore MD 
CES/NINDS 
Bldg 10 Room 
7D43 
301-496-1505 
theodorw@ninds.nih.gov 
 
Lead Associate Investigator 
Rosemarie 
Cuento CRNP 
 
CES NINDS  
10-CRC/7-
5644 
301.451.9284 
rosemarie.cuento@nih.gov 
 
Associate Investigators 
Peter Herscovitch MD 
 
Sara Inati MD  
 
Edythe Wiggs PhD  
 
Carlos Zarate MD  
 
 
 
Robert Joshua MD 
 
Shubhi Agrawal MD 
 
 
 
Daniel Goldenholz MD  
 
David Goldman MD  
 
PET CC  
 
EEG 
Laboratory  
OCD NINDS  
OCD NINDS  
 
NIMH  
 
 
CES NINDS  
 
EEG 
Laboratory 
OCD NINDS  
 
CES NINDS  
 
NIAAA/DICBR/
LN/SHN 
10/1C-455 
 
10-CRC/7-
5680 
 
 
10-CRC/7-
3445 
 
 
10-CRC/7-
5644 
10-CRC/7-
5680 
 
 
 
 
10-CRC/7-
5644 
5625FL/3S-32 
301-451-4248 
 
301-496-5121 
 
 
 
301.451.0861 
 
 
 
301.451.9282 
 
301-496-5121 
 
 
 
301.451.9282 
 
301.443.0059 
herscovitch@n
ih.gov 
 
inatis@nih.gov  
 
 
zaratec@mail.
nih.gov 
 
joshuar@mail.
nih.gov 
 
AgrawalS@m
ail.nih.gov 
 
 
goldenhd@ma
il.nih.gov 
 
Dg7q@nih.gov 
 
Research Contact  
Tamika Mason 
CES NINDS 
10-CRC/7-5644 
301-496-1923 
masont@mail.nih.gov 
 
 
Total requested accrual 
30 Patients with localization-related epilepsy              
  
 
Project Uses Ionizing Radiation:   No  
X Yes  
  
 
Medically-indicated only 
  
 
X Research-related only 
  
 
Both 
 
IND/IDE  
 
 
 No   
xYes  
Drug/Device/#   
1) 18FCWAY IND #  59163  Sponsor: NIH Nuclear Medicine Department 
2) PRX-00023 IND # 110522 Sponsor   William H Theodore MD 
 


 
 
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Durable Power of Attorney  
 
x No  
 
 Yes  
 
Multi-institutional Project 
 
x No  
 
 Yes  
 
 
 
 
 
Institution_________________    FWA #_________  
Date of IRB approval_________ (attach IRB documentation) 
 
Data and Safety Monitoring Board  
xNo  
 
Yes  
 
Technology Transfer Agreement   No   
x Yes  
Agreement type and number _CRADA 2010-0071_Expiration Date: June 2020 
 
The protocol is being carried out under a cooperative research and development 
agreement with the pharmaceutical company, Proximagen Limited.  Proximagen 
will provide the study drug to NIH without cost.  Proximagen will receive data from 
the study but will not receive any personally-identifying information on 
participants.  
 
None of the NIH investigators has any financial arrangements with Proximagen or 
receives any payment related to the study. 
 
Confidential Disclosure Agreement     
 No 
 
 Yes 
 
Samples are being stored  
 
 No 
  
x Yes  
 
Flesch-Kincaid reading level of consent form: ____10.3________ 
 
 


 
 
CNS IRB Protocol Template (rev.03-25-10) 
 
 
 
 
 
 
page 3 of 36 
2. Table of Contents 
 
Title Page ...................................................................................................................................... 1 
2. Table of Contents .................................................................................................................. 3 
3. Precis: ........................................................................................................................................ 5 
4. Introduction/ Scientific Rationale .................................................................................. 6 
4.1 The role of 5HT in epilepsy ...........................................................................................................6 
4.11 Preclinical studies .................................................................................................................................. 6 
4.12 Clinical Studies - AED mechanisms ................................................................................................ 6 
4.13 Sudden death in epilepsy ................................................................................................................... 7 
4.2 Depression and Epilepsy ................................................................................................................7 
4.3 Human Imaging data .......................................................................................................................7 
4.31 Genetic markers ..................................................................................................................................... 8 
4.4 PRX-00023 .........................................................................................................................................8 
4.41 Pre-Clinical Experience ....................................................................................................................... 8 
4.42 Clinical Experience......................................................................................................................9 
4.43   Dose Justification .............................................................................................................................. 12 
5. Study Objectives or Hypotheses ................................................................................... 14 
5.1 Primary Hypothesis: .................................................................................................................... 14 
5.2 Secondary Hypotheses ................................................................................................................ 14 
5.3 Safety Hypothesis ......................................................................................................................... 14 
6.  Subjects ................................................................................................................................. 14 
6.1 Description of Study Population ............................................................................................... 14 
6.2 Inclusion criteria ........................................................................................................................... 14 
6.3 Exclusion Criteria.......................................................................................................................... 15 
7 Study Design and Methods .............................................................................................. 15 
7.1 Study Overview ............................................................................................................................. 15 
7.2 Recruitment ................................................................................................................................... 16 
7.3 Screening ........................................................................................................................................ 16 
7.4 Study design ................................................................................................................................... 16 
7.5 Study procedures: ......................................................................................................................... 16 
7.54 Washout Period ................................................................................................................................... 17 
7.55 Period 2 ................................................................................................................................................... 18 
7.56 End of study........................................................................................................................................... 18 
7.57 Tests during the study ...................................................................................................................... 18 
7.58 Description of procedures .............................................................................................................. 19 
7.584 Total blood to be drawn ................................................................................................................ 20 
7.6 Follow-up and termination procedures .................................................................................. 21 
7.62 Information to be shared with subjects or health care providers ................................ 21 
7.7 Research and clinical care procedures .................................................................................... 21 
7.72 Study Drug (see Investigator's Brochure). .............................................................................. 21 
7.73 Source of materials/storage/handling ...................................................................................... 22 
7.73 Radiation ................................................................................................................................................ 22 
7.74 Relationship of this study to other protocols ......................................................................... 22 
7.75 Storage of data and samples .......................................................................................................... 23 
8. Risks and discomforts ...................................................................................................... 23 


 
 
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8.1 PRX-00023 ...................................................................................................................................... 23 
8.4 Venous and arterial blood sampling ........................................................................................ 23 
8.6 Neuropsychological and mood testing .................................................................................... 24 
8.7 Genetic Testing: ............................................................................................................................. 24 
9. Subject Monitoring ............................................................................................................ 24 
9.1 Parameters to be monitored ...................................................................................................... 24 
9.2 Toxicity tables/ criteria to be used .......................................................................................... 24 
9.3 Criteria for Breaking the Blind and Premature Termination or withdrawal ................. 25 
10. Outcome Measures ......................................................................................................... 25 
11. Statistical Analysis .......................................................................................................... 25 
11.1 Analysis of Primary Endpoint ................................................................................................. 25 
11.2 Analysis of Secondary Endpoints ........................................................................................... 25 
11.21 Neuropsychological testing and mood scores ..................................................................... 25 
11.22 5HT1A Receptor Binding .............................................................................................................. 26 
11.23 Polymorphism analysis ................................................................................................................. 26 
11.3 Safety Analysis ............................................................................................................................ 26 
11.4 Sample size and power calculation ........................................................................................ 26 
11.41 Independent period analysis ...................................................................................................... 27 
11.42 Analysis populations....................................................................................................................... 27 
11.5 Accrual number request ........................................................................................................... 28 
12. Human Subjects Protection ......................................................................................... 28 
12.1 Rationale for Subject Selection ............................................................................................... 28 
12.2 Justification for exclusion of children .................................................................................... 28 
12.3  Justification for exclusion of those over age 65 ................................................................. 28 
Patients over age 65 years old are excluded form this study because they are more likely 
than younger persons to have co-morbid conditions.  Furthermore, previous clinical 
experience with PRX-00023 has been limited to those ages 18 – 65. .................................... 28 
12.4 Vulnerable subjects .................................................................................................................... 28 
12.5 Justification for use of placebo ................................................................................................ 28 
12.6 Qualifications of investigators................................................................................................. 29 
13. Potential Benefits ............................................................................................................ 29 
14. Summary/ classification of risk: for the study as a whole ................................ 29 
15. Consent documents and process ............................................................................... 29 
15.1  Non-English Speaking Participants ....................................................................................... 29 
16. Data and Safety monitoring ......................................................................................... 30 
16.1 Criteria for stopping the study ................................................................................................ 30 
17. Quality Assurance (QA) ................................................................................................. 31 
18. Reporting of Unanticipated problems, adverse events and protocol 
deviations .................................................................................................................................. 31 
19. Alternative therapies ..................................................................................................... 31 
20.  Privacy ................................................................................................................................ 31 
21. Confidentiality .................................................................................................................. 31 


 
 
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22. Conflict of Interest .......................................................................................................... 32 
23.  Technology Transfer ..................................................................................................... 32 
24.  Research and Travel Compensation ........................................................................ 32 
25. References ......................................................................................................................... 32 
26. Attachments/ Appendices ............................................................................................ 36 
27. Consent forms ................................................................................................................... 36 
 
 
3. Precis: 
 
Introduction: PRX-00023 is a selective 5HT1A agonist being developed as an oral therapeutic 
treatment for epilepsy.  
 
Objective:  To initiate a pilot clinical trial assessing the safety, tolerability and efficacy of the 
5HT1A receptor agonist PRX-00023 in patients with localization-related epilepsy. PRX-00023 is a 
5HT1A receptor agonist that has shown promise in clinical trials of depression (Rickels et al 
2008).  Patients with localization-related epilepsy have reduced 5HT1A receptor binding on 
18FCWAY positron emission tomography (PET). (Toczek et al 2003)  Increasing neurotransmitter 
activity at 5HT1A receptor sites might ameliorate seizures. Moreover, depression is a common 
co-morbidity in people with epilepsy (Theodore et al 2006).  Altered 5HT1A receptor binding has 
been found in depression.   
   
Study Population:  Thirty adults with localization-related epilepsy.   
 
Design:  A randomised, double blind, placebo-controlled cross-over, phase II clinical trial.  
Subjects will be screened under protocol 01-N-0139 and will undergo medical and epilepsy 
history and physical examination, vital signs, ECG,clinical laboratory studies including standard 
clinical chemistry and hematology studies, urinalysis, pregnancy test for females of childbearing 
potential, and MRI scan and video EEG monitoring will be performed if not previously completed 
successfully, and measurement of plasma AED levels (for those AEDs in which an assay is 
available at NIH). 
 
