Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
Phase: PHASE2
Conditions: Metabolic Disease, Seizures
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Protocol Title: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde 
Dehydrogenase Deficiency 
 
NCT #: 02019667 
 
Date:  02.13.2020 
 
 
Explanation of dates: 
 
The protocol uploaded to the Documents Section of clinicaltrials.gov represents the final 
IRB approved version of the protocol.   
 
The study team submitted the final amended version of the protocol on March 26, 2019, 
which was approved by the IRB on April 3, 2019. 
 
This version of the protocol was submitted to the IRB for final Continuing Review and was  
approved by the IRB on August 8, 2019. 
 
 

 
 
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Protocol Title: Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase 
Deficiency 
Abbreviated Title: SGS-742 in SSADH Deficiency 
Protocol Number: 14-N-0033 
Date of This Submission/Version:  March 26, 2019/Version 17 
 
Principal Investigator 
 
Sara Inati M.D. 
 
OCD NINDS 
 
10/7-5680 
 
301-435-6269 
inatisk@mail.nih.gov 
 
 
 
Adjunct Principal Investigator   
Phillip L. Pearl, M.D 
Boston 
Children’s 
Hospital, 
Boston, MA 
300 Longwood 
Avenue 
9th floor 
Boston, MA 02115 
202- 884-5439 
PPEARL@cnmc.org 
 
Lead Associate Investigator   
William H Theodore 
MD 
CES/NINDS 
10/7D-43 
301-496-1505 
theodorw@ninds.nih.gov 
 
Associate Investigators  
Rosemarie 
Cuento CRNP 
NINDS CTU 
10-CRC  
7-5644 
 rosemarie.cuento@nih.gov 
301-451-9284 
John 
Schreiber MD 
CNMC NEUROLOGY 
Washington DC 
 
John.schreiber@cnmc.org 
202-884-5439 
Eric 
Wassermann 
MD 
BNU DIR NINDS 
10/7D-41 
WassermannE@ninds.nih.gov 
K Michael 
Gibson PhD 
Professor and Chair) 
WSU College of 
Pharmacy 
PBS Building 
room 347 
412 E. Spokane 
Falls Blvd 
Spokane, WA 
99202 
Mike.gibson@wsu.edu 
Edythe Wiggs, 
PhD 
NINDS/DIR/CNP/OCD 
10-CRC  
7-5685 
wiggsse@ninds.nih.gov 
301-451-9285 
Gina Norato, 
ScM 
NINDS CTU 
10/2A23 
gina.norato@nih.gov 
301-496-4358 
 
Research Contact  
Rosemarie 
Cuento CRNP 
NINDS CTU 
10-CRC  
7-5644 
 rosemarie.cuento@nih.gov 
301-451-9284 
 
Total requested accrual:  
 
22 adults and children, 4 and older, with documented SSADH Deficiency       
   
Project Uses Ionizing Radiation:   x No   oYes  
 
IND/IDE 
 
o No   
x Yes (attach FDA documentation) 
Drug/Device/#: SGS-742 
 
 Sponsor: National Institute of Neurological Disorders and Stroke (NINDS) 
 

 
 
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Durable Power of Attorney   
o No   
X Yes  
 
Multi-institutional Project 
 
o No   
x Yes  
 
 
 
 
 
Institution#1: Washington State University 119535-001     FWA # 
00000326 
 
 
Approval Date: 5/29/14 
Data and Safety Monitoring Board  
o No   
x Yes  
 
Technology Transfer Agreement  o  No   
x  Yes  
Agreement type and number: MTA 119535 Expiration Date: None 
 
 
 
Samples are being stored   
 
o No   
x Yes  
 
Flesch-Kincaid reading level of consent form & single patient consent form: 9.0  
Minor Assent 12-17 & Adult Assent: 5.3 
Minor Assent 8-11: 4.2 
 

 
 
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Précis: 
 
Objective:  To perform a clinical trial assessing the safety, tolerability and efficacy 
of the GABA(B) receptor antagonist SGS-742 in patients with SSADH deficiency.  
   
Study Population:  Twenty-two children and adults with SSADH deficiency.   
 
Design:  Double-blind, cross-over, phase II clinical trial.  SGS-742 is a GABA (B) 
receptor antagonist that has shown to be safe and well-tolerated in clinical trials 
in adults with cognitive impairment.  In addition, preliminary data in the SSADH 
knockout mouse model suggest efficacy in this specific syndrome. The primary 
outcome measure will be a change in the Auditory Comprehension subtest of the 
Neuropsychological Assessment Battery Language Module score; the secondary 
outcome measure will be a change in cortical excitation and inhibition measured 
by transcranial magnetic stimulation (TMS).   Additional evaluations will include 
neurological and neuropsychological examinations, magnetic resonance 
spectroscopy and CSF collection to measure GABA levels.  The trial will have a 
baseline phase in which each patient will undergo a neurological examination 
and a neuropsychological evaluation.  During the subsequent treatment phase, 
patients will be randomized to SGS-742, supplied by IRIX Pharmaceuticals, and 
based on weight given a maximum tolerated dose not to exceed 600 mg t.i.d. 
orally, or placebo, each for 6 months.  Patients will then have repeat TMS, 
neurological and neuropsychological evaluations, followed by cross-over to the 
alternate treatment arm, and re-evaluation after 6 months.  
 
Outcome Measures:  The primary outcome measures for drug efficacy will be 
performance on neuropsychological testing and responses to parent 
questionnaire. The secondary outcome measure will be TMS parameters of 
cortical excitation and inhibition.  The outcome measures for safety will include 
clinical examination and neuropsychological tests.  
 
 

 
 
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Table of Contents 
1. Introduction: .......................................................................................................................... 6 
1.1 Background and Significance .................................................................................................. 7 
1.2 Murine SSADH Deficiency ......................................................................................................... 8 
1.2.1 Receptor binding studies in SSADH-/- Mouse brain .............................................................. 9 
1.2.2 SGS 742 Application in Mouse Model ......................................................................................... 9 
1.3 Human SSADH Deficiency ...................................................................................................... 10 
1.3.1 Neuroimaging Findings ................................................................................................................. 10 
1.3.2 Neurophysiologic findings ........................................................................................................... 12 
1.4 Treatment ................................................................................................................................... 13 
2 Study objectives .................................................................................................................. 15 
2.1 Hypotheses: ................................................................................................................................ 15 
3.  Subject Population ........................................................................................................... 16 
3.1 Description of Study Population ......................................................................................... 16 
3.2 Inclusion Criteria (See checklist Appendix 1) ................................................................ 16 
3.3 Exclusion Criteria (See checklist Appendix 1) ............................................................... 16 
4. Study Design and Methods: ............................................................................................ 17 
4.1 Study overview .......................................................................................................................... 17 
4.1.1 Study Phases (see Study Schedule Appendix 2):................................................................. 17 
4.2 Recruitment ................................................................................................................................ 18 
4.3 Screening ..................................................................................................................................... 18 
4.4 Study Procedures ..................................................................................................................... 19 
4.4.1 Structural MRI Scans (OPTIONAL) ........................................................................................... 19 
4.4.2 Magnetic Resonance Spectroscopy (MRS) (OPTIONAL) .................................................. 19 
4.4.3 Transcranial Magnetic Stimulation (TMS) Procedure ...................................................... 19 
4.4.5 Lumbar Puncture Procedure (OPTIONAL): .......................................................................... 21 
4.4.6 EEG ......................................................................................................................................................... 21 
4.4.7 Blood draw .............................................................................................................................. 21 
4.5.1 Randomization .................................................................................................................................. 22 
4.5.2 Study Drug Administration .......................................................................................................... 22 
4.5.3 Drug titration ..................................................................................................................................... 23 
4.54 Drug taper schedule ......................................................................................................................... 24 
4.6  Sedation ...................................................................................................................................... 24 
4.7 End of Participation ................................................................................................................. 25 
5. Storage of data and samples .......................................................................................... 27 
6.  Additional Considerations ............................................................................................ 27 
7. Risks and discomforts ..................................................................................................... 27 
7.1 SGS-742 ........................................................................................................................................ 27 
7.2 MRI and MRS (OPTIONAL) ..................................................................................................... 28 
7.3 TMS ................................................................................................................................................ 29 
7.4 Lumbar Puncture (OPTIONAL) ............................................................................................ 29 
7.5 Neuropsychological testing .................................................................................................. 30 
7.6 Sedation ....................................................................................................................................... 30 
8. Subject Safety monitoring .............................................................................................. 30 
8.1 Criteria for Breaking the Blind and Premature Termination or withdrawal ..... 32 

 
 
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9. Outcome measures ........................................................................................................... 32 
9.1 Primary outcome measure ................................................................................................... 32 
9.2 Secondary outcome measures for efficacy will be: ...................................................... 32 
9.3 Outcome measures for safety will include: ..................................................................... 32 
10. Data Analysis .................................................................................................................... 33 
10.1 Power calculation: ................................................................................................................. 33 
10.2 TMS .............................................................................................................................................. 33 
10.3 MRS ............................................................................................................................................. 33 
10.4 Neuropsychological tests .................................................................................................... 33 
10.5 CSF analysis .............................................................................................................................. 34 
11. Human Subjects Protection ......................................................................................... 34 
11.1 Subject Selection .................................................................................................................... 34 
11.2. Justification for inclusion of children ............................................................................ 34 
11.3 Justification for inclusion of vulnerable subjects ....................................................... 35 
11.4 Justification of sensitive procedures (using placebo) .............................................. 35 
11.5 Safeguards for vulnerable populations ......................................................................... 35 
11.6 Qualifications of investigators .......................................................................................... 35 
12. Anticipated Benefit ........................................................................................................ 36 
13. Classification of risk (for the study as a whole) ................................................... 36 
14. Consent documents and process ............................................................................... 37 
Capacity Assessment: ..................................................................................................................... 38 
15. Data and Safety monitoring ........................................................................................ 39 
15.1 Study Monitor .......................................................................................................................... 39 
15.2 Criteria for stopping the study .......................................................................................... 40 
16. Quality Assurance ........................................................................................................... 40 
17. Reporting of Unanticipated Problems, Adverse Events and Protocol 
Deviations ................................................................................................................................ 41 
18. Alternatives to participation ...................................................................................... 42 
19. Privacy ................................................................................................................................ 42 
20.  Confidentiality ................................................................................................................ 42 
21. Conflict of Interest .......................................................................................................... 43 
21.1 Distribution of NIH Guidelines .......................................................................................... 43 
21.2 Conflict of interest ................................................................................................................. 43 
21.3 Role of a commercial company  ........................................................................................ 43 
22. Technology Transfer ..................................................................................................... 43 
23. Research and Travel Compensation ........................................................................ 43 
24. References. ........................................................................................................................ 43 
25. Attachments/ Appendices ........................................................................................... 53 
26. Consent forms .................................................................................................................. 54 
 