The trial will have a baseline phase, which will last up to 6 weeks.  Baseline may occur concurrent 
with screening procedures. The baseline phase will include measurement of seizure frequency 
(patient will record via seizure calendar).  In addition the following will be administered, unless 
previously completed:  Columbia Suicide Severity Rating Scale, neuropsychological and mood 
evaluations, FCWAY PET (if not already performed), EEG, measurement of plasma AED levels (if 
assay available), and pregnancy test (for women of child bearing potential), saliva samples will be 
obtained for genetic testing (if not previously obtained) and blood samples will be obtained during 
the PET procedure for cortisol and ACTH levels.   
 
Following baseline, patients will begin the treatment phase (consisting of Period 1 and Period 2).  
Patients will be randomized to PRX-00023 (120mg BID) or matching placebo. After completion of 
the first treatment period, patients will undergo a washout period after which patients will be 
crossed over to the alternate treatment period.   
 
Outcome measures: 
   
1. Seizure frequency counts during the 3 month placebo and active treatment phases 
2. Neuropsychological and mood indices 
3. Safety assessment will include adverse events, vitals signs, laboratory signs and physical 
examination.  


 
 
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4. Introduction/ Scientific Rationale 
 
Despite the introduction of a range of new antiepileptic drugs, about 30% of patients, particularly 
with localization-related epilepsy, have uncontrolled seizures.  Uncontrolled epilepsy is a serious 
disorder associated with increased morbidity and mortality, neuropsychological and mood 
disorders, particularly depression and anxiety as well as social and economic disadvantages.   
 
Unfortunately many current anti-epileptic drugs (AEDs) share common mechanisms, possibly 
accounting for the failure to reduce the proportion of patients with intractable epilepsy (French 
and Faught 2009).  Enhancing activity at 5HT1A receptors would offer a novel mechanism of 
action that could potentially treat depression and anxiety as well as seizures. 
 
4.1 The role of 5HT in epilepsy 
 
4.11 Preclinical studies 
 
5-HT1A receptor activation shows antiseizure effects in partial seizure models, including 
picrotoxin in rat hippocampal slices (Lu and Gean 1998), hippocampal kindled seizures in cats 
(Wada et al 1992, 1993), bicuculline-induced (Salgado and Alkadhi 1995), kainic acid-induced 
seizures in rat hippocampal slice preparations (Salgado-Comissariat 1997), and intrahippocampal 
kainic acid induced seizures in freely-moving rats (Gariboldi et al 1996).  5HT1A agonists 
decreased the incidence of tonic seizures and the mortality rate induced by PTZ in male Wistar 
rats (Lopez-Meraz et al 2005).  The highly selective 5-HT1A antagonist WAY100635 blocked the 
protective effect of 5HT infusion on pilocarpine-induced seizures in conscious rats (Clinckers et al 
2004).  
 
5HT inhibited stellate and pyramidal neuron excitability in entorhinal cortex, and led to 
hippocampal inhibition.  The effects of 5HT were mediated via 5HT1A receptors (Deng et al 
2007).    Application of 5HT inhibited low-Mg(2+)-induced seizure activity in slices via 5HT1A and 
5HT2A receptors,  suggesting that 5HT-mediated depression of neuronal excitability and increase 
in GABA release contribute to its anti-epileptic effects in the EC (Deng and Lei 2008).   
 
Genetic epilepsy prone rats showed reduced hippocampal 5HT1A receptor density (Dailey et al 
1992). Moreover, these rats showed depressive-like behaviors (as measured on the forced 
swimming test) that responded to antidepressant drugs and abnormal stress responses 
(Sarkisova et al 2003). Dietary fluoxetine supplementation abolished handling-induced seizure 
susceptibility in El mice.   
   
4.12 Clinical Studies - AED mechanisms 
 
Carbamazepine (Yan et al 1992, Dailey et al 1997) and valproate (Biggs et al 1992) release 5-HT 
as part of their mechanism of action, while lamotrigine inhibits 5-HT re-uptake (Southam et al 
1998).   In the genetically epilepsy-prone rat (GEPR) carbamazepine, produced dose-related 
anticonvulsant effects and increases in extracellular serotonin (Dailey et al 1996). Accentuation of 
serotonin release by treating GEPRs with fluoxetine and 5-hydroxytryptophan increased the 
anticonvulsant effect produced by fluoxetine.  Pretreating animals with PCPA to block 5HT 
synthesis significantly reduced the antiseizure effect of carbamazepine in GEPRs (Yan et al 
1992).  
 
Antidepressant SSRIs may decrease seizures. A meta-analysis of  Food and Drug Administration 
(FDA) Phase II and III clinical trials including 75,873 patients between 1985 and 2004 showed 
that incidence of seizures was significantly lower among patients on antidepressants (except 
buproprion) compared to placebo (standardized incidence ratio 0.48; 95% CI, 0.36-0.61). In 
patients assigned to placebo, seizure incidence was greater than the published incidence of 
unprovoked seizures in community nonpatient samples (Alper et al 2007).   


 
 
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Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) reduced complex partial seizures by 
30% in 17 patients (Favale et al 1995).  An open-label trial of citalopram 20 mg/day was given to 
11 non-depressed patients with poorly controlled epilepsy as add-on treatment for 8–10 months 
(Favale et al 2003). Median seizure frequency dropped by 55.6% in the whole group, with nine 
patients improving by at least 50%.  
 
Very large intentional overdoses of fluoxetine (up to 1400 mg) have been reported to cause 
seizures (Suchard 2008).   In animals, proconvulsant effects are observed at doses of 10-20 
mg/kg, although antiseizure effects have been observed in other studies in the same dose range 
(Hernandez et al 2002; Pericic et al 2005, Freitas et al 2006).   
 
4.13 Sudden death in epilepsy 
 
Serotonergic mechanisms may also be involved in sudden unexplained death in epilepsy 
(SUDEP). Transgenic mice lacking serotonin neurons have severe apnea and high mortality 
during development (Hodges et al 2009). Raphé 5-HT neurons excite key circuit components 
required for generation of respiratory motor output (Ptak et al 2009).  Fluoxetine reduced 
respiratory arrest after audiogenic seizures in DBA/2 mice, a proposed model for human SUDEP 
(Tupal and Faingold 2006).   
 
4.2 Depression and Epilepsy 
 
Depression is one of the most common and severe co-morbidities of patients with epilepsy, 
affecting up to 55% of patients in some studies (Hasler et al 2007), higher than those for other 
chronic health conditions including asthma and diabetes, with a severe impact on quality of life 
(Ettinger et al 2004). Patients with depression in addition to epilepsy report greater seizure 
severity than those with epilepsy alone (Cramer et al 2003).  Patients with temporal lobe epilepsy 
(TLE) appear to be more likely to suffer from depression than those with other seizure types; the 
majority has unipolar depression (Jones et al 2005). Several factors might lead to depression in 
people with TLE, including social and psychological stresses, as well as biological factors such as 
the side of the focus, and the presence of mesial temporal sclerosis (MTS) (Quiske et al., 2000). 
Epidemiological data suggest a potential biological link: Longitudinal studies in epilepsy and 
depression reported a bidirectional temporal association between the two conditions: epilepsy 
was frequently followed by depression, and a history of depression was a considerable risk factor 
for subsequent epilepsy onset (Hesdorfer et al, 2000). Both epilepsy and depression are 
associated with reduced hippocampal volume (Geuze et al 2005). Decreased serotonergic 
function may be a major pathogenic mechanism underlying development of depression (Hasler et 
al 2004). In patients with major depressive disorders (MDD), bilateral limbic 5HT1A receptor 
binding reductions have been reported in regions including raphe and mesiotemporal cortex 
(Drevets et al., 2007).  
 
4.3 Human Imaging data 
 
Reduced 5HT1A receptor binding may be related to increased limbic excitability in patients with 
TLE as well as in animal models.   Since our first PET study using 18FCWAY, a WAY100,635 
analog  (Toczek et al 2003), additional studies using 5HT1A receptor ligands showed reduced 
binding in mesial temporal structures ipsilateral to the epileptic focus, as well as in additional 
regions including  insula and anterior cingulate  (Merlet et al 2004, Savic et al 2004, Giovacchini 
et al 2005).   Moreover, PET results suggest that altered  5HT1A receptor binding may be a 
mediator of depression in people with epilepsy (Hasler et al 2007, Theodore et al 2007, Lothe et 
al 2008).  
 


 
 
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4.31 Genetic markers 
Several allelic variations may affect serotonergic neurotransmission, epileptogenesis, and 
depression in patients with epilepsy.  Serotonin transporter polymorphisms affecting serotonin 
transporter mRNA synthesis lead to changes in SERT expression and 5HT cellular uptake (Lesch 
et al 1996). The short SERT variant is associated with a 50% reduction in transcriptional activity 
and serotonin uptake (Heils et al 1996).  The frequency of SERT alleles in patients with epilepsy 
with or without depression is not known.     
 
Differences in COMT genotype may affect frontal lobe function (Egan et al 2001).  This is 
potentially relevant for our study, as our preliminary data links frontal lobe 5HYT1A receptor 
binding strongly to depression in epilepsy (Hasler). The TPH1 allele in the gene regulating activity 
of the serotonin synthesis enzyme tryptophan hydroxylaze (TPNH) may play a significant role in 
the etiology of psychiatric disorders in at least one population studied (Liu et al 2006). 
 
BDNF alleles may be genetic markers that indicate an enhanced susceptibility to seizures 
(Kanemoto et al 2003).  BDNF is associated with 5HT neuronal sprouting in animal epilepsy 
models (Scharfman 2005).  GABAA and GABAB polymorphisms have been associated with the 
development of both partial and generalized epilepsies (Urak et al 2006, Kinirons et al 2006).   
 
4.4 PRX-00023   
 
4.41 Pre-Clinical Experience 
 
PRX-00023 has a high affinity for serotonin (5-HT1A) receptors (Ki = 5-11nM) and displays 
agonist activity on that receptor with an EC50 of 20nM. PRX-00023 has no significant affinity for 
benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in 
preclinical models.  PRX-00023 has no significant binding to other serotonin receptors, α1 
(Ki=1600nM) or α2 adrenergic receptors.  In vitro testing of PRX-00023 demonstrated no 
significant inhibition of the following P450 enzymes: 1A2, 2C9, 2C19, 2D6, and 3A4).  Non-
sedating doses of PRX-00023 reduce ultrasonic vocalizations in infant rats bred for high anxiety 
(Brunelli et al 2009).  
 
The repeated administration of PRX-00023 for 90 days in rat (Study 801097) defined a No-
Observed-Adverse-Effect-Levels (NOAEL) of 6 mg/kg/day compared to a NOAEL of 10 
mg/kg/day in Beagle dog (5.6 mg/kg; study 801098).   
 
At the dose level of 30 mg/kg/day in rat the major observations were slight anemia and other 
hematological changes, slight decrease in serum albumin and total protein levels in females, 
increased liver and spleen weights and decreased uterus weight; all changes were absent in the 
recovery group.  Increased and persistent diestrus, mucification of the vagina and mammary 
hyperplasia were observed in females with decreased incidence in the recovery group.  None of 
these changes found in rat were observed at the next dose level (50 mg/kg/day) above the 
NOAEL in dog. 
 
Common findings between rat and dog were ptosis, with inactivity and poor coordination in dog 
only. These effects were observed post dosing and were transient in nature.  Additionally pigment 
deposition in macrophages was observed in rat (minimal) and dog (minimal to slight). In rat 
deposition was predominately in the mesenteric lymph node and occasionally in spleen.  In dog 
deposition was observed in liver, mesenteric lymph node, gastrointestinal tract, gall bladder, bone 
marrow and thymus, but not spleen.  The incidence was higher in dog than rat, and in dog more 
noticeable in females.  These findings were partially resolved in recovery animals.  The pigment 
deposition was not correlated with any pathological findings in either species. 
 


 
 
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4.42 Clinical Experience 
 
A total of 442 human subjects have received at least one dose (up to 320 mg/day) of PRX-00023 
in the seven single or repeat-dose clinical studies (Table 1) conducted to date.  Adverse events 
have generally been reported as mild to moderate with no treatment-related serious adverse 
event (SAE) having occurred throughout the development program to date.  Pharmacokinetic 
analyses from these studies provide evidence that the drug is absorbed, with peak concentrations 
within four hours and an elimination half-life estimated to be 9.8 to 13.5 hours. Of the several 
metabolites identified to date (include deacylated and hydroxylated species) none have been 
determined to be active. 
 
Table 1: 
Completed Clinical Studies with PRX-00023 
 
Study 
Number 
Study Design 
Number 
(population) 
Age 
(gender) 
Dosage 
(regimen) 
Primary 
Endpoints 
CP-001 
single-dose 
escalation 
52 
(healthy) 
18-45 
(male) 
10-60 mg 
(single dose) 
safety, PK 
CP-002 
multiple-dose 
escalation 
32 
(healthy) 
18-55 
(male & 
female) 
10-60 mg 
(28 days) 
safety, PK, 
PD 
CP-003 
multiple-dose 
escalation 
20 
(healthy) 
18-45 
(male & 
female) 
30-120 mg qd 
(12 days) 
then 
150 mg qd 
(4 days) 
safety, PK, 
food effect 
CP-006 
open-label, 
Phase II 
21 
(GAD) 
18-65 
(male & 
female) 
40 mg qd 
(4 days) 
then 
80 mg qd 
(10 days) 
then 
120 mg 
(14 days) 
HAM-A 
CP-007 
randomized, 
double-blind, 
placebo-
controlled, 
phase II 
311 
(GAD) 
18-65 
(male & 
female) 
80 mg qd 
(8 weeks) 
HAM-A 
(primary) 
 
MADRS 
(secondary) 
CP-019 
multiple-dose 
escalation 
18 
(healthy) 
18-55  
(male & 
female) 
80 mg qd/bid 
(4 day) 
then 
160 mg qd/bid 
(10 day) 
then 
320 mg qd/bid 
(7 days) 
safety, PK 
CP-020 
randomized, 
double-blind, 
placebo-
controlled, 
phase II 
360 
(MDD) 
18-65 
(male & 
female) 
120 mg bid 
(8 weeks) 
MADRS  
 
Table 2 summarizes the most common (cumulative) AEs across the first four clinical studies of 
PRX-00023 (CP-001, CP-002, CP-003, CP-006), Table tabulates the severities of the drug 


 
 
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related (defined as those which the Investigator considered possibly, probably, or definitely 
related to study drug) AEs of the same trials (Iyer et at, 2007, Mathew et al, 2008) 
 
Table 2: Most Common Adverse Events Observed with PRX-00023 in Clinical Trials CP-001, CP-
002, CP-003 and CP-006. 
 
Adverse Event 
Placebo (n=39) 
≤ 90mg (n=101) 
120-150mg (n=38) 
Headache 
1 (2.6%) 
4 (4%) 
7 (18.4%) 
Nausea 
1 (2.6%) 
6 (5.9%) 
6 (15.7%) 
Dizziness 
1 (2.6%) 
7 (6.9%) 
6 (15.7%) 
Diarrhoea 
0 
4 (4%) 
3 (7.8%) 
Abdominal Pain 
3 (7.7%) 
7 (6.9%) 
1 (2.6%) 
Flatulence 
0  
9 (8.9%) 
2 (5.2%) 
Infection 
4 (10.3%) 
8 (7.9%) 
1 (2.6%) 
 
Table 3: Severity of Adverse Events, Attributed to PRX-00023, in Clinical Trials CP-001, CP-002, 
CP-003 and CP-006. 
 
Severity 
Placebo 
≤ 90mg 
120-150mg 
Mild 
4% 
26.3% 
75.0% 
Moderate 
0 
11.1 
15.0 
Severe 
0 
1.0 
5.0 
 
A Phase II study (CP-007) of PRX-00023 in 311 subjects with general anxiety disorder (GAD) 
was conducted to evaluate the efficacy, safety, and tolerability of PRX-00023 in patients with 
GAD.     
 
Adult (18-65 years old) subjects with ≤ 20% reduction in HAM-A scores from screening to the end 
of the placebo run-in were randomized to double-blind study medication (PRX-00023 40 mg or 
placebo), once daily by mouth.  On study Day 4, the subjects’ dose of study drug was increased 
to 80 mg for the remainder of the 8-week double-blind treatment period.   
 
A total of 448 subjects were screened, of which 311 entered the placebo run-in phase and 277 
were randomized to receive either placebo (N=137) or PRX-00023 (N=140) (Rickels et al, 2008).  
The primary efficacy measure was the mean change in total HAM-A score from baseline (Week 
0) to study end (Week 8).  By Week-8, the PRX00023 group decreased to 14.7 ± 7.73 and the 
placebo group decreased to 16.3 ± 8.21. The difference in change from baseline values was not 
statistically significant (p =0.116).  A significant reduction in MADRS depression score was 
observed, following 8 weeks of treatment. One-hundred and two (72.9%) of subjects receiving 
PRX-00023 and 88 (64.2%) of those receiving placebo reported at least one AE.  All AEs were 
rated as mild to moderate.  One subject experienced an SAE (diverticulitis) that was not attributed 
to the study medication.  Early terminations due to AEs consisted of 2 subjects receiving PRX-
00023 (rash; palpitations) and 4 subjects receiving placebo (rash; infection; injury; dizziness).  
Headache was the most common AE, having been reported in 22 (15.7%) and 15 (10.9%) of the 
subjects receiving PRX-00023 and placebo, respectively (Table 4). 
 
Table 4: Adverse Events Occurring in at Least 5% of Subjects Who Received PRX-00023 in 
Clinical Trial CP-007. 
 
 
Preferred Term 
PRX-00023 (n=140) 
Placebo (n=137) 
Headache 
22 (15.7%) 
15 (10.9%) 


 
 
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Nasopharyngitis 
11 (7.9%) 
10 (7.3%) 
Diarrhoea 
10 (7.1%) 
8 (5.8%) 
Nausea 
12 (8.6%) 
2 (1.5%) 
 
A dose escalating study (CP-019) entitled: “A phase I randomized, placebo-controlled, double-
blind, multiple dose titration study to evaluate the safety, tolerability, and pharmacokinetics of 
PRX-00023 in healthy subjects” has been completed.   
 
Eighteen healthy adult (18-55 years old) volunteers were enrolled to either of two PRX-00023 
dosing regimens (or matching placebo).  Subjects were randomized to double-blind, dose 
escalating regimens of 80-160-320 mg qd PRX-00023 (N=8) (or matching placebo; N=2) or 40-
80-160 mg bid PRX-00023 (N=6) (or matching placebo; N=2).  In each cohort, dose escalation 
occurred on Days 5 and 15.  
 
Six (60%) of the subjects in the qd cohort and 4 (50%) of those in the bid cohort reported at least 
one AE though the cumulative total was 38.  The most prevalent AEs reported during the study 
period are summarized in a blinded manner by cohort (qd vs. bid) in table 5. There were no 
clinically significant alterations in blood pressure, heart rate, or ECG values in any subject in this 
study.   
 
Table 5: Adverse Events (Blinded) Reported in ≥2 Subjects During Clinical Trial CP-019. 
 
Adverse Event  
Total 
(N=18) 
PRX-00023 qd or 
Placebo 
(N=10) 
PRX-00023 bid or 
Placebo 
(N=8) 
headache 
5 (28%) 
4 (40%) 
1 (13%) 
rash/inflammation 
3 (17%) 
2 (20%) 
1 (13%) 
pruritis/itch 
2 (11%) 
0 
2 (25%) 
dizziness/lightheadednes
s 
2 (11%) 
2 (20%) 
0 
pectoral pain/muscular 
pain to chest & back on 
inspiration 
2 (11%) 
1 (10%) 
1 (13%) 
tired 
2 (11%) 
1 (10%) 
1 (13%) 
.  
Table 6 summarizes the results of the PK analysis conducted on the PRX-00023 concentration 
data. 
 
Table 6: Preliminary Pharmacokinetic Profile of PRX-00023 in Clinical Trial CP-019. 
 