 
 
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1. INTRODUCTION 
 
SSADH deficiency, also called 4-hydroxybutyric aciduria (McKusick 279180), is a 
rare autosomal recessive disorder caused by an enzyme deficiency in the GABA 
degradation pathway (Gibson and Jakobs 2001).  In the absence of SSADH, 
transamination of GABA to succinic semialdehyde is followed by its conversion to 
4-hydroxybutryic acid (gamma-hydroxybutyric acid, or GHB).   About 400 patients 
with SSADH deficiency have been identified and more than 80 clinical cases 
have been reported in the primary literature, which makes this the most prevalent 
PND (Pediatric Neurotransmitter Disorder) (Gibson et al 1998; Gibson 1997; 
Pearl et al 2003a; Pearl and Gibson 2004).  SSADH deficiency is linked to GABA 
and γ-hydroxy butyrate (GHB) accumulation in the CNS.  GHB possesses a 
number of neuropharmacological properties (Maitre 1997, Wong et al. 2003), 
most notably the ability to inhibit presynaptic dopamine release and potentate 
dopamine turnover. 
 
The index case of SSADH was identified in 1981 (Jakobs et al 1981).  The 
investigators’ studies utilizing a detailed clinical questionnaire and standardized 
interview in 60 patients have documented the clinical features of the syndrome, 
including early history of developmental delay (100%), intellectual disability with 
disproportionate deficit in expressive language (100%), hypotonia (82%), ataxia 
(77%), seizures (45%), and multiple neuropsychiatric symptoms including sleep 
disturbances (45%), attention deficit (45%), anxiety (27%), obsessive-compulsive 
disorder (25%), and autistic traits (25%) (Pearl et al 2009).  Some patients have 
occasional, relatively mild seizures; others, recurrent bouts of generalized 
convulsive status epilepticus (Pearl et al 2003b).   An initial diagnosis of autism 
spectrum disorder has occurred in a disproportionate amount in patients 
subsequently identified as having SSADH deficiency (Gibson et al 2003).   
 
CSF metabolite profiles from 13 unrelated patients demonstrated significantly 
elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and 
low glutamine (Gibson et al 2003).  These findings, including a drop in glutamine 
over time, have been documented in the affected animal model (Gupta et al 
2003).  In addition, there was a linear correlation in both HVA and 5-HIAA levels 
with increasing GHB concentration, suggesting enhanced dopamine and 
serotonin turnover (Gibson et al 2003).   
 
Preliminary studies in animal and human subjects have identified three systems 
with significant changes: 1) the GABA neurotransmitter system with marked 
elevations of GABA; 2) glutamine alterations which may affect both GABAergic 
and glutamatergic systems; and 3) GHB elevations which likely disrupt dopamine 
and serotonin homeostasis.   The investigators hypothesize that the elevated 
GABA combined with low glutamine suggest disruption of the glial-neuronal 
glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal 
neurotransmitters.  In addition, the altered dopamine and serotonin metabolism 

 
 
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may be causally linked to the behavior disturbances seen in SSADH deficient 
patients (Gibson et al 2003).   
 
1.1 Background and Significance 
 
SSADH deficiency is a human condition that presents itself through dysfunction 
of the developing nervous system, which is associated with chronic elevation of 
GABA and GHB.  The biochemical hallmark, GHB, is increased in the 
physiological fluids (CSF, plasma and urine) for all patients of SSADH that have 
been studied clinically.  GABA is increased in the CSF of those patients for whom 
a diagnostic lumbar puncture was performed. 
 
GABA is the earliest neurotransmitter expressed during development with 
several critical roles during CNS development.  Elevated GABA levels in early 
development may result in altered neuronal migration, neurogenesis, myelination 
and synaptogenesis.  While detailed neurometabolic and genetic studies of the 
murine model of this disorder are in progress, there have been no prospective 
studies of the human condition.   
 
GHB is employed to induce a model of absence in rodents, to treat cataplexy and 
alcohol/opiate-withdrawal syndromes, as a recreational drug of abuse, and to 
subdue victims for the purpose of sexual assault (Okun et al 2001).  Indeed, GHB 
has emerged as an increasingly common drug of abuse, associated with 
psychosis.  GHB consumption may be associated with addiction and withdrawal 
(Mason and Kerns 2002). 
 
The role of GHB and GABA (both elevated in this disorder) in the 
pathophysiology of SSADH deficiency remains unclear. Developed as an 
anesthetic/sedative (Roth and Giarman 1966), GHB is an endogenous metabolite 
(< 1% of GABA levels) and may be a neurotransmitter (Snead 2000).  The 
primary literature suggests that physiologic levels of GHB (~2 uM in mammalian 
brain) act on the high-affinity GHB receptor (GHBR, a G protein coupled receptor 
that may be a GABAB receptor (GABABR) subtype).  However, at non-physiologic 
concentrations (~ 200-1000 uM, as in SSADH deficiency), GHB acts as a weak 
GABABR agonist (Lingenhoehl et al 1999).  As a GABABR agonist, it is possible 
that increased GHB activity results in increased inhibition of interneurons having 
GABAB receptors, leading subsequently to disinhibition of glutamatergic neurons.  
MR spectroscopy studies have revealed decreased cellular GABA levels in some 
adult and pediatric patients with epilepsy (Petroff et al, 1996, 2001; Novotny et al, 
1999), unipolar depression, alcohol withdrawal, and hepatic encephalopathy 
(Behar et al, 1999; Sanacora et al, 1999; Goddard et al, 2001); the latter 
diseases show impaired GABAergic function. 
 
To our knowledge, SSADH deficiency represents the first pediatric/adult epilepsy 
disorder with increased GABA levels.  However, the pathogenesis of seizures in 

 
 
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SSADH deficiency remains unknown.  The accumulation of GABA and GHB may 
underlie the pathology of seizures and hyperactive behavior in SSADH 
deficiency.  There may be down-regulation of pre- and post-synaptic GABA 
receptor (GABAR) expression by accumulated GHB/GABA.  This may be 
associated with increased glutamatergic excitatory transmission, linked to 
disinhibition and glutamate release, with the subsequent appearance of seizures.  
In addition, a primary pharmacologic action of high-dose GHB is inhibition of 
presynaptic dopamine release (Maitre 1997).  Subsequent increased dopamine 
turnover, as demonstrated by elevated CSF HVA levels in SSADH-deficient 
mice, may help to explain hyperactive behavior in humans.  Evidence from the 
murine SSADH-deficient model (discussed below), and preliminary metabolite 
findings in human patients have supported these hypotheses (Gibson et al 2003; 
Gupta et al 2003). 
 
1.2 Murine SSADH Deficiency 
 
The murine knockout of SSADH was developed using standard gene-targeting 
methodology in the 129Sv/C57Bl background (Hogema et al 2001b).  Deletion of 
exon 7 (encompassing an active-site cysteine) led to the complete absence of 
SSADH enzyme activity in neural and peripheral tissue extracts.  SSADH-/- mice 
are born in the expected autosomal-recessive inheritance pattern with a 
phenotype paralleling the human disease including neurological impairment, 
ataxia, and seizures. At postnatal day 16-22, SSADH-/- mice demonstrate a 
transition from absence to myoclonic to repetitive tonic-clonic seizures resulting 
in 100% mortality (Cortez et al 2004).  The reason for seizure onset remains 
unknown, although it may relate to the switching of GABA from excitatory to 
inhibitory synaptic transmission during development (Ganguly et al 2001). Other 
factors, including the appearance of new receptors and the relative resistance of 
the central nervous system (CNS) of immature animals to convulsant assault, 
may also be involved.  Continuous inbreeding of the SSADH-/- strain has led to 
an attenuated phenotype, with average life expectancy for mutant mice extending 
just beyond 2 months (KM Gibson personal communication). 
 
Absence of SSADH enzyme activity is associated with a significant elevation of 
GHB (35-40 fold) and total GABA (2.5-3.0 fold) in urine, brain and peripheral 
tissue extracts (Hogema et al 2001b; Gibson et al 2002a), similar to metabolite 
findings in human patients.  SSADH-/- mice manifested regional brain 
abnormalities for both GABA and glutamine, with normal glutamate levels. 
 