Parameters 
PRX-00023 QD Dosing Regimen 
Geometric mean (%CV) 
PRX-00023 BID Dosing Regimen 
Geometric mean (%CV) 
80 mg  
(N=8) 
160 mg 
(N=7) 
320 mg 
(N=7) 
40 mg 
(N=6) 
80 mg 
(N=4) 
160 mg 
(N=4) 
Tmax (h) 
(Median) 
3 
2 
2 
2 
1.5 
2 
Cmax (ng/mL) 
81.8 (44) 
353 (59) 
762 (22) 
42.1 (84) 
140(100) 
332 (92) 
AUC0-last 
(ng*h/mL) 
472 (54) 
1640 (48) 
3674 (29) 
N/C 
N/C 
N/C 
AUC0-8 
(ng*h/mL) 
361 (56) 
1333 (48) 
2878 (26) 
159 (90) 
522 (117) 
1373 (100) 


 
 
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A Phase II study (CP-020) of PRX-00023 in 360 subjects with major depressive disorder (MDD) 
was conducted to evaluate the efficacy, safety, and tolerability of PRX-00023 in patients with 
MDD.     
 
Adult (18-65 years old) subjects who met the DSM-IV diagnostic criteria for MDD (single or 
recurrent episode) and with > 20% reduction in HAM-D17 scores with the psychic anxiety > 2  
were randomized to double-blind study medication (PRX-00023 40 mg or placebo), twice daily by 
mouth.  On study Day 4, the subjects’ dose of study drug was increased to 80 mg twice daily and 
on Day 8 the subjects’ dose of study drug was increased to 120 mg twice daily for the remainder 
of the 8-week double-blind treatment period.   
 
A total of 419 subjects were screened, of whom 359 entered the placebo run-in phase and 360 
were randomized to receive either placebo (N=180) or PRX-00023 (N=180)  
 
The primary efficacy measure was the mean MADRS score change from baseline (Week 0) to 
study end (Week 8).  The active treatment group showed a decline in the MADRS score that was 
0.7 greater than the placebo group but the difference was not statistically significant.  However, in 
study CP007, a significant reduction in MADRS depression score was observed following 8 
weeks of treatment. 
 
Treatment emergent adverse events (TEAEs) were reported by 202 subjects (56.3%), overall. 
The frequency of TEAEs was similar between the 2 treatment groups:  58.3% of PRX-00023 vs, 
54.2% of placebo subjects. 
 
The 2 most frequently reported TEAEs were in the category of Nervous System Disorders. 
Headache was the most frequent TEAE, occurring most frequently in PRX-00023 subjects, 25 
(13.9%) compared to placebo subjects, 14 (7.8%). Dizziness was the next most frequently 
reported TEAE and was also more frequent in PRX-00023 subjects, 16 (8.9%), compared to 4 
(2.2%) of placebo subjects.  
 
The next most frequently reported TEAE was in Gastrointestinal Disorders: nausea, occurring in 
15 (8.3%) of PRX-00023 subjects and 9 (5.0%) of placebo. In Infections and Infestations, upper 
respiratory tract infection was reported with similar frequency in both PRX-00023 and placebo 
subjects; 8 (4.4%) and 6 (3.4%), respectively. In Psychiatric Disorders, insomnia was the fifth 
most frequently reported TEAE and occurred more frequently in PRX-00023 subjects, 10 (5.6%) 
compared to placebo, 3 (1.7%).  
 
Most AEs were rated mild to moderate.  Only a few were considered to be severe in the PRX-
00023 group:  cholecystitis, increase in alanine aminotransferase, fibromyalgia, pain in extremity, 
headache, depression in one subject each, and insomnia in two subjects:  in the placebo group, 
fungal infection, depression, restlessness and urine retention were rated severe in one subject 
each and headache in two subjects. 
 
The overall frequency of SAEs was low, occurring in only 5 (1.4%) of subjects. The frequency of 
SAEs was somewhat higher in the placebo group 4 (2.2%) than in the PRX-00023 group, 1 
(0.6%). There were no SAEs that occurred in more than 1 subject and none of the SAE was 
considered treatment related.  
 
4.43   Dose Justification 
 
The repeated administration of PRX-00023 for 90 days in rat (Study 801097) defined a No 
Observed Adverse Effect Levels (NOAEL) of 6 mg/kg/day (HED =0.97 mg/kg) compared to a 
NOAEL of 10 mg/kg/day in Beagle dog (Study 801098; HED =5.6 mg/kg).  Therefore the rat is 


 
 
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considered the more sensitive species, compared to dog, for evaluating the toxicological profile of 
PRX-00023.   
 
Exposure and Cmax levels of PR-00023 in dog and rat at the respective NOAELs were 
comparable (65 - 71%) to the estimated exposure and Cmax levels for a total daily dose of 240 mg 
(given as a 120 mg dose twice daily) administered to humans (Table 7).  
 
Table 7: Summary of Select Pre-Clinical Pharmacokinetics and Estimated Human Equivalencies.  
 
Species 
Total Daily Dose 
Cmax (ng/mL) 
AUClast (ng*h/mL)a 
Humanb 
360 mg 
332 
NC 
Humanc 
360mg 
762 
3674 
Humand 
240 mg 
191 
1311 
90-Day Rat 
6e mg/kg 
534 
1416 
30 mg/kg 
2029 
17256 
90-Day Dog 
10e mg/kg 
556 
1564 
50 mg/kg 
4088 
15405 
a Last serum concentration measurement was 24 hours postdose (human) and 8 
hours postdose (rat and dog) 
b 160mg BID at Day 21 (CP-019) 
c 360mg QD  at Day 21 (CP-019) 
d Administered as two 120 mg doses in a 24 hour period, values estimated from 
results of the maximum tolerated dose PK study (CP-019) using bid dosing 
regimen 
e NOAEL 
 
At the next dose level of PRX-00023 above the NOAEL in rat (30 mg/kg) and dog (50 mg/kg) Cmax 
levels are 10 fold and 20 fold, respectively, above the estimated human Cmax for a single 120 mg 
dose, given twice daily.   Additionally, the exposures (AUClast) observed in rats and dogs are 13-
fold and 11-fold higher, respectively, than that estimated for a 240 mg daily dose (120 mg bid 
dosing).    
 
In the Phase II clinical study where 180 patients with major depressive disorder were randomized 
to receive PRX-00023 120mg BID, and 180 patients were randomized to the placebo, PRX-
00023 was generally well tolerated.  The overall frequency of TEAEs and those leading to 
discontinuation were similar between treatment groups. Some TEAEs occurred more frequently in 
PRX-00023-treated subjects compared to placebo, particularly those in the CNS system organ 
class and that were study drug related (i.e. dizziness headache). There were no obvious trends in 
mean laboratory values over time in either treatment group. There were some differences 
between treatment groups for certain AEs, laboratory shift frequencies, and QTcB and QTcF 
ranges; however, these were either transitory and/or not of significant clinical importance, and did 
not result in a difference between the 2 groups in withdrawals due to AEs. 
 
This data is supported by the maximum tolerated dose study CP-019.  Oral doses of 80, 160 and 
320mg PRX-00023 administered QD or 40, 80, and 160mg administered BID for up to 21 days 
appeared to be safe and well-tolerated in healthy adult men and women.  Following ascending 
multiple oral PRX-00023 dose titration, absorption of PRX-00023 was fairly rapid (Tmax one to 
four hours) and mean serum concentrations appear to increase with increasing doses of 80 to 
320mg QD or 40 mg BID to 160 mg BID, respectively. 
 


 
 
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Overall, 41% of patients on active drug and 30% on placebo reported an adverse event.  1.4% of 
patients on active drug and 2.9% of patients on placebo stopped the study due to an adverse 
event.   
 
Based on these preclinical and clinical data, oral administration of PRX-00023 120 mg twice daily 
to patients with localization related epilepsy for up to 12 weeks is expected to be safe and well 
tolerated.  
 
5. Study Objectives or Hypotheses 
 
The aim of this study is to evaluate the efficacy, safety, and tolerability of PRX-00023 following 12 
weeks of treatment in patients with localization-related epilepsy.   
 
5.1 Primary Hypothesis: 
 
PRX-00023 treatment will lead to reduced seizure frequency compared with placebo. 
 
5.2 Secondary Hypotheses 
 
1. PRX-00023 will lead to improved anxiety and depression rating scores compared with placebo. 
2. The degree of baseline 5HT1A receptor binding reduction in the epileptic focus will predict drug 
response. 
3. Polymorphisms in SERT, TPNH, COMT, BDNF and GABA genes that have been associated 
with psychiatric disorders and epileptogenesis may be related to drug response.  
 
5.3 Safety Hypothesis 
 
PRX-00023 is safe and well tolerated in adult patients with localization-related epilepsy. 
 
6.  Subjects 
 
6.1 Description of Study Population 
 
The study will accrue up to thirty patients aged 18 to 65 inclusive with localization-related epilepsy 
with the goal of obtaining 20 completers, unless a carry-over effect is detected, in which case 24 
completers would be required (see statistical analysis section 11. 4 and 11.41). 
 
6.2 Inclusion criteria 
 
1. Enrolled in protocol 01-N-0139 
 
2. Age 18 – 65 years 
 
3. Localization-related epilepsy diagnosed by standard clinical criteria that has not responded to 
treatment with up to two standard antiepileptic drugs either sequentially or in combination.    
 
4. Patients must be able to provide informed consent. 
 
5. Patients must be able to remain on their baseline AED drugs and doses for the duration of the 
study. 
 
6. Patients must be able to use seizure calendars to record seizures throughout the trial. 
 
7. Experience 4 seizures within a 6-week period.  
 


 
 
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6.3 Exclusion Criteria 
 
1. Pregnancy or lactation  
2. Women of child-bearing potential and men who are unable or unwilling to take adequate 
contraceptive precautions, including one of the following:  
hormonal contraception (birth control pills, injected hormones or vaginal ring);  intrauterine device; 
barrier methods (condom or diaphragm) combined with spermicide; surgical sterilization 
(hysterectomy, tubal ligation, or vasectomy in a partner). 
 
2. Current treatment for another significant medical disorder, such as diabetes, or heart disease, 
or an untreated disorder, that is discovered during the screening examination and might interfere 
with the study and is determined by the PI to warrant exclusion of the participant. 
 
3. An abnormality on clinical laboratory tests, physical examination, EEG or ECG that might 
increase the risk associated with trial participation or investigational product administration, such 
as hepatic enzyme elevation greater than twice normal, or hematocrit lower than 30.  
 
4. A level 4 or 5 on the Columbia Suicide Severity Rating Scale rating for symptoms during the 
last month  
 
5. Concomitant treatment with more than 2 AEDs. 
 
6. Evidence for a potentially progressive neurologic disorder, such as an astrocytoma  
 
7. Use of sublingual lorazepam for seizure clusters more than once per week.  
 
8. Use of any of the following with less than required interval 
 
Prohibited Medications/Classes 
Required interval Period (Weeks Prior to baseline) 
Any other Investigational drugs 
4 
benzodiazepines 
Chronic or daily use: 4  
Occasional or PRN use: 1 
MAO Inhibitors anti depressant  
4 
Citalopram 
4 
Buspirone  
2 
other psychotropic medicines 
2 
potent CYP3A4 inducers/inhibitors: 
2 
• 
itraconazole 
• 
ketoconazole 
• 
HIV antivirals 
• 
clarithromycin 
• 
phenytoin 
• 
barbiturates 
• 
rifampin 
• 
St. John’s Wort 
propranolol 
2 
 
 
7 Study Design and Methods 
 
7.1 Study Overview 
 
The study is a single center, Phase II randomised, double-blind crossover placebo-controlled trial 
in patients with localization-related epilepsy.  Patients and examining physicians will be blinded to 
the treatment arm in which the patient is enrolled. Patients will use seizure calendars to record 
seizure frequency during baseline, active, and placebo phases.  The study will last approximately 
42-46 weeks (+/- 4 weeks).  There will be up to 8 clinic visits.  Patients may be inpatients for 
some study visits.  


 
 
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7.2 Recruitment  
 
Subjects will be recruited from referrals to the NINDS Clinical Epilepsy Section (CES). Self-
referral is permitted. We may make presentations at meetings of the Epilepsy Foundation and 
other non-profit venues to inform the public of the study.  Patients and families who express 
interest will be given the approved NIH protocol description and appropriate contact information. 
We will advertise on IRB approved patient focused and research focused websites. 
 
7.3 Screening 
 
Patients will be screened in the Clinical Epilepsy Section (CES) outpatient clinic for inclusion in 
the protocol by CES physicians or licensed and credentialed practitioners under protocol 01-N-
0139.  MRI will be done under the screening protocol 01-N-0139.  If inpatient video-EEG 
monitoring is needed to confirm seizure type, it will be performed under 01-N-0139 as well.  That 
screening will include the following procedures which are standard care for intractable epilepsy: 
 
Physical examination, vital signs, ECG   
Clinical laboratory studies including standard clinical chemistry and hematology studies, urinalysis 
Pregnancy test for females of child-bearing potential 
Review of epilepsy and general medical history 
MRI scan if an adequate scan has not been performed before 
Video-EEG monitoring if not performed previously   
Measurement of plasma AED levels, if assay available 
 
7.4 Study design 
 
Following screening and a baseline phase (up to 6 weeks), patients will enter a treatment phase 
of 2 periods (Period 1 and Period 2) with a washout phase between periods 1 and 2.   If patients 
have 4 seizures in less than six weeks during the baseline phase, they do not need to wait the 
entire 6-weeks to begin the treatment phase (Period I) of the study. Each treatment period will 
last approximately 12-16 weeks..  Following Period 1, there will be a wash-out of 4 – 6 weeks 
where no study medication will be taken. During each treatment period, there will be two Clinical 
Center visits.  The first visit will entail clinical assessments and will occur 6-week +/- 2 weeks 
after starting the study drug and the second visit will entail clinical assessments and 
neuropsychological and mood assessment and will occur at the end of each maximum tolerated 
dose (MTD) treatment period.  In addition, a follow-up visit will occur approximately one month 
following the end of the second treatment period that will include a physical examination and 
review of any adverse events..  The total duration of the study is 42-46 weeks (+/- 4 weeks).  
Each clinic visit will last approximately one hour. The neuropsychological and mood evaluation at 
the end of each treatment period will last up to three hours.  
 
7.5 Study procedures: 
 
All specific study procedures are research-related.  The PET scans and study drug administration 
are performed under INDs.  
 
7.51 Baseline: 
 
Baseline phase may occur concurrent with screening procedures and may last up to 6 weeks.  
During baseline, patients will record seizures on a seizure calendar, while on their baseline 
treatment with one or two AEDs. They will be eligible for this study if they have at least four 
seizures during a 6-week baseline phase.  If patients have 4 seizures in less than six weeks, they 
do not need to wait the entire 6-weeks to begin Period 1 of the treatment phase.  No changes in 


 
 
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patients’ baseline AEDs will be allowed during this period, or subsequent study phases.  Patients 
who use sublingual lorazepam for seizure clusters may continue to do so.   
 
During the Baseline phase the following tests (described in section 7.57 and 7.58) will be 
performed (unless previously completed, as noted): 
 
Columbia Suicide Severity Rating Scale 
Neuropsychological testing   
Mood testing 
Measurement of plasma AED levels, if assay available  
Pregnancy test 
EEG 
18F-FCWAY PET to measure 5HT1A receptor binding  (if not already performed) 
Saliva samples to test for polymorphisms in SERT, TPNH, COMT, BDNF and GABA genes that 
have been associated with psychiatric disorders and epileptogenesis (if not previously performed)   
Blood samples for cortisol and ACTH level will be obtained at the time of PET (if performed).  
 
7.52 Randomization to Active drug or Placebo 
 
Subjects will be randomized at the end of baseline to either active drug or placebo using a 1:1 
ratio per the randomization schedule.  The randomization schedule will be generated, secured, 
distributed, and stored by the NIH Pharmacy.   Patients may be outpatients or inpatients during 
titration depending on their geographical location, need for additional education on the titration 
process or if they are participating in concurrent studies with the Clinical Epilepsy Section.  All 
patients will be given an exact written titration schedule to follow.  
 
7.53 Period 1: 
 
During Period 1 there will be regular communication with patients/families by phone, secure 
email, and/or the clinical trial database.  Communication with patients/families will occur 
approximately 6 times during each treatment period, about once every two weeks. 
 
PRX-00023 or matching placebo will be titrated up starting at an oral dose of 40 milligrams (Mg) 
twice daily for five days; the dose will then be increased to 80 milligrams twice daily for five days, 
and then to 120 milligrams twice daily for approximately 70 days.  After which the dose will be 
tapered off as follows: 80 milligrams twice daily for five days, 40 milligrams twice daily for five 
days, followed by discontinuation of study drug. If patients experience side effects during the 
titration up, the next scheduled dose increase will be delayed until they abate.  If this does not 
occur, the dose will be reduced in 40mg per day increments.  Period 1 will last approximately 12-
16 weeks. The above description and table below provides a targeted dosing schedule, however, 
adjustments may be made if, for example, the patient experiences side effects during titration. 
 
 
Titration 
MTD 
Taper 
Day 
Day 0-4 
Day 5-9 
Day 10-79 
Day 80-84 
Day 85-90 
No. of days 
5 days 
5 days 
70 days 
5 days 
5 days 
Dose 
40mg bid 
80mg bid 
120mg bid 
80mg bid 
40 mg bid 
 
Patients will keep seizure calendars. Patients will return to NIH 6 weeks +/- 2 weeks after the 
start of Period 1 and the tests listed in section 7.571 will be performed.  At the end of the 
Maximum Tolerated Dose (MTD) period, patients will again return to NIH for repeat of baseline 
testing (see section 7.572).  Following testing, patients will be tapered off of Period 1 study drug 
and begin washout period.  
7.54 Washout Period 
 


 
 
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Following the completion of Period 1, there will be a washout period for approximately 4 to 6 
weeks.  
 
7.55 Period 2 
 
Following a washout period, patients will be crossed over to the alternative treatment arm, using 
the same titration schedule as for Period 1. Patients may be outpatients or inpatients during 
titration.  Outpatients will be given an exact written titration schedule to follow.  During Period 2, 
there will be regular communication with patients/families by phone, secure email and/or the 
clinical trial database.  Communication with patients/families will occur approximately 6 times 
during treatment Period 2; about once every two weeks.  Patients will keep seizure calendars. 
Patients will return to NIH 6 weeks +/- 2 weeks after the start of Period 2 and the tests listed in 
section 7.571 will be performed.  At the end of the Maximum Tolerated Dose period, patients will 
again return to NIH for repeat of baseline testing (see section 7.572).  Following testing, patients 
will be tapered off of Period 2 study drug.. 
 
The same titration, MTD treatment, and taper schedule as described in Period 1 will be used for 
Period 2.  Period 2 will last approximately 12-16 weeks.. 
 
7.56 End of study 
 
Patients will have a final follow-up visit approximately one month after the last dose of study drug.  
During this visit patients will have a physical examination and review any adverse events, ECG, 
blood and urine testing, and.mood tests. 
 
7.57 Tests during the study 
 
7.571 During the 6 week +/- 2 week visit the following evaluations will be completed: 
 
Physical Exam 
Blood drawing for: CBC, acute care panel, hepatic panel  
Measurement of plasma AED levels, if assay available  
Urine Pregnancy test (for women of child bearing potential) 
Seizure calendar review 
Adverse event and toxicity record review 
Hamilton depression rating scale 
 
7.572 At the end of each MTD treatment Period the following evaluations will be completed:  
 
Physical Exam 
ECG 
EEG 
Blood drawing for: CBC, acute care panel, hepatic panel  
Measurement of plasma AED levels, if assay available  
Urine Pregnancy test  (for women of child bearing potential) 
Neuropsychological tests and mood rating scales (see section 7.581) 
Columbia Suicide Severity Rating Scale 
 


 
 
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7.573 Patient Monitoring 
 
Patients will be monitored carefully by CES for any change in their clinical status, using reports of 
seizure frequency, adverse events and toxicity at regular patient contact about once every 2 
weeks, and clinical exam, laboratory studies, and Hamilton Depression rating scale at clinic visits. 
Criteria to be used to decide whether a report or test result requires intervention include Grade 3 
NCI CTC  toxicity, a laboratory test twice the upper limit of normal, an abnormal finding on EEG 
or ECG not present at baseline, or an increase of 7 on the Hamilton Depression Scale.  
Intervention will be determined by the safety monitor and may include consultation, additional 
studies, or withdrawing the patient from the protocol.   
 
7.58 Description of procedures 
 
7.581 Neuropsychological and Mood Assessments  
 
Attention: 
Brief Test of Attention (Schretlen 1997) 
Cancellation test from the WAIS-IV (Wechsler 2008). 
 