Glutamine is interconverted to glutamate, which may in turn be metabolized to 
GABA, glutathione (tripeptide of glutamate/cysteine/glycine) or 2-oxoglutarate.  
Glutamine is incorporated into glutamate and GABA in neurons and 
synaptosomes (Sonnewald and McKenna 2002).  The “glutamine-glutamate” 
shuttle provides astrocytic glutamine as precursor for neuronal glutamate and 
GABA. Thus, trafficking of glutamine between glia and neurons is essential for 

 
 
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neuronal neurotransmitter pool maintenance.  Decreased glutamine suggests 
dysregulation of extracellular fluid glutamate, possibly leading to lethal seizure 
activity in the mouse.  Glutamine synthetase is exclusively localized within glia, 
while L-glutaminase (producing glutamate) is neuron specific.  High-dose GHB 
application results in absence seizures (Hu et al 2000).  It is thus proposed that 
GABA and glutamate play a prominent role in generalized seizures in murine and 
human SSADH deficiency. Alterations in these amino acids may underlie the 
pathology in mice with homozygous deficiency for SSADH.  Further animal 
studies of these transmitter pools, with repeated measurements of concentration 
changes over the lifetime of the SSADH deficient mouse, are in progress (Gupta 
et al 2003).  
 
1.2.1 Receptor binding studies in SSADH-/- Mouse brain 
Based upon high GABA and GHB levels in SSADH-/- brain, the Gibson lab 
investigated [3H]NCS-382 (a specific GHB receptor antagonist) binding in brain 
membrane preparations (Mehta 2001).  Homozygous deficient mice displayed 
decreased NCS-382 binding in cerebral cortex (binding decreased by 12% as 
compared with controls) and hippocampus (21% decrease), consistent with 
downregulation of GHB receptors.  Even heterozygous animals exhibited lower 
binding of NCS-382 in hippocampus in comparison to wild type animals.  Mehta 
et al (2002) demonstrated [3H]GABA binding was decreased in the SSADH -/- 
mice by 43% in cerebral cortex.   
 
Further receptor binding and electrophysiologic studies have demonstrated use-
dependent downregulation of GABAA and GABAB activity.  A progressive 
decrease in binding of the selective GABAA receptor antagonist (35)STBPS (tert-
butylbicyclophosphorothionate) was observed in the mutant strain cerebral 
cortex, hippocampus, and thalamus from postnatal day seven until its nadir at 
three weeks, coincident with the emergence of generalized convulsive seizures 
(Wu et al., 2006).  There were also reduced GABAA mediated inhibitory 
postsynaptic potentials and enhanced postsynaptic population spikes recorded 
from hippocampal slices.  There was a significant decrease in binding of a 
specific GABAB receptor antagonist in SSADH null mice compared to wild type 
control animals, and decreased GABAB mediated synaptic potentials (Buzzi et 
al., 2006).  Taken together, these results suggest that SSADH deficiency results 
in down-regulation of GHB, GABAA and GABAB receptors, and suggest a 
heterozygote effect on GHB binding as well.   
 
1.2.2 SGS 742 Application in Mouse Model 
Preliminary animal work in the SSADH mutant model has suggested benefit from 
treatment with SGS 742, a GABAB receptor antagonist.  Early reports showed 
cognitive enhancement such as improved attention, reaction time, visual 
information processing and working memory in mice, rats and monkeys (Helm et 
al 2005).  Electrocorticography (ECoG) has been used to study the effects of 

 
 
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SGS 742 vs topiramate vs saline in SSADH deficient (Aldh5a1-/-) mice (Pearl et 
al 2009).   Topiramate is a polymechanistic antiepileptic, with properties including 
enhancement of GABAergic effects, attenuation of voltage-gated Na+ currents, 
and inhibitory actions on kainate and AMPA receptors (Landmark 2007).  ECoG 
recordings (n=4) were taken from frontal and parietal cortex bilaterally following 
electrode implantation at day-of-life 18 (P18).  The drugs were administered 
intraperitoneally under continuous ECoG monitoring at P19 with topiramate (3, 
4.5, and 6 mg/kg) and SGS-742 (30, 100 mg/kg).  SGS-742 showed a dramatic 
dose-dependent improvement in the ECoG tracings, while topiramate was 
ineffective.  As the ECoG is state dependent, the doses of SGS-742 and 
topiramate utilized were chosen by experimentally determining the dose below 
the threshold for sleep. 
 
The minimum level of SGS-742 found to be effective in the ECoG studies was 
used for assessment of spike-wave discharges and survival.  At baseline (no 
drug administered), Aldh5a1-/- mice displayed significantly higher spike-wave 
discharge duration as compared to their wild-type (Aldh5a1+/+) littermates 
(p<0.05) (Pearl et al 2009).  SGS742 significantly improved the spike-wave 
duration in dose-dependent fashion and controlled absence seizures. These data 
support earlier data using CGP 35348 (Cortez et al 2004) and verify a prominent 
GABAB component associated with the absence seizures in Aldh5a1-/- mice.  
SGS742 significantly reduced spike-wave duration in animals of both mutant 
SSADH-deficient mice and wildtype mice who received gamma-butyrolactone, a 
precursor of GHB.  
 
1.3 Human SSADH Deficiency  
1.3.1 Neuroimaging Findings 
Neuroimaging modalities utilized in the evaluation of patients with SSADH 
deficiency have included cranial MRI, CT, FDG PET, and MRS. Human 
neuroimaging data, identified in 29 published cases studied with cranial MRI (23 
patients) or CT (6 patients), combined with data from our new cohort, show 
specific results.  These methods revealed T2 hyperintensities in multiple regions, 
most commonly of the globus pallidus.  A pattern of dentate-pallidal 
hyperintensity has been described (Yalcinkaya et al 2000; Ziyeh et al, 2002).  
There are also areas of abnormal T2-weighted signal in cerebral white matter 
and brainstem.  Other findings on structural imaging have included atrophy of the 
cerebrum and cerebellum, the latter preferentially affecting the midline vermis.  
PET scanning using the FDG radioisotope revealed cerebellar hypometabolism 
in two patients previously identified with cerebellar atrophy on MRI, and 
otherwise was normal in one patient (Al-Essa et al 2000; Pearl et al 2003b).   
Both of these patients had known cerebellar atrophy on standard MRI.   
 
Neuroimaging has shown abnormalities in two thirds of patients in our database, 
most characteristically increased T2-weighted signal in the globus pallidus, 
subcortical white matter, cerebellar dentate nucleus, and brainstem (Pearl et al., 

 
 
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2007a).  Other findings include cerebral atrophy, cerebellar atrophy, delayed 
myelination, and a pattern of dentate-pallidal hyperintensity (Yalcinkaya et al., 
2000; Ziyeh et al., 2002).  While the pallidal hyperintensity is usually 
homogeneous and equally affects the internal and external portions, we have 
had occasional patients with heterogeneous involvement and persistent 
asymmetry of the signal abnormality of the globus pallidus.  Of seven patients 
studied in our recent clinical protocol at NIH, five had bilaterally symmetric 
homogeneous signal abnormalities in the globus pallidus and dentate nuclei, as 
well as subthalamic nuclei (Pearl et al 2009).  One patient had asymmetric 
involvement of the globus pallidus which has proven to be stable over seven 
years, with minimal abnormality on the right but marked increased T2-weighted 
and decreased T1-weighted signal on the left accompanied by expansion of the 
left globus pallidus and bilateral ventriculomegaly.  In the oldest patient studied 
(age 27 years), the pallidal signal abnormality was subtle, but associated with 
clear volume loss and commensurate ex vacuo dilatation of the third ventricle, 
without abnormalities of the subthalamic or dentate nuclei.  Magnetic resonance 
spectroscopy that is edited for small molecules has shown elevated levels of 
GABA and related compounds (including GHB and homocarnosine) in patients 
but not obligate heterozygotes (Ethofer et al 2004; Pearl et al 2004a) 
 
PET has been used to image a number of receptor systems successfully in man, 
including benzodiazepines (Henry et al 1993; Richardson et al 1996; Richardson 
et al 1997; Savic et al 1993; Savic et al 1995; Savic et al 1996) as well as opiates 
(Frost et al, 1988; Madar et al 1997; Mayberg et al, 1991; Theodore et al, 1992) 
and monoamine oxidase (Kumlien et al, 1995).  Mu-opiate receptor binding is 
increased in temporal neocortex ipsilateral to the epileptogenic area (Frost et al   
1988).  Not all studies on receptors have adequately corrected the data for 
possible alterations in brain volume, or underlying pathology. 
 
The most widely used GABAA ligand currently used for PET is [(11)C] Flumazenil, 
a highly selective benzodiazepine antagonist.   A number of studies have shown 
reduced FMZ binding in patients with partial seizures, closely correlated with 
EEG distribution of epileptiform discharges (Koepp et al 1997, 1998).  In some 
cases, reduced FMZ binding has been found in patients with normal MRI, as well 
as after partial volume correction in patients with MTS (Koepp et al 2000, 
Lamusuo et al 2000).   
 
A flumazenil PET study of 15 children (ages 1-8 years) showed that prolonged 
vigabatrin (VGB) treatment is associated with decreased binding in children with 
epilepsy (Juhasz et al 2001).  Regional flumazenil volume of distribution values 
of the VGB-treated patients were significantly lower in all cortical regions and the 
cerebellum, whereas the difference was not significant in the thalamus and basal 
ganglia. The authors concluded that VGB induces a decrease in GABAA receptor 
binding in the cortex and cerebellum of the developing epileptic brain.  These 
results suggested down regulation of GABA receptors related to increased GABA 
levels.   

 
 
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We compared 11C-FMZ PET GABAA receptor binding in patients, their parents 
(obligate heterozygotes) and healthy volunteers. Flumazenil attaches to the 
benzodiazepine binding site on the GABAA receptor and has been used as a 
ligand to image the distribution of GABAA receptors in patients with epilepsy 
(Koepp et al 2000).  Patients had decreased binding compared to controls and 
obligate heterozygotes for SSADH deficiency (Pearl et al 2009b).  This is 
consistent with downregulation of receptors due to increased agonist availability, 
as demonstrated in the transgenic animal model. 
 
Altered GABAA receptor function may be related to increased GHB levels as well 
as increased GABA levels.  GHB is a GABAB receptor agonist, and several 
studies have shown that GABAB receptor activation may modulate 
neurotransmission at  GABAA synapses (Patenaude et al 2003, 
Balasubramanian et al 2004).  
 