Memory: 
Hopkins Verbal Learning Test, versions 1,3 &4 (Brandt and  Benedict 2001). 
Brief Visuospatial Memory Test-Revised (Benedict 1997) 
 
Executive Functions: 
Controlled Oral Word Association Test: 3 different forms (FAS, CFL, PRT) (Spreen and Strauss 
1998) 
Trail Making Test (Spreen and Strauss 1998) 
Design Fluency (Delis et al 2001). 
 
Mood rating scales: 
Hamilton Depression Rating Scale-24 item  
Hamilton Anxiety Rating Scale  
Beck-2 Depression Self Inventory 
Columbia Suicide Severity Rating Scale 
 
7.582 PET Scan: 
 
A PET scan with 18F-FCWAY and a  transmission scan will be performed once (if patients have 
not had them already) in a single session before initiation of study drug. 
 
For the PET scans, patients will be in a fasting state for three hours prior to the procedure.  
Patients may not use any alcohol or recreational drugs for the two weeks preceding the PET 
scan.  EEG leads may be attached to the scalp to record EEG during the PET scan if warranted 
by the patient’s seizure pattern.  The thermoplastic facemask will be used in the standard manner 
for NIH PET scans.  An IV infusion of 0.9% saline solution will be started to provide IV access for 
radiotracer administration.   
 
Following transmission scans, 10 mCi of [F-18]FCWAY will be administered.  Scanning will 
proceed for 120 minutes. If necessary, scanning can be interrupted to allow the patient to sit up 
and rest, and resumed for the remainder of the predetermined time. 
 


 
 
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During the [F-18]FCWAY study, up to 40 arterial blood samples (approximately 250 cc) will be 
collected and radioactivity concentration in whole blood and plasma will be determined. A 
catheter will be placed in the patient’s radial artery by the NIH Anesthesia Department.   The skin 
at the site of the puncture will be anesthetized with 1% lidocaine.  The catheter will be perfused 
(3ml/hr) with heparin solution (600 units/l) during the procedure.   The amount of heparin infused 
will be much smaller than the amount necessary to produce any systemic anticoagulant effect.  
The arterial input function is necessary for quantitation of 5HT1A receptor volume of distribution.  
In addition, at selected sample times, samples will be used to measure the fraction of the 
radioactivity in plasma that has not been metabolized. The fraction of plasma radioactivity 
unbound to protein will also be determined. 
 
Scans will be performed with the PET/CT or the High Resolution Research Tomograph (HRRT). 
The slice separation is 2.0 mm. The transverse resolution is 4.4 mm in HIREZ and the axial 
resolution is 4.5 mm in HIRES. All scans will be acquired in 3D mode and start with an 8-min 
transmission scan with 2 rotating rod sources for the purpose of attenuation correction. 
  
Blood samples for cortisol and ACTH level will be obtained at the time of PET, through the A line 
or IV line.  
 
IV and arterial catheters will be removed after scanning is completed.  The patient will be asked 
to urinate after the scan and again two hours later.   
 
7.583 Genetic Testing: 
 
Testing for polymorphisms in genes related to serotonin transport, depression, and 
epileptogenesis 
 
If patients have not provided DNA samples previously, we will obtain saliva samples to test for 
polymorphisms in SERT, TPNH, COMT, BDNF and GABA genes that have been associated with 
psychiatric disorders and epileptogenesis.  DNA testing is optional. 
Samples and data may be used for comparison with samples from epilepsy patients and normal 
controls obtained in future studies.   
 
DNA and cell lines will be processed, tested for polymorphisms, and maintained in the Laboratory 
of Dr David Goldman, NIAAA, using the established procedures of his laboratory.  
7.584 Total blood to be drawn 
 
 
Screen 
Baseline 
Treatment Phase 
Period 1 
6 Weeks (+/- 2 
weeks) and 12 -16 
Weeks  
Wash out 
4-6 
weeks 
 
Treatment Phase 
Period 2  
6-weeks (+/- 2 
weeks) and 12-16 
Weeks  
Approx.1 
month post 
study follow 
up 
Acute care panel 
and Hepatic panel 
10 mL 
AED level  
8 – 16 mL 
Acute care panel 
and Hepatic panel 
30 mL 
 
Acute care panel 
and Hepatic panel 
30 mL 
Acute care 
panel and 
Hepatic panel 
8 mL 
CBC 3 mL 
ACTH 2 mL 
Done with 
PET 
CBC 9 mL 
 
CBC 9 mL 
CBC 3 mL 
AED level 
8 – 16 mL 
Cortisol 10 
mL 
Done with 
PET 
AED level 
24 - 48 mL 
 
AED level  
24 – 48 mL 
AED level  
8 – 16 mL 


 
 
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PET study 
250 mL 
 
 
 
 
Max 29 mL 
Max 278 mL 
Max 87 mL 
 
Max 87 mL 
Max 29 mL 
 
7.6 Follow-up and termination procedures 
 
7.61 Transfer / Continuity of care 
 
During the study, AEDs will be managed by NINDS neurology staff.  At the end of the study, 
patients may be considered for inclusion in additional NINDS protocols.  If they do not qualify or 
wish to participate, they will be referred to the care of their referring physicians.  Patients who do 
not have a referring physician or wish to find an alternative will be assisted in locating a 
neurologist skilled in the care of people with epilepsy. 
 
7.62 Information to be shared with subjects or health care providers 
 
All clinical data obtained during screening, as well as any other data relevant to standard epilepsy 
care obtained during the protocol, will be shared with patients and with the participant’s written 
permission, their health care providers.   
 
7.7 Research and clinical care procedures 
 
All procedures performed under this protocol are research-related.  
 
7.71 Medications requiring IND 
 
18F-FCWAY: Sponsor NIH PET Department. Approved 
PRX-00023: Sponsor William H Theodore MD. Approved  
7.72 Study Drug (see Investigator's Brochure).  
 
 
 
Following ascending multiple oral PRX-00023 dose titration, absorption of PRX-00023 was fairly 
rapid (Tmax one to four hours) and mean serum concentrations appear to increase with 


 
 
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increasing doses of 80 to 320mg QD or 40 mg BID to 160 mg BID, respectively. Elimination half-
life is estimated to be 9.8 to 13.5 hours.  Plasma protein binding is approximately 90%.   
 
PRX-00023 is metabolized mainly by CYP 3A4 and to a lesser extent by CYP 2D6.  It may 
interact with inducers such as phenobarbital or phenytoin.  Felbamate, oxcarbazepine, and 
topiramate are weak inductors of the CYP isoenzyme 3A4, and would be less likely to alter the 
metabolism of PRX-00023.   For carbamazepine, potential induction of metabolism may be 
balanced by inhibition of PgP brain efflux transport, for which PRX-00023 is a substrate. PRX-
00023 does not to inhibit or induce any CYP enzymes.  
 
7.73 Source of materials/storage/handling 
 
Trial Product 
Compound 
PRX00023 
Product Name 
PRX-00023  (Naluzotan) 
 
 
Dosage Route 
Oral Capsule 
Strength 
37.2mg (equivalent to 40mg bis salt) 
Manufacturer 
Clinical Center Pharmacy Department Building #10 
Room 1N-257 MSC-1196 10 Center Drive Bethesda, 
MD 20892-1196 
 
 
 
Comparator 
Product 
PRX-00023 Placebo capsule 
Manufacturer 
Clinical Center Pharmacy Department Building #10 
Room 1N-257 MSC-1196 10 Center Drive Bethesda, 
MD 20892-1196 
 
 
Drug Substance (API) has been manufactured by 
Johnson Matthey Pharma Services, 70 Flagship Drive, 
North Andover, MA 01845in accordance with the Clinical 
Trials Directive 2001/20/EC, GMP Directive 2003/94 and 
21 CFR Parts 210 and 211 for Investigational Medicinal 
Products. 
 
 
The NIH Pharmacy will dispense three month's supply of study drug (PRX-002 or placebo) to 
subjects. Patients will be encouraged to bring pill bottles to each visit.  If patients bring pill bottles, 
pill counts will be performed.  Patients will be advised to take a missed dose they remember 
within 4 hours; otherwise, to take the next scheduled dose and record the missed dose on their 
seizure calendar.  Patients will be advised to take their study drug with food.  
 
All unused investigational product will be returned to the NIH Pharmacy for disposal.   
 
7.73 Radiation 
  
All radiation administered under the protocol is for research only. 
 
7.74 Relationship of this study to other protocols  
 


 
 
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Patients will be screened under protocol 01-N-0139. 
 
7.75 Storage of data and samples 
 
Study data will be stored in password-protected NINDS and NIH Clinical Center computer 
systems.  
 
DNA and cell lines will be maintained in the Laboratory of Dr David Goldman, NIAAA, using the 
established data protection procedures of his laboratory.  
 
8. Risks and discomforts 
 
8.1 PRX-00023 
 
PRX-00023 has been studied in approximately 100 healthy human volunteers and in 340 patients 
with generalized anxiety disorder (GAD) and major depression disorder (MDD).  Safety data for 
doses up to 320 mg per day have been reported.   The most common side effects include 
headache, dizziness, nausea, diarrhea, dyspepsia and insomnia.  In clinical trials, 5-10% more 
patients on active drug than on placebo reported at least one side effect (see section 4.42). Drug 
side effects are expected to be transient, and respond to dose reduction if necessary. 
 
Considering PRX-00023 pharmacokinetics, patients not on the AEDs listed in exclusion criteria 
are considered unlikely to show significant drug interactions, although unexpected risks are 
possible.  
 
A possible small increase in 'suicidality' has been associated with SSRIs and AEDs but not direct 
5HT1A agonists.  
 
The potential risk for birth defects in children of parents taking PRX-00023 is unknown. Men and 
Women must use an effective method of contraception during the study and for three months 
afterwards. If a woman becomes pregnant, she will be dropped from the study and the blind will 
be broken.  Appropriate counseling will be provided.  
 
PRX-00023 has not been given to patients with epilepsy. Risk will be minimized by screening for 
exclusion criteria, and careful clinical monitoring, weekly contact, and at each clinic visit.    
 
8.2 PET 
 
PET scans require exposure to radiation.  All tests requiring patient exposure to ionizing radiation 
should be considered to be potentially hazardous. Detailed breakdown of the radiation exposures 
to be expected in subjects enrolled in this protocol are included in the attached radiation safety 
form (NIH 88-23(a) revised).  Although each organ will receive a different dose, the amount of 
radiation exposure is equal to a uniform whole-body exposure of 0.77 rem.  This calculated value 
is known as the “effective dose” and is used to relate the dose received by each organ to a single 
value. The doses to be administered have been approved by the NIH radiation safety committee.  
The total anticipated 'effective dose,' equivalent to whole-body exposure, is less than the RSC 
exposure limit for research subjects of 5.0 REM per year.  Some patients may become 
uncomfortable while lying in the scanner.   
 