1.3.2 Neurophysiologic findings  
Electroencephalography:  A majority (64%) of patients in our database have 
abnormal electroencephalograms, characterized by background slowing, 
epileptiform abnormalities (usually generalized and sometimes multifocal), and 
rarely photoparoxysmal responses and electrographic status epilepticus of slow 
wave sleep (Pearl et al 2007a).   
 
Polysomnography: A study of a single patient having two nights of 
polysomnography demonstrated prolonged stage REM onset and, on the second 
consecutive night, excessive EEG background slowing after a generalized 
seizure during stage 4 sleep (Arnulf et al., 2005).  We have studied ten patients 
with overnight polysomnography and daytime multiple sleep latency testing and 
have reported prolonged REM latency and reduced stage REM percentage with 
over 90% sleep efficiency and absence of decreased daytime sleep latency or 
sleep-onset REM (Pearl et al., 2005a).  Thus, there appears to be a reduction in 
REM sleep in SSADH deficiency.  Animal models have demonstrated that 
hyperGABAergic states, e.g. via inhibition of GABA transaminase using L-
cycloserine, are associated with reduction of REM sleep and prolongation of the 
transition phase between sleep stages NREM and REM (Scherschlicht, 1985). 
 
We quantified the magnitude of excitation and inhibition in primary motor cortex 
(M1) in SSADH deficiency patients, their parents (obligate heterozygotes), age-
matched healthy young controls and healthy adults using single and paired pulse 
transcranial magnetic stimulation (TMS) (Reis et al, in Press). Long interval 
intracortical inhibition was significantly reduced and the cortical silent period 
significantly shortened in SSADH deficiency patients compared to heterozygous 
parents and control groups. Since long interval intracortical inhibition and cortical 
silent period are thought to reflect GABAB receptor mediated inhibitory circuits, our 
results point to GABAB –related motor cortex dysfunction in SSADH deficiency 

 
 
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patients. This human phenotype is consistent with the proposed mechanism of 
use-dependent downregulation of postsynaptic GABAB receptors in SSADH 
deficiency animal models. Additionally, the results suggest autoinhibition of GABA-
ergic neurons. This first demonstration of altered GABAB function in patients with 
SSADH deficiency may help to explain clinical features of the disease, and suggest 
pathophysiological mechanisms in other neurotransmitter-related disorders.  
Moreover, the TMS findings provide a reliable measure of altered cortical 
excitability that can be used in a clinical trial. 
 
1.4 Treatment   
 
The treatment for SSADH deficiency remains problematic and no consistently 
successful therapy has emerged (Gropman, 2003).  Treatment is generally 
symptomatic and targeted.  Options include anxiolytic agents or SSRI and related 
medications for obsessive-compulsive disorder.  Appropriate antiepileptics are 
chosen for generalized epilepsy other than avoidance of valproate due to its 
ability to inhibit any residual SSADH enzymatic activity (Shinka et al., 2003).  
Vigabatrin, an irreversible inhibitor of GABA-transaminase, is a logical choice 
because it will inhibit the conversion of GABA to gamma-hydroxybutyrate, a 
putative pathogen in this condition.  Vigabatrin, however, has not been 
consistently helpful, with many reports of inefficacy or, worse, worsening of 
symptoms ranging from seizure control to alertness.  While vigabatrin will lead to 
at least transient decreases in CSF GHB levels (Ergezinger et al., 2003), there 
may be a deleterious effect related to attendant increases in CSF (and brain) 
GABA levels (Pearl & Gropman, 2004).  Further, there have been concerns 
regarding vigabatrin, resulting thus far in absence of United States Food and 
Drug Administration approval, initially because of intramyelinic edema and white 
matter vacuolation in rats and dogs (Butler et al., 1987; Qiao et al., 2000; Peyster 
et al., 1995).  In clinical trials, 30% of patients treated with vigabatrin for epilepsy 
report visual field defects following one year of treatment (Krauss et al., 1998; 
Spence & Sankar, 2001; Vanhatalo et al., 2002).   As this deficit begins with 
peripheral visual field constriction, it would be particularly difficult for patients with 
a neurodevelopmental disorder such as SSADH deficiency to be alert to the early 
signs of visual toxicity.  We have recently identified MRI signal changes, 
particularly prominent in the thalamus and basal ganglia, in infants treated with 
relatively high doses of vigabatrin (Pearl et al, 2008).   
 
The GABAB receptor antagonist SGS-742, an investigational drug that has 
shown positive effects in the SSADH deficiency mouse model, and has 
demonstrated good safety and tolerability in clinical trials for dementia, is the best 
candidate for a human experimental trial (Froestl et al 2004; Investigator’s 
Brochure).   
 
 
SGS-742, 3-aminopropyl-n-butyl phosphinic acid, is an achiral molecule with a 

 
 
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molecular weight of 179.2 and occurs as a white crystalline solid.   
 
 
 
In man, drug absorption is rapid, with peak plasma concentration within 4 hours 
of single oral doses, with maximum AUC at a dose of 900 mg. Absorption was 
reduced by food intake. > 99% of drug is excreted unchanged in urine. 
Elimination t ½ was about 4 hours.  There was no difference in pharmacokinetic 
profile between young and older healthy volunteers. Interaction potential appears 
to be low, although specific data are not available. 
 
 
In rhesus monkeys and rats, the drug improved performance on several cognitive 
assessments. In rats there was no evidence of overt toxicity at single i.v. doses 
up to 300 mg/kg, or 100 mg/kg i.p. Similar results were found in dogs. In two-
week daily intravenous dosing, there was no observable effect in rats up to 30 
mg/kg; daily oral doses of 100 mg/kg for 12 months produced no toxicity in dogs.  
There was no evidence of mutagenic potential in vitro; adverse maternal and 
fetal effects in rats were noted at 2000 but not 600 mg/kg.  
 
At 50 to 400 mg/kg administered intraperitoneally to genetically epilepsy prone 
rats, SGS742 induced a dose dependent and progressive suppression of spike-
wave discharges (Investigator’s Brochure). 
 
SGS–742 was compared to topiramate in immature SSADH-deficient (Aldh5a1j/j) 
mice who had continuous electrocorticography recordings (Pearl et al 2009a). 
SGS–742 showed a dramatic dose-dependent improvement in reduction of 
spike-wave discharges and absence seizures while topiramate was ineffective.  
 
In fasting adult healthy volunteers given single oral doses of 250-1200 mg, peak 
plasma levels were reached in 4 hours. More than 99% was excreted unchanged 
in urine, with a half-life of 4-5 hours.   In phase 1 studies, using single oral doses 
from 10 to 2100 mg, multiple oral doses from 300 to 1200 mg t.i.d. (900 to 3600 
mg/day), and single intravenous doses from 315 to 1800 mg, there were no 
serious adverse events.  One of two subjects who received 1800 mg i.v. had 
moderate to severe headache, drowsiness, nausea and vomiting.  Other subjects 
had mild to moderate headache, tiredness, sleepiness, and dizziness. All AEs 
resolved fully and spontaneously. 

 
 
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In a Phase II double-blind, placebo-controlled study in 110 adults with mild 
cognitive impairment, oral administration of 600 mg t.i.d. for 8 weeks significantly 
improved attention, reaction time, visual information processing, and working 
memory (Froestl et al., 2004, Tomlinson et al 2004).  No clear drug-related 
serious adverse events or drug related effects on cardiovascular or laboratory 
variables were reported (Froestl et al 2004).  One patient had a syncopal 
episode; the patient had experienced a similar episode two years before starting 
SGS-742 treatment.  One patient had AST elevation present at screening that did 
not worsen during the study, and persisted afterwards.  One patient had an eye 
hemorrhage attributed to concomitant warfarin use. Mild to moderate nonspecific 
and non-dose-related adverse events included headache, tiredness, diarrhea, 
nausea and vomiting, sleepiness and dizziness. There was no difference in 
incidence between patients on active drug and placebo, except possibly for 
nausea and dizziness, which occurred in 7-10% of patients on active drug 
(Investigator’s Brochure).  All adverse events resolved fully and spontaneously.   
The drug has not yet been used in children.  
 
 
2 STUDY OBJECTIVES 
 
The aims of this proposal are to conduct a clinical study of a small group of 
patients with SSADH deficiency before and during a therapeutic trial of SGS-742, 
assessing the effect on cortical excitability and neuropsychological function. We 
hope to establish validated markers in SSADH-deficient patients that can be 
measured during therapeutic intervention.  Data acquired in this study should 
have relevance to conditions beyond SSADH deficiency, as they will enhance our 
ability to understand inborn metabolic errors that present with prevalent 
phenotypes such as intellectual disability or autism spectrum disorder, and to 
make optimal therapeutic decisions in SSADH deficiency patients.  
 
2.1 Hypotheses: 
 
H1: Patients will show improvement in the Auditory Comprehension subtest of 
the Neuropsychological Assessment Battery Language Module during treatment 
with SGS-742 and improvements in activities of daily living based on parent 
questionnaire.  
 
H2: Patients with SSADH deficiency will have lengthening toward normal values 
of the cortical silent period, and return of long interval intracortical inhibition, 
during a therapeutic trial of SGS-742 
 
H3:  Patients will show improvement on global assessment ratings 
 
 

 
 
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3.  SUBJECT POPULATION 
 
3.1 Description of Study Population 
 
The proposed research protocol will investigate patients with documented 
succinic semialdehyde dehydrogenase deficiency, a rare autosomal-recessively 
inherited defect of 4-aminobutyric acid (GABA) metabolism.  We propose to 
enroll 22 patients with SSADH deficiency with the goal of obtaining 16 
completers for the cross-over study.  Those who withdraw before completion of 
at least 3 months of their second treatment phase will be replaced.  
 
3.2 Inclusion Criteria (See checklist Appendix 1) 
 
• 4-hydroxybutyric aciduria (gamma-hydroxybutyric aciduria) on two 
separate tests. 
• Documented succinic semialdehyde dehydrogenase enzyme deficiency. 
• Patients must have clinical features consistent with SSADH deficiency 
including developmental delay especially deficit in expressive language, 
hypotonia, ataxia, seizures, and other neuropsychiatric symptoms 
including sleep disturbances (45%), attention deficit (45%), anxiety (27%), 
obsessive-compulsive disorder (25%), and autistic traits (25%). 
• During the study, women of child-bearing potential must use a reliable 
method of birth control until one month after the final drug taper is 
complete.  
• Patients will be 4 years or older. 
• Based on HSPU/ACAT evaluation must meet one of the following criteria:  
o subject has capacity to consent 
o subject has a documented legal guardian to provide consent 
o subject lacks capacity and no legal guardian but HSPU determines 
1) the subject has a DPA, or 2) the subject has capacity to 
designate an NIH DPA, or 3) a Next of Kin surrogate may be 
appointed as outlined in MAS 87-4. 
 
3.3 Exclusion Criteria (See checklist Appendix 1) 
 
• Current alcohol use (>14 drinks/wk in men and >7 drinks/wk in women) or 
recreational drug use for the 16 month period of this study. 
• Patients with a history of other major medical disorders with clinical 
fluctuations, or requiring therapy that might affect study participation or 
drug response such as severe depression or psychoses, renal or hepatic 
disease.  

 
 
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• Patients requiring treatment with drugs known to affect the GABAergic 
system, including vigabatrin and benzodiazepines. 
• Pregnant and lactating women 
 
 
4. STUDY DESIGN AND METHODS: 
 
4.1 Study overview 
 
This is a 16-21 month randomized, double-blind cross-over phase two clinical 
trial of SGS-742 versus placebo in 22 patients age 4 years and older with 
SSADH deficiency.  
 
4.1.1 Study Phases (see Study Schedule Appendix 2):  
• Screening (1-3 days)—outpatient.  May be combined with baseline visit. 
• Baseline visit (1 - 3 days)—inpatient or outpatient.  The first dose of study 
pills will be administered at the NIH.  The patient will stay for 30 – 90 
minutes following the first dose.  The patient will be permitted to return to 
local accommodations overnight and return 12 - 24 hours after the first 
dose to be assessed for any skin reactions, and then discharged home. 
• Titration one: 9 - 15 days (titration is 9 days and if they only get one or two 
doses on day one they will have an additional day of drug titration). 
 
Phase 1 (six months +/- 2 weeks of SGS-742 or placebo)—during phase one 
there will be regular communication, at least once every two weeks, with 
patients/families by phone and/or the clinical trial database. If indicated, based on 
reports during these regular communications, an outpatient visit will be arranged 
at NIH or with a local provider for safety monitoring or pregnancy testing.  If this 
is to be done by local providers, we will have patients designate the local 
provider in advance.  We will contact the local provider and arrange for payment 
of any visits or testing by the NIH and also document a plan in the progress notes 
for how individual providers will communicate findings and test results.  We will 
request local providers provide written documentation of outpatient visits and 
pregnancy testing results by facsimile to include in the NIH patient medical 
record.   
 
• End of phase 1 testing: (At 6 mo +/-2 weeks of phase 1) inpatient or 
outpatient 3 day evaluation including: EEG, TMS, neuropsychological 
tests, blood and urine tests, and optional LP, MRI/MRS. 
• Washout 9 weeks (+/- 2 weeks), including 9 days to taper and discontinue 
phase I medication, at least 7 weeks medication free and titration to phase 
2 medication 9 - 15 days (taper is 9 - 15 days and if they only get one 
or two doses on day one they will have an additional day of drug 
taper). 

 
 
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Phase 2 (six months +/- 2 weeks of phase 2 treatment)— during phase two there 
will be regular communication, at least once every two weeks, with 
patients/families by phone and/or the clinical trial database. If indicated, based on 
reports during these regular communications, an outpatient visit will be arranged 
at NIH or with a local provider for safety monitoring or pregnancy testing.  If this 
is to be done by local providers, we will have patients designate the local 
provider in advance.  We will contact the local provider and arrange for payment 
of any visits or testing by the NIH and also document a plan in the progress notes 
for how individual providers will communicate findings and test results.  We will 
request local providers provide written documentation of outpatient visits and 
pregnancy testing results by facsimile to include in the NIH patient medical 
record.   
 
• End of phase 2 testing: (At 6 mo +/-2 weeks of phase 2) inpatient or 
outpatient evaluation including: EEG, TMS, neuropsychological tests, 
blood and urine tests, and optional LP, MRI/MRS. 
• Taper off drug:  9 – 15 days. 
• Final visit: 4-7 weeks after completion of the final drug taper.  
 
Some variability in scheduling will be based on whether a participant has a 
seizure. 
 
4.2 Recruitment 
 
Most subjects will be patients with SSADH deficiency followed by Dr. Pearl in the 
Boston Children’s Hospital Neurology Department. Dr. Pearl may be the treating 
clinician for these patients or patients may be referred to him by their treating 
physicians specifically for consultation regarding management and treatment of 
SSADH deficiency.  During the course of routine clinical care, patients will be 
informed about the study and, upon their request, will be provided the information 
to contact the NIH personnel on their own initiative.  The referral will not be made 
directly by Dr.Pearl and the NIH is not contacted by Dr. Pearl on behalf of the 
patient. 
 
Letters will also be mailed to families with a history of SSADH and the letter will 
be posted to the SSADH Association website (See Appendix VII). 
 
4.3 Screening  
 
Consent will be obtained before any study procedures, including screening 
procedures, are done. 
 

 
 
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Patients will be screened in the CES outpatient clinic for inclusion in the protocol 
by CES physicians or licensed practitioners.   Dr Pearl, who is a special volunteer 
at NIH with clinical privileges, will supervise confirmation of the diagnosis.    
Screening will include review of the information collected by the referring doctors 
to determine suitability for the protocol, physical and neurological examination, 
urine tests to confirm the diagnosis if not performed previously, 
electrocardiogram, CBC, blood chemistries, and antiepileptic drug levels if 
clinically indicated and the testing is available in our lab. 
 
4.4 Study Procedures  
 
All procedures performed at NIH will be for research.  Each procedure will be 
performed at baseline and at the end of each 6-month treatment arm (3 total). 
Procedures include electroencephalogram, neuropsychological testing, 
transcranial magnetic stimulation, and optional lumbar puncture and optional 
MRI/MRS.  All participants will be asked to undergo LP, however, refusal to have 
an LP or inability to tolerate an LP will not be exclusionary for the study.    
 
TMS and optional MRS will not be done within 24 hours of a reported seizure. 
The studies will be rescheduled.  
 
At each visit during drug treatment, patients will have a medical history and 
physical examination and will review seizure calendars and be asked about 
adverse effects.  Laboratory tests, including urine pregnancy for females of child 
bearing potential, will be obtained if indicated based on a change in clinical 
status. 
4.4.1 Structural MRI Scans (OPTIONAL) 
3.0 Tesla anatomical T1 and T2-weighted MRI images will be obtained both for 
clinical evaluation and partial volume correction / co-registration for MRS. 
Approximately 45 minutes will be needed to obtain the images.  
 
4.4.2 Magnetic Resonance Spectroscopy (MRS) (OPTIONAL) 
MRS will be performed using a 3-T whole-body scanner and a transmit-receive 
head coil. MRS spectra will be acquired from 2 voxels globus pallidus and 
cerebral cortex (frontal or parietal).   GABA will be measured using an interleaved 
PRESS-based J editing method (Hasler et al 2005).   The study will last a 
maximum of 90 minutes.   
4.4.3 Transcranial Magnetic Stimulation (TMS) Procedure 
Before and after TMS, patients will be screened for hearing by the NIH Audiology 
Service.  Each test will take up to 30 minutes.  TMS will be applied using a coil 
placed on the scalp.  Surface EMG will be recorded from the first dorsal 
interosseus (FDI) muscle.  The coil will be manually positioned, and the electrode 
position will be marked with a pen for eliciting motor evoked potentials (MEPs) 

 
 
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from the FDI muscle.  After the subject is seated in a comfortable position, an 
adjustable head restraint will be applied to prevent head movements.  Indices for 
cortical excitability will be obtained including motor threshold (MT), recruitment 
curve, intracortical inhibition (ICI), intracortical facilitation (ICF), and cortical silent 
period (CSP) from motor cortex.   
 
The MT is defined as the minimum percentage of the stimulator output that 
evoked a motor evoked potential of more than 50 µV in at least 5 out of 10 trials.  
For recruitment curve determination, TMS will be applied over the same 
hemisphere from which MT is measured, while 5 responses are recorded at each 
of a range of different stimulus intensities.  Stimulus intensity will be increased in 
steps of 10% of the individual MT from 90 to 160% MT.  MEP size will be 
measured peak-to-peak in single trials and averages will be calculated for each 
intensity.  ICI and ICF will be studied using a paired stimulus paradigm.  The 
conditioning stimulus (70% MT) followed by the test stimulus (120% MT) will be 
delivered at 3 different interstimulus intervals (ISI); 2 ms for short ICI, 10 ms for 
ICF, and 100 ms for long ICI.  Each run will consist of 10 trials, and the amplitude 
ratio of the mean conditioned MEP to control MEP will be determined for each 
ISI.  Measurement of the CSP will be carried out from the tonically active FDI, 
performing 10 trials each of the intensities at 10, 20, 30, and 40% above MT.  
CSP onset and termination will be measured in the rectified single trials as the 
times of the end of the preceding MEP and the return of sustained activity in the 
EMG, respectively.  The conditional averages will be calculated from the single-
trial data.  TMS will take up to 90 minutes.  
 