8.4 Venous and arterial blood sampling 
 
Venous blood sampling is associated with possible bruising, discomfort, and superficial infection.   


 
 
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Some discomfort is associated with the placement of the arterial needle. Bruising or swelling at 
the site of the arterial catheter occurs in 5 to 20 percent of patients, but is only temporary.  
Fainting is remotely possible.  Permanent damage from these complications is extremely rare.  
Blockage of the artery by the catheter can occur, but is unlikely because the catheter is left in for 
only a short period of time. There have been two delayed complications from wrist arterial 
catheters at NIH. One person developed a small radial artery aneurysm 2 years after arterial 
catheterization. A second developed a blocked artery a few days after arterial catheterization. 
Both required surgical repair. 
 
8.5 EEG and ECG 
 
EEG and ECG may cause skin irritation.  This risk will be minimized by following the standard 
procedures of the NIH EEG lab.  
 
8.6 Neuropsychological and mood testing 
 
Neuropsychological and mood testing have minor risks, including boredom and frustration.  Some 
patients may be disturbed by test results, or by questions about issues such as depression and 
suicide risk.  Counseling will be provided under the supervision of the psychiatrist co-investigator 
should this occur.   
 
8.7 Genetic Testing:  
 
Risks of genetic testing include emotional distress due to learning about increased risk of 
disease, and problems, such as with insurance or employment discrimination.  All data from this 
protocol will be kept confidential.  In addition, the polymorphisms to be tested for are still 
undergoing study and have not definitely been associated with any specific illnesses or shown to 
have any clear medical implications.  
 
9. Subject Monitoring 
 
9.1 Parameters to be monitored 
 
Patient reports of seizure frequency, adverse events and toxicity at regular phone/secure 
email/computer contact.  Clinical exam, laboratory studies, seizure calendars, adverse events 
and toxicity reports and Hamilton Depression rating scale at clinic visits.   
 
9.2 Toxicity tables/ criteria to be used 
 
Toxicity will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(appendix). Dose limiting toxicities will be considered any NCI grade 3 toxicity felt to be probably 
or definitely related to study medication; grade 4 or 5 toxicity judged to be possibly, probably or 
definitely related to study medication by the safety monitor.  
 
In the event of a Grade 3 toxicity felt to be probably or definitely related to study medication by 
the study investigator or safety monitor a one-step dose reduction will be initiated (i.e., from 240 
to160 milligrams per day) until the toxicity resolves to Grade 0 or decreases to Grade 1.  If NCI 
Common Terminology Grade 4 toxicity is felt to be possibly, probably or definitely related to study 
medication by the study investigator, the patient will be withdrawn from treatment.  All dose 


 
 
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changes and/or dose interruptions will be recorded on case report forms. 
 
9.3 Criteria for Breaking the Blind and Premature Termination or withdrawal 
 
Criteria to be used to decide whether a report or test result requires intervention include Grade 3 
NCI CTC toxicity, a laboratory test twice the upper limit of normal, an abnormal finding on EEG or 
ECG not present at baseline, an increase of 7 on the Hamilton Depression Scale.  Intervention 
will be determined by the safety monitor and may include consultation, additional studies, or 
withdrawing the patient from the protocol.   
 
The blind for an individual may need to be broken even for non-serious, expected, or unrelated 
AEs or as requested by local regulatory authorities or where, in the view of the safety monitor, 
knowledge of the identity of the study drug is essential to appropriately manage an adverse 
event. 
 
Patients will be removed from the study if they become pregnant, are unable to continue to 
cooperate, or have an alteration in clinical status, other than that related to their epilepsy, needing 
medical intervention.  Patients may withdraw from the trial at any time at their own request.  The 
Investigators may withdraw a subject for safety or behavioral reasons.  
 
10. Outcome Measures   
 
The primary outcome measures for drug efficacy will be: 
Mean difference in seizure frequency comparing the active and placebo periods.   
 
Secondary outcome measures for efficacy will be: 
Proportion of patients with ≥ 50% lower seizure rate on PRX-00023 than placebo 
Hamilton Depression and Anxiety Rating scales  
Performance on neuropsychological testing scales 
 
Outcome measures for safety will include: 
Columbia Suicide Severity Rating Scale 
Hamilton Depression Rating Scale 
Clinical examination 
CBC and clinical chemistry studies 
ECG 
Adverse event reports 
Seizure Calendars 
 
11. Statistical Analysis 
 
11.1 Analysis of Primary Endpoint 
 
Analysis of variance will be used to test for a treatment order effect.  A carry-over effect is unlikely 
due to the long washout period.  A paired samples Student's T-test will then be used to compare 
seizure frequencies during placebo and active treatment periods (see sample size calculation 
below).    If the carry-over effect is significant, a two group T-test will be applied separately for 
each period. 
11.2 Analysis of Secondary Endpoints 
11.21 Neuropsychological testing and mood scores 
 


 
 
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Analysis of variance with repeated measures will be used to compare neuropsychological and 
mood rating scores for the baseline, placebo, and active drug periods.   
11.22 5HT1A Receptor Binding 
 
FCWAY functional images will be corrected for partial volume effects as previously described, 
and gray-white matter ratios on a pixel by pixel basis.  Regions of interest drawn on MRI scans 
will be co-registered with the PVC-corrected V images.  For each patient, side-side asymmetry 
values will be obtained, in order to detect alterations of binding ipsilateral to the epileptic focus.  
 
A binding potential measurement will be  derived using the cerebellum as a region devoid of 5-
HT1A receptors, and calculated as: 
 
 
BP = [(VROI-VCEREB)/f1)]  
(Eq. 1) 
where VROI and VCEREB are the distribution volumes in the target ROI and in the cerebellum 
respectively, and f1 is [18F]FCWAY plasma free fraction.    
 
Values in regions of interest will be compared between baseline and peak dose scans using a 
paired Student's T-test with correction for repeated measures.  It is anticipated that 12 subjects 
will have a scan at baseline and on active drug, while 12 will have a scan at baseline and on 
placebo, providing a measure of test-rest reliability.   
 
11.23 Polymorphism analysis 
 
The presence or absence of the polymorphisms detected will be compared to 5HT1A receptor 
PET binding and seizure frequency outcome in an exploratory manner.  
 
11.3 Safety Analysis 
 
Adverse events will be recorded at each clinic visit or more frequently as reported by patients.   
Safety data (adverse events, vital signs, laboratory tests and physical examination) will be subject 
to clinical review and summarized by appropriate descriptive statistics. 
 
11.4 Sample size and power calculation 
 
We assume that the mean difference between drug and placebo will be a 15% lower seizure rate, 
(representing a 30% improvement on drug versus 15% improvement on placebo versus 
baseline), and that the standard deviation of difference is 22%.  
 
Based on a paired t-test, the estimated sample size is 19 to obtain 80% power at a significance 
level of 0.05. In order to balance the two arms we will accrue patients until 20 completers have 
been obtained.  We request a total of 30 subjects to take into account a possible 20% dropouts.  
 
Paired t-test of mean difference equal to zero 
1 
2 
3 
4 
 Test significance level,  
 0.050 
 0.050 
 0.050 
 0.050 
  1 or 2 sided test? 
  2 
  2 
  2 
  2 
         First condition mean, 
1 
  30.000 
  30.000 
  30.000 
  30.000 


 
 
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         Second condition mean, 
2 
  15.000 
  15.000 
  15.000 
  15.000 
     Mean difference, 
d= 
1 - 
2 
  15.000 
  15.000 
  15.000 
  15.000 
     Standard deviation of differences, 
d 
  22.000 
  23.000 
  20.000 
  25.000 
 Effect size,  = |
d| / 
d 
   0.682 
   0.652 
   0.750 
   0.600 
 Power ( % ) 
    80 
    80 
    80 
    80 
 n 
19 
21 
16 
24 
 
11.41 Independent period analysis 
 
Based on calculations by the NINDS statistician, 24 completers would be needed in the event of 
detection of a carryover effect.  If we detect a carryover effect, the additional sample size of 24 
patients will have 80% power to detect a 45% decrease in seizure frequency in the PRX 00023 
group, versus 15% in the placebo group, assuming the 25% common standard deviation.   
 
Alpha =        0.050 
                             Power =        0.800 
                             Model = Two Sample t-test 
                       Effect Size =        1.200 
                       Pooled S.D. =        0.250 
  
                          Mean(01) =        0.450 
                          Mean(02) =        0.150 
  
                      GROUP        GROUP 
                         1            2        POWER 
  
                         2            2        0.114 
                         3            3        0.207 
                         4            4        0.299 
                         5            5        0.386 
                         6            6        0.468 
                         7            7        0.541 
                         8            8        0.608 
                         9            9        0.667 
                        10           10        0.718 
                        11           11        0.763 
                        12           12        0.802 
                 Total Sample Size = 24   
 
11.42 Analysis populations 
 
Intent To Treat (ITT) 


 
 
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The Intent-to-Treat (ITT) population includes all randomised subjects with at least one efficacy 
evaluation for at least one double-blind treatment period. The Safety Population consists of all 
subjects who administered at least one application of trial medication. The primary statistical 
analyses of efficacy will be performed on the ITT population and will compare the treatment 
groups on the basis of randomized treatment sequence regardless of the treatment actually 
received. All secondary efficacy analyses will be performed on the ITT population. Safety 
analyses will be performed on the safety population on the basis of treatment actually received 
where possible. 
 
11.5 Accrual number request 
 
In order to accrue 24 subjects, we are requesting a total potential sample size of 30.  This should 
account for patients who do not have enough seizures to qualify during baseline, as well as 
dropouts.   
 
12. Human Subjects Protection 
 
12.1 Rationale for Subject Selection 
 
Subjects will be selected based upon their meeting the study's eligibility criteria. Subjects will be 
admitted to the protocol without regard to ‘race,’ ‘ethnicity,’ gender, ‘sexual orientation,’ or other 
regardless of any non-medical personal characteristics.  
 
12.2 Justification for exclusion of children  
 
PRX-00023 has not yet been given to children.  Children are excluded from this study because 
safety has not been established in children and the efficacy for epilepsy is undetermined. 
 
 
12.3  Justification for exclusion of those over age 65 
 
Patients over age 65 years old are excluded form this study because they are more likely than 
younger persons to have co-morbid conditions.  Furthermore, previous clinical experience with 
PRX-00023 has been limited to those ages 18 – 65. 
 
 
12.4 Vulnerable subjects  
 
Adults unable to give consent will not be included. If capacity is uncertain, 
NIH/CC/Bioethics/HSPU will be consulted.  Pregnant women will be excluded, as PRX-00023 
teratogenicity potential is unknown.  Woman who are able to become pregnant, and men will be 
required to use contraception throughout the protocol participation.   
 
12.5 Justification for use of placebo 
 
Placebo-controlled studies are the only way to obtain reliable data on AED efficacy in a clinical 
trial in any epilepsy syndrome, including localization-related epilepsy.  Seizures are largely self-
reported, and placebo effects occur in all AED trials.  Since this is an add-on study, patients will 
still be on their baseline AEDs during all treatment phases, and will not be exposed to any risk 
greater than their standard therapy while on placebo. 
 


 
 
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12.6 Qualifications of investigators 
 
The Principal Investigator, William H. Theodore MD is board-certified in Internal Medicine, 
Neurology, and Clinical Neurophysiology, and has extensive experience in epilepsy research, 
including serving as principal investigator on several AED trials. He may obtain consent.  
 
Rosemarie Cuento CRNP has many years of experience in the evaluation and treatment of 
patients in the clinical research setting. Ms Cuento will participate in patient care. She may obtain 
consent.  
 
Peter Herscovitch MD will participate in FCWAY PET studies.  He is Chief of the NIH PET 
Department. 
 
Sara Inati MD will participate in patient evaluation and care.  She is Chief of the NIH EEG 
laboratory and has extensive experience in Epilepsy, EEG, and AED Clinical trials.  She may 
obtain consent. 
 
Edythe Wiggs PhD, the NINDS clinical psychologist will perform neuropsychological evaluations. 
 
Carlos Zarate MD is a board-certified psychiatrist and NIMH Senior Investigator with extensive 
experience in the evaluation, treatment, and investigation of depression.  He will provide 
psychiatric consultation and oversee evaluation.  
 
Dr Goldenholz is a fellow who has completed a neurology residency and two years of epilepsy 
fellowship.  He will participate in patient evaluation and care. He may obtain consent. 
 
Dr. Agrawal and Dr. Joshua are clinical fellows who have completed a neurology residency.  They 
are starting their epilepsy fellowship.  They will participate in patient evaluation and care.  They 
may obtain consent. 
 
David Goldman MD is a geneticist who is Chief of the NIAAA/DICBR/LN/SHN.  He will be 
responsible for polymorphism analysis.  
 
13. Potential Benefits 
 
Patients may experience direct benefit while on the active medication due to:  
Reduction of seizure frequency  
Amelioration of depression and anxiety  
Increased information on localization of their epileptic focus due to 18F-FCWAY PET 
 
14. Summary/ classification of risk: for the study as a whole 
 
This protocol is more than minimal risk. 
 
The risks are reasonable in relation to anticipated benefit.  Uncontrolled epilepsy is a serious 
illness with increased morbidity and mortality compared with the general population. Previous 
experience suggests that PRX-00023 has low toxicity.   The radiation exposure from the PET 
scans to be performed is within the limits set by the NIH Radiation Safety Committee.   
 
15. Consent documents and process 
 
The study investigators authorized to obtain consent are indicated in section 12.6.   
15.1  Non-English Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the CC standard 
short written consent form in the appropriate language and a written summary of what the 


 
 
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Investigator will say to the participant will be used as part of an oral consent process.  The IRB 
approved English written consent form will serve as the written summary if the short form process 
is used.  The investigator will obtain an interpreter unless the investigator is fluent in the 
prospective participant’s language. Preferably, the interpreter will be someone who is 
independent of the participant (i.e., not a family member). Interpreters will be found through the 
Department of Social Work. The interpreters will translate the current IRB-approved English 
version of the consent verbatim and facilitate discussion between the participant and investigator.  
 
The written summary will be signed by the investigator obtaining consent and a witness to the 
oral presentation.  The short written consent form will be signed by the participant and a witness 
who observed the presentation of information.  The interpreter may sign the consent document as 
the witness and, in this case, will note “Interpreter” under the signature line. A copy of the signed 
form will be provided to the participant to take home. 
 
The investigator obtaining consent will document the consent process in the participant’s medical 
record, including the name of the interpreter. Further, all instances of use of the short form 
process will be reported to the IRB at the time of annual review. 
 
 
16. Data and Safety monitoring 
 
This protocol will utilize a Safety Monitoring Committee (SMC) and an Independent Medical 
Monitor (IMM) to review AEs and safety reports.  The Safety Monitoring Committee will be 
composed of: 
 
Dr. Mohamad Koubeissi MD. Board Certified in Neurology, Clinical Neurophysiology and 
Epilepsy, GW Medical Faculty Associates 
Dr Gerald Overman NIH CC Pharmacy Pharm.D., BCPP, Clinical Pharmacy Specialist for NIMH 
Ms Jean Radcliffe  RN NIMH  
 
The Safety Monitoring Committee (SMC) will meet in advance of enrolling the first subject to confirm 
the monitoring plan.  The SMC will meet at intervals specified by the needs of the trial, via 
conference call, email, or web-meeting by a password protected phone line/secured email/web 
meeting.  The SMC will meet at least annually while the study is open to enrollment or has 
participants in active follow-up, and more frequently if needed.  Additional meetings may be 
scheduled when necessary for adequate monitoring. Safety data reports will be provided annually, 
including seizure frequency, toxicity reports, neuropsychological and mood testing, laboratory tests, 
EEG, ECG and clinical examination until the end of the trial.  Results will be reported to the Principal 
Investigator, IRB, and NINDS Clinical Director.  Data review will be blinded, and no interim analysis 
is planned.  
 
Dr Eric Wassermann, a Board-Certified neurologist with extensive clinical trial experience, will 
serve as Independent Medical Monitor (IMM). Patients will be monitored carefully by CES 
clinicians for any change in their clinical status, using reports of seizure frequency, adverse 
events and toxicity during patient/family communications, clinical exam, laboratory studies, and 
Hamilton Depression rating scale at clinic visits. The IMM will be notified regarding clinical issues 
that may arise during this trial. Intervention may be determined by the IMM and may include 
consultation, additional studies, or withdrawing the patient from the protocol.   
16.1 Criteria for stopping the study 
 
The study will be suspended if a serious adverse event, as determined by the SMC, occurs in a 
patient found to be on active treatment after breaking the blind occurs.  The study will not be 
restarted until reviewed by the IRB. The study may be stopped if in the judgment of the SMC 


 
 
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there is evidence that Grade 3 toxicity on the NCI CTC, or an increase in seizures of more than 
three times baseline, has occurred in more than 50% of the patients.  
 
17. Quality Assurance (QA) 
a. Quality assurance monitor 
The EMMES Corporation will perform protocol monitoring. 
b. Quality assurance plan 
QA review will performed in accordance with the QA Monitoring/Auditing algorithm included in 
the NINDS Quality Assurance Protocol Audit Plan. The EMMES Corporation will perform 
protocol monitoring annually. 
 
18. Reporting of Unanticipated problems, adverse events and protocol deviations 
 
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
problems, adverse events (AEs), including serious adverse events (SAEs), and deviations in 
accordance with NIH policy, IRB requirements, and federal regulations. Relatedness to the 
research of all serious adverse events will be determined by the PI in consultation with the CD. 
  
Serious unanticipated problems, serious adverse events (including deaths) that are not 
unanticipated problems, and serious protocol deviations will be reported to the IRB and CD as 
soon as possible and in writing not more than 7 days after the PI first learns of the event, unless 
immediate reporting is waived for specific serious adverse events as noted below. Not serious 
unanticipated problems and not serious deviations will be reported to the IRB and CD as soon as 
possible and in writing not more than 14 days after the PI first learns of the event. Written reports 
will be submitted in PTMS. 
 
All adverse events, deviations, and unanticipated problems will be summarized and reported at 
the time of Continuing Review. 
 
The PI will immediately report SAEs to the Sponsor according to the requirements of 21 CFR 
312.64(b) and as agreed upon with the sponsor. The PI will record nonserious AEs and report 
them to the Sponsor at the time of Continuing Review. 
 
The following expected Serious Adverse Events will not be reported to the IRB immediately and 
within 7 days unless they occur at a rate or severity greater than expected:  
Emergency Room visits and hospitalization related to seizure activity including seizure clusters, 
falls and injuries related to falls. 
 
19. Alternative therapies 
 
There is no other way to receive PRX-00023 for epilepsy.  Alternative possible approaches 
include additional current marketed AEDs, participation in other experimental drug trials, brain 
stimulation therapy, and surgical evaluation.  
 
20.  Privacy 
 
All research activities will be conducted in as private a setting as possible. 
 
21. Confidentiality 
 
To ensure confidentiality, research records will be kept in locked files in the principal 
investigator's office, and clinical files will be kept in the NIH Medical Records department. Image 
files that include experimental details will be maintained in file systems accessible only to the 
physicians and other scientific and technical staff working with the principal investigator.  Subjects 
will be identified by code on all case report forms.   
 


 
 
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22. Conflict of Interest 
 
NIH guidelines on conflict of interest have been distributed to all investigators. No NIH 
investigators have reported a conflict-of-interest. 
 
23.  Technology Transfer 
 
The study will be carried out under CRADA 2010-0071_with Proximagen Limited, Hodgkin 
Building, Guy's Campus, King's College London, London UK, SE1 1UL.    
 
Proximagen is providing drug to NIH, and allowing NIH to cross-reference it's previous IND filings 
in filing the IND for the study.  NIH will provide Proximagen the results of the study, with all data 
deindentified, as well as copies of annual and other reports to the FDA.   
 
24.  Research and Travel Compensation  
 
No financial compensation will be provided to patients in the study.  
Reimbursement for travel expenses will be provided, based on NINDS and NIH guidelines. 
 
 
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26. Attachments/ Appendices 
 
Study Calendar 
Eligibility checklist 
Case report / monitoring form 
NCI CTC 
Investigator’s Brochure 
NIH 88-23a 
Jump Text Page 
 
27. Consent forms 
 
Adult subject