4.4.4 Neuropsychological Assessments 
Patients will undergo comprehensive language and cognitive evaluations using a 
selection of assessments based on age and ability such as the following:   
 
1. WNV (Wechsler Nonverbal Scale of Ability) for patients up to age 22, an 
individually-administered, standardized test that provides an IQ score and 
insights into cognitive functioning.  The test requires approximately 30 
minutes to administer. 
 
2. WAIS-IV (Wechsler Adult Intelligence Scale) for patients age 22 and 
older, also an individually-administered test of ability will be administered 
using the subtests that overlap the WNV.  These are nonverbal because 
of the language limitations of this population.   
 
3. The Neuropsychological Assessment Battery: Language 
Module.  Subtests to be administered include confrontation Naming and 
following directions (Auditory Comprehension) to assess language 
competence. 
 

 
 
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4. Rule Shift from the Behavioral Assessment of Dysexecutive Syndrome 
is a short (5 minute) test of working memory. 
 
5. Computerized tests of reaction time and go-no-go to assess the 
constructs of reaction time and attention. 
 
6. Texas Functional Living Scale is an assessment of practical reading, 
math, language comprehension and memory developed for individuals 
with cognitive limitations.   
 
7. ABAS: Adaptive Behavior Assessment Scale to be completed by 
parent.  Queries on functional skills.   
 
8.  Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-
IV), for patients between the ages of 2.5 and 7, is an individually-
administered, standardized test that provides scores for verbal and 
nonverbal domains of intellectual ability.  The test requires between 45 
minutes and 75 minutes to administer, depending on the age.  
 
9.  Wechsler Intelligence Scale for Children-V (WISC-V), for patients 6 
years of age through age 17, is an individually administered, standardized 
test of cognitive ability.  This test provides scores for verbal and nonverbal 
domains of intellectual ability.  The test requires between 60 minutes and 
90 minutes to administer, depending on age 
4.4.5 Lumbar Puncture Procedure (OPTIONAL): 
Lumbar puncture will be performed according to standard procedure utilizing 
sterile technique in the lateral recumbent position. Lumbar puncture will be 
carried out in the awake state utilizing local 1% lidocaine anesthesia.  
Approximately ten ml of CSF will be collected for routine studies and special 
metabolites including GABA-related compounds and biogenic amines.  The fluid 
designated for special metabolites will be placed immediately in dry ice and then 
stored in a -70 degree freezer.   
4.4.6 EEG  
EEG will be performed according to standard procedures using the international 
10-20 standard method of electrode placement. 
 
4.4.7 Blood draw 
Approximately ten cubic centimeters of blood will be drawn at screening, and at 
the end of each treatment phase, for CBC, clinical chemistry, and hepatic panels.   
 
4.4.8 Seizure and side effect calendar 
Patients and families will be asked to keep a record of seizures and any possible 
medication side effects. 
 

 
 
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4.4.9: Pregnancy tests 
Patients of child-bearing potential will have a urine pregnancy test at screening 
and each out-patient visit.   Pregnancy testing may also be done based on safety 
monitoring and clinical assessment.  Pregnancy testing may be done by local 
providers. In this case, we will have patients designate the local provider in 
advance.  We will contact the local provider and arrange for payment of testing 
by the NIH and also document a plan in the progress notes for how individual 
providers will communicate test results.  We will request local providers provide 
written documentation of pregnancy testing results by facsimile to include in the 
NIH patient medical record.   
 
As outlined in the minor assents, if the pregnancy testing for a minor patient, 
performed at the NIH or through a local provider, is positive, we will inform the 
parent or guardian.   
 
 
4.5 Drug Treatment  
4.5.1 Randomization 
A crossover design will be employed where patients are randomized into a six-
month trial of treatment versus placebo.   
 
Subjects will be randomized at the end of baseline testing 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.    
4.5.2 Study Drug Administration 
Patients may be outpatients or inpatients during titration. The first dose of study 
pills will be administered at the NIH.  The patient will stay for 30 – 90 minutes 
following the first dose.  The patient will be permitted to return to local 
accommodations overnight and return 12 - 24 hours after the first dose to be 
assessed for any skin reactions, and then discharged home. 
 
All patients will be given an exact written titration schedule to follow, and will be 
contacted by phone and/or clinical trials database at least every two weeks 
during the study.  
 
Following a 9 week +/- 2 weeks total washout period, including drug taper, 
described below, patients will enter the other treatment arm. For the second 
phase of the study patients may also be inpatients or outpatients. The first dose 
of study pills will be administered at the NIH.  The patient will stay for 30 – 90 
minutes following the first dose.  The patient will be permitted to return to local 
accommodations overnight and return 12 – 24 hours after the first dose to be 
assessed for any skin reactions, and then discharged home. 
 

 
 
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 The active treatment will be SGS-742, synthesized by IRIX pharmaceuticals in a 
GCP facility. The target dose will be 10 mg/kg with a maximum of 600 mg given 
orally three times daily for six months, with an increasing titration over nine to 
fifteen days.  The placebo arm will be inert placebo given orally three times daily. 
It is recommended to take the medication three times each day prior to meals 
because administration of food decreases oral systemic availability of SGS-742. 
The drug and matching placebo will be encapsulated by the NIH pharmacy. The 
pharmacy will draw up a randomization schedule and ensure blinding. 
 
Patients and examining physicians will be blinded as to the treatment arm in 
which the patient is enrolled. 
 
The NIH Pharmacy will dispense three month's supply of study drug SGS-742 or 
placebo) to subjects for each study treatment phase. The second three-month 
supply can be picked up by the patient or sent by mail.  Patients will be asked to 
bring study pill bottles to each clinic visit.  Pill counts will be performed at each 
visit if patients bring study pill bottles. Patients will be advised to take a missed 
dose if they remember within 4 hours; otherwise, to take the next scheduled dose 
and record the missed dose on their seizure/medication calendar.  Patients will 
be advised to take their study drug about one hour before food.  
 
All unused investigational product will be returned to the NIH Pharmacy for 
disposal if patients bring study pill bottles.   
 
At the end of phase 2, the study drug will be tapered off as described below.  If 
patients only get one or two doses the first day, an additional day may be added 
to the titration and taper schedule.  Patients will have a final follow-up visit four to 
seven weeks after completion of the final drug taper. 
4.5.3 Drug titration 
The following drug /placebo titration schedule will be used for patients weighing 
30 kg or greater:  
 
2.5 mg/kg/dose (up to 150 mg) tid X 3 days;  
5 mg/kg/dose (up to 300 mg) tid X 3 days; 
7.5 mg/kg/dose (up to 450 mg) tid X 3 days; 
10 mg/kg/dose (up to 600 mg) tid (target dose). 
 
The drug is only available in 75- and 150-mg capsules. Thus, for patients 
weighing less than 30 kg, the dosing regimen may be modified to reflect the use 
of specific size capsules and dose limits for small participants.  
 
Dosing may be modified as close as possible to the weight-specified dose 
without exceeding it. Modified dosing schedules for children weighing less than 
30 kg will allow us to come as close as possible to the final weight-based 
protocol-specified dose without exceeding it.  The dosing schedule in these 

 
 
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children may be modified from TID dosing to QD and BID to extend the titration 
period to avoid large dose jumps between titration levels. 
 
If patients experience side effects, the next scheduled dose increase will be 
delayed until they abate.  If this does not occur, the dose will be reduced in 2.5 
mg/kg per day increments until side effects abate. 
 
The final maximum dose will be determined by the patient’s weight but will not 
exceed 600 milligrams three times per day.  
4.5.4 Drug taper schedule 
The following drug /placebo taper will follow the reverse schedule of the drug 
titration: 
 
For patients weighing 30 kg or greater: 
7.5 mg/kg/dose (up to 450 mg) tid X 3 days; 
5 mg/kg/dose (up to 300 mg) tid X 3 days; 
2.5 mg/kg/dose (up to 150 mg) tid X 3 days;  
then stop. 
 
For patients weighing less than 30 kg: 
 
The drug /placebo taper will follow the reverse schedule of the drug titration for 
each patient. 
 
Placebo will be titrated and tapered in capsules matching the SGS-742 dosing 
stages. 
 
4.6  Sedation   
 
For adults needing sedation for optional MRI/MRS, the NIH Anesthesia 
Department will use Dexmedetomidine, a highly selective alpha-adrenoreceptor 
agonist that exerts its hypnotic effects at the locus coeruleus, and has minimal 
cardiovascular and virtually no respiratory depressant effects (Correa-Sales 
1992; Maze et al 2001; Nelson LE 2003). In addition, the drug has no effect on 
release or extracellular levels of glutamate, aspartate and GABA (Valtonen et al 
1995).  It has been shown to be a safe and well-tolerated agent, and is approved 
by the FDA for use in the intensive care unit setting. The drug is routinely used 
clinically in intensive care units and operating rooms, and for imaging studies 
(Mason 2008, Yuen 2008).   According to the package insert, adverse effects in 
clinical trials included hypotension (28% versus 13% in patients receiving 
placebo), hypertension (16% versus 18%), nausea (11% versus 9%) and 
bradycardia (7% versus 3%).  This medication was used without incident in our 
previous SSADH deficiency study. If sedation is required for MRI/MRS, the LP 

 
 
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may be done while under sedation.  No sedation will be used for research 
purposes in minors.  
 
4.7 End of Participation 
 
Participants will remain under the care of their own physicians while in this study.  
The study physicians may, in cooperation with the treating physicians, manage 
neurologic treatment.    
 
Clinically relevant results of study procedures such as MRI findings will be given 
to the patients and their parents or guardians.

 
 
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4.8 Study Schedule 
 
 
* OPTIONAL 
 
 
 
Study 
phase 
Length 
 
Clinic 
visit, 
physical  
exam 
SGS-
742 
or 
place
bo 
EEG 
Blood 
tests  
Urine 
tests 
EKG 
Lumbar 
puncture
* 
MRI 
MR
S*  
TMS 
NP 
tests 
Screening 
 
 
1-3 days 
X 
 
 
X 
X 
X 
 
 
 
  
Baseline 
 
1-3 days  
X 
 
X 
 
 
 
X 
X 
X 
X 
Titration 
9 -15 
days 
 
X 
 
 
 
 
 
 
 
 
Phase 1 
Month 1 
 
 
 
 
 
 
 
 
 
 
 
Month 2 
 
 
 
 
 
 
 
 
 
 
 
Month 3 
 
 
 
 
 
 
 
 
 
 
 
Month 4 
 
 
 
 
 
 
 
 
 
 
 
Month 5 
 
 
 
 
 
 
 
 
 
 
 
Month 6  
(+/- 2 
addition
al 
weeks) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Washout 
Month 1 
 
 
 
 
 
 
 
 
 
 
 
Month 2  
(+/- 2 
addition
al 
weeks) 
 
 
 
 
 
 
 
 
 
 
Titration 
9 – 15 
days 
 
X 
 
 
 
 
 
 
 
 
Phase 2 
Month 1 
 
 
 
 
 
 
 
 
 
 
 
Month 2 
 
 
 
 
 
 
 
 
 
 
 
Month 3 
 
 
 
 
 
 
 
 
 
 
 
Month 4 
 
 
 
 
 
 
 
 
 
 
 
Month 5 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
(+/- 2 
addition
al 
weeks) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Taper off 
9 – 15 
days 
 
 
 
 
 
 
 
 
 
 
FINAL 
VISIT 
4-7 
weeks 
later 
X 
 
 
 
 
 
 
 
 
 

 
 
CNS IRB Protocol Template (rev 9.21.11) 
 
 
5. STORAGE OF DATA AND SAMPLES 
 
Study data will be stored in password-protected NINDS and NIH Clinical Center 
computer systems.  
 
Deidentified coded CSF samples will be stored in the Laboratory of Dr K Michael 
Gibson, WSU, using the established data protection procedures of his laboratory.  
 
 
6.  ADDITIONAL CONSIDERATIONS 
 
Research with investigational drugs or devices: 
SGS-742 requires an IND. 
SGS-742 will be obtained from IRIX pharmaceuticals, and encapsulated and 
stored by the NIH Pharmacy. 
Investigator’s brochure Attached 
 
 
7. RISKS AND DISCOMFORTS 
7.1 SGS-742 
 
Patients are at risk for developing an allergic reaction to the study pills. 
Animal toxicology studies showed development of ataxia at doses of 100-300 
mg/kg in mice and rats, and seizures at > 300 mg/kg. In 6/12-month oral toxicity 
studies, the clear “no observable effect” level in dogs was 100 mg/kg; in rats, the 
only observation was a slight reduction in body weight gain in males at 200 and 
600 mg/kg. Gastrointestinal and hepatic toxicity was found after administration of 
300 mg/kg for three months in rats.  
 
In the phase 2 blinded placebo-controlled study, the following side effects 
occurred in more than 5% of subjects: 
 
 
Active drug (n=75) 
Placebo (n=35) 
Diarrhea 
8% 
8% 
Nausea 
8% 
6% 
Dizziness 
7% 
3% 
 
Side effects reported less frequently included headache, arthralgia, peripheral 
edema, unspecified infections, infestations, respiratory, and skin disorders. 
These did not differ between subjects taking active drug and placebo.  
 
Three serious adverse events were reported.  One syncopal episode occurred in 
a patient with a previous history of transient ischemic attacks lasted 30 minutes, 
resolving spontaneously without medical intervention or sequelae.  One 

 
 
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intraocular hemorrhage occurred in a patient on warfarin.  One subject had a 
preexisting liver function test elevation that did not change on SGS-742. 
 
There were no clinically significant changes in laboratory tests, vital signs, 
weight, or ECG results. 
 
SGS-742 is not metabolized, and >99% of the drug is excreted unchanged in 
urine.  Thus, no clinically important drug interactions are anticipated. 
 
Pregnancy testing and contraception: 
Since the teratogenic potential of SGS-742 is unknown, women of child-bearing 
potential must use an effective form of birth control during the study and for a 
month after final drug taper is complete. Patients should not breast-feed during 
the study or for one month after the study is completed. 
 
Effective methods of contraception for this study include  
1. hormonal contraception (birth control pills, injected hormones or vaginal ring);  
2. intrauterine device; 
3. barrier methods (condom or diaphragm) combined with spermicide;  
4. surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner). 
Should a subject have a positive pregnancy test, the principal investigator or lead 
associate investigator will meet with the family to discuss the results and will be 
referred to the NIH OB-gyn service for counseling.  The study drug will be 
stopped and patients followed until pregnancy outcome.  
 
7.2 MRI and MRS (OPTIONAL) 
 
People are at risk for injury from the MRI magnet if they have pacemakers or 
other implanted electrical devices, brain stimulators, some types of dental 
implants, aneurysm clips (metal clips on the wall of a large artery), metallic 
prostheses (including metal pins and rods, heart valves, and cochlear implants), 
permanent eyeliner, implanted delivery pump, or shrapnel fragments. Welders 
and metal workers are also at risk for injury because of possible small metal 
fragments in the eye of which they may be unaware. Subjects will be screened 
for these conditions before having any scan, and if they have any, they will not 
receive an MRI scan.   
 
People with fear of confined spaces may become anxious during an MRI. Those 
with back problems may have back pain or discomfort from lying in the scanner.  
The noise from the scanner is loud enough to damage hearing, especially in 

 
 
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people who already have hearing loss. Everyone having a research MRI scan will 
be fitted with hearing protection. Subjects will be asked to complete an MRI 
screening form for each MRI scan you have. There are no known long-term risks 
of MRI scans. 
 
A pregnancy test will be performed before MRI/MRS for any subject of child 
bearing potential. The scan will not be done if the pregnancy test is positive. 
 
7.3 TMS 
 
Both single and paired-pulse TMS will be performed.  Single pulse TMS is a 
minimal risk procedure.  Side effects include headaches and scalp tingling.  The 
noise of the TMS magnet can potentially damage hearing; patients will be fitted 
with earplugs by technicians trained to do so.  Additionally, hearing in participants 
will be tested before and after exposure to TMS in order to check whether the 
TMS caused a change in hearing. If there is an auditory threshold shift of 15dB at 
any frequency, auditory testing will be repeated after 24 hours.  If three people 
have a change in auditory threshold after TMS, the TMS portion of the study will 
no longer be carried out.  Children may be more susceptible to hearing adverse 
events from TMS due to immaturity of the young brain and ear canal.  TMS can 
interfere with implanted medical devices and will not be done in people who have 
pacemakers, implanted pumps, or stimulators, such as cochlear implants or in 
people who have metal objects inside the eye or skull.   
 
Garvey et al employed a self-report questionnaire to collect children's subjective 
response to single-pulse TMS.  They found that TMS was well tolerated by the 
majority of subjects, and was favorably compared to seven common childhood 
experiences.  Notably, of the 40 children in the study, 34 subjects (85%) said 
they would voluntarily undergo TMS again.  Because it presents no greater risk 
of discomfort than other potentially distressing childhood experiences of daily life, 
the study concluded that TMS falls within the category of no greater than minimal 
risk. (Garvey et al, 2001).  Paired-pulse TMS carries no more than a minor 
increment over minimal risk.  
 
7.4 Lumbar Puncture (OPTIONAL) 
 
Lumbar puncture is a routine clinical procedure that has a minimal level of risk of 
local infection and discomfort.  All efforts will be made to minimize these risks, 
including performance of the procedure during the provision of generalized 
anesthesia when applicable, use of local anesthesia when generalized 
anesthesia is not applicable, and use of sterile technique.  Post-lumbar puncture 
headache may occur in one-third of people, which is usually not severe and 
improves without treatment other than a mild pain reliever. Headaches lasting 
longer than 7 days develop with one in 50 to 200 lumbar punctures and usually 

 
 
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improve gradually over 2 weeks. In rare cases, headaches have persisted longer. 
Prolonged headaches may be due to persistent leakage of CSF from the area of 
the lumbar puncture, and will be treated with an epidural blood patch.   
7.5 Neuropsychological testing  
 
Neuropsychological testing has only minor risk, including boredom and 
frustration.  
 
7.6 Sedation 
 
Sedating medicines may cause decreased blood pressure, irregular heartbeats, 
depressed breathing, and muscle spasms.  Uncommon side effects are very low 
blood pressure, nausea and vomiting, respiratory insufficiency, and a severe 
allergic reaction.  On extremely rare occasions breathing may stop.   
Dexmedetomidine has been shown to be a safe and well-tolerated agent, and 
was used without incident in our previous SSADH deficiency study.  The drug is 
routinely used clinically in intensive care units and operating rooms, and as a 
sedative for individuals undergoing imaging studies (Mason 2008, Yuen 2008).   
According to the package insert, adverse effects in clinical trials included 
hypotension (28% versus 13% in patients receiving placebo, hypertension (16% 
versus 18%), nausea (11% versus 9%) and bradycardia (7% versus 3%).  
 
 
7.7 EEG  
 
There is no risk associated with having an EEG. The patient may feel 
uncomfortable while the electrodes are attached to their scalp. The conductive 
gel sometimes causes some mild irritation. They may not like the smell of the 
paste or the glue remover, but they are not harmful.  
 
 
7.8 Blood Draw 
 
There may be some discomfort and bruising at the site of needle entry. There is 
a very small risk of fainting. Infection in the area of the needle insertion is rare.  
10 CC will be drawn three times during the protocol for CBC, liver function tests 
and electrolytes. 
 
 
8. SUBJECT SAFETY MONITORING 
 
Patients will be monitored by CES Staff, including PI, nurse practitioner and 
fellows, and by Dr Phillip Pearl, a board-certified pediatric neurologist, who is a 

 
 
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special volunteer with clinical privileges at NIH, and has the world’s largest 
experience with SSADH deficiency.  
 
Dr Debra Ehrlich will serve as Independent Study Safety Monitor (ISSM).  Dr 
Ehrlich is a Board-Certified Neurologist with Fellowship training in Movement 
Disorders who is conducting clinical research with Dr Mark Hallett.   
 
The ISSM will serve as the IND sponsor’s medical monitor and will make the final 
determinations of relatedness of safety events to the investigational product on 
behalf of the sponsor (NINDS). The ISSM will review serious adverse events, 
and serious unanticipated problems. SAEs that are at least temporally associated 
with the use of the study drug (whether assumed to be related or not) will be 
given to the ISSM immediately, but no later than 48hrs from the time the PI 
learns of an event. The PI will record nonserious AEs and report them to the 
ISSM at the time of 1) IRB continuing review and 2) the annual Safety Monitoring 
Committee’s annual meeting. The ISSM will review these reports and provide 
feedback to the PI and NINDS in a timely manner.   
 
 
Patients will be monitored carefully by CES clinicians for any change in their 
clinical status during clinic visits and self-report during phone and computer 
contact.  Intervention will be determined by the independent subject safety 
monitor and may include consultation, additional studies, or withdrawing the 
patient from the protocol.   
 
Parameters to be monitored include seizure frequency, neurological examination, 
fluctuations in cognitive and behavioral features.  Specific drug-related side 
effects to be monitored include headache, tiredness, nausea and vomiting, 
sleepiness and dizziness. 
 
Patients who cannot tolerate the study drug will be taken off of it.  Following 
review and approval by the Independent Subject Safety Monitor, patients who 
stopped taking the study drug can remain in the study and complete follow-up 
visits and assessments.   
 
Females who become pregnant will stop the study drug however will remain in 
the study and can be followed under the protocol.  They will not complete any 
assessments that pose risk to the pregnancy or fetus but can do other non-
invasive procedures such as neuropsychological testing.  They will be followed 
until the end of the study or pregnancy outcome, whichever is later. 
 
Patients will be removed from the study if they are unable to cooperate, or have 
an alteration in clinical status 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.  
 

 
 
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Toxicity will be graded according to the NCI Common Terminology Criteria for 
Adverse Events (appendix 2). 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, one-step dose reductions 
will be initiated until the toxicity resolves.  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 the study medication.  
All dose changes and/or dose interruptions will be recorded on case report forms. 
 
 
8.1 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 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. 
 
9. OUTCOME MEASURES 
9.1 Primary outcome measure 
 
The primary outcome measures for drug efficacy will be: 
Performance on neuropsychological testing and responses to parent 
questionnaire. 
 
9.2 Secondary outcome measures for efficacy will be: 
 
TMS parameters of cortical excitation and inhibition 
9.3 Outcome measures for safety will include: 
 
Clinical examination 
Neuropsychological tests 
 

 
 
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10. DATA ANALYSIS 
 
10.1 Power calculation: 
 
We performed a power analysis, in Systat 11.  Using a paired Student’s t design, 
comparing measurements on placebo and SGS-742, 16 patients would be 
needed to detect a change in the Auditory Comprehension subtest of the 
Neuropsychological Assessment Battery Language Module score of 0.75 SD.   
 
Thus, we are requesting 22 subjects to allow for dropouts. Dropouts will be 
replaced with new subjects until we attain 16 completers.  
 
We will record the reasons for any dropouts, allowing performance of sensitivity 
analyses to account for a number of scenarios, including assuming dropouts all 
had a negative outcome in our analysis of efficacy, and using imputation to 
model the effects of dropouts based on the profile of each dropout.  
 
10.2 TMS  
 
Indices for cortical excitability will be obtained including motor threshold (MT), 
recruitment curve, intracortical inhibition (ICI), intracortical facilitation (ICF), and 
cortical silent period (CSP) from motor cortex.  Motor evoked potential (MEP) 
size will be measured peak-to-peak in single trials and averages will be 
calculated for each intensity.  ICI and ICF will be studied using a paired stimulus 
paradigm.  CSP onset and termination will be measured in the rectified single 
trials as the times of the end of the preceding MEP and the return of sustained 
activity in the EMG, respectively.  The conditional averages will be calculated 
from the single-trial data.  These parameters will be compared for intra-individual 
and inter-individual differences pre- and post-therapy with SGS 742.   
 
10.3 MRS  
 
MRS will be analyzed with the GABA editing sequence provided by the 
NIH/NIMH MRS Core.   
 
10.4 Neuropsychological tests 
 
The neuropsychological tests were selected by the investigators as representing 
those assessments which could be completed by this group of patients with 
adjustments made for the cohort’s age group, including WNV (Wechsler 
Nonverbal Scale of Ability) for patients up to age 22; WAIS-IV (Wechsler Adult 
Intelligence Scale) for patients age 22 and older; the Neuropsychological 

 
 
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Assessment Battery: Language Module; Rule Shift from the Behavioral 
Assessment of Dysexecutive Syndrome; Computerized tests of reaction time and 
go-no-go to assess the constructs of reaction time and attention; Texas 
Functional Living Scale; ABAS: Adaptive Behavior Assessment Scale to be 
completed by parent and Queries on functional skills.   
 
The combination of clinical interview, observations, intellectual testing, and 
executive function tests was devised for a logistically achievable assessment of 
cognitive and executive function.   The testing will be administered at baseline 
and then at the end of the two six-month treatment arms, which includes a two-
month washout period between arms.   
10.5 CSF analysis 
 
Quantitation of GABA, GHB, succinic semialdehyde, homocarnosine, 4,5-
dihydroxyhexanoic acid (DHHA) and D-2-hydroxyglutaric acid in CSF samples 
will be achieved using isotope dilution liquid chromatography-tandem mass 
spectrometry.  These metabolites (all of which are interrelated to GABA 
metabolism) are increased to varying degrees in both CSF derived from SSADH 
deficient patients and brain tissue derived from SSADH-deficient mice. 
 
In addition, for all CSF samples comprehensive amino acid analysis will be 
performed.  The rationale of this analysis is based upon the clear depletion of 
glutamine observed in the brain of SSADH-deficient mice.  Amino acid analysis is 
performed by HPLC with ninhydrin post column detection.  As well, we have 
documented in earlier studies that glutamine is low, to borderline-low, in CSF 
samples derived from SSADH-deficient individuals.  
 
 
11. HUMAN SUBJECTS PROTECTION 
11.1 Subject Selection 
 
Subjects will be selected equitability, based upon their meeting the study's 
eligibility criteria. Although there is no known human subpopulation incidence 
variation, the majority of the patients identified have been of ‘Caucasian’ 
background. 
11.2. Justification for inclusion of children 
 
SSADH is a severe pediatric neurotransmitter disease without any effective 
therapy.  The majority of the patients identified are under 18.  Patients over the 
age of four are included because the parent questionnaires measuring activities 
of daily living as primary outcome data are valid at any age. Early intervention is 
desirable in a genetic disease.  

 
 
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11.3 Justification for inclusion of vulnerable subjects  
 
Patients with SSADH deficiency frequently have cognitive impairment and may 
lack consent capacity.  The effect of SGS-742 on neuropsychological function is 
one of the main outcome measures of the protocol.  
11.4 Justification of sensitive procedures (using placebo) 
 
Placebo-controlled studies are the best way to obtain reliable data on drug 
efficacy in a clinical trial in any neurological disorder. Patients will still be on their 
baseline drug therapy during all treatment phases, and will not be exposed to any 
risk greater than their standard therapy while on placebo. 
 
11.5 Safeguards for vulnerable populations 
 
Protections for vulnerable populations will include evaluation by the HSPU/ACAT, 
obtaining consent from DPA for adults without capacity, assent from participants, 
pregnancy testing for women of childbearing potential, and use of pediatric-
trained staff and facilities.  Dissent will be respected.  
 
11.6 Qualifications of investigators 
 
Sara Inati, MD will serve as the principal investigator.  She is a  
board-certified in Neurology, Epilepsy and Clinical Neurophysiology, and has 
extensive experience in clinical research, including serving as principal 
investigator on several trials. She will oversee all aspects of the protocol, 
including study procedures and data analysis. Dr. Inati will be obtaining informed 
patient consent.  
 
William H. Theodore, MD is  board-certified in Internal Medicine, Neurology, and 
Clinical Neurophysiology, and has extensive experience in clinical research. He 
will serve as the lead associate investigator, and will be obtaining informed 
patient consent and will participate in study procedures and data analysis. 
 
Dr Philip Pearl, MD is a board-certified pediatric neurologist with extensive 
experience in the treatment of pediatric seizure disorders and SSADH deficiency 

 
 
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and is credentialed at NIH.  He will be participating in study procedures. 
 
Drs John Schreiber, MD is a board-certified neurologist and pediatrician.  He will 
participate in patient evaluation and data analysis and will be obtaining informed 
consent. 
 
Dr Eric Wassermann, MD is a neurologist with extensive experience in 
neurophysiological and behavioral research. He will not be obtaining informed 
patient consent. He will supervise TMS. 
 
Rosemarie Cuento, CRNP has twelve years of experience in the evaluation and 
treatment of patients in the clinical research setting.  Ms. Cuento will participate 
in patient care.  She will obtain informed consent. 
 
Dr. Edythe Wiggs, PhD is the NINDS clinical neuropsychologist who will perform 
neuropsychological evaluations. She will not be obtaining informed patient 
consent. 
 
Dr. K. Michael Gibson, PhD has extensive experience in heritable disorders of 
human metabolism.  Patients with heritable SSADH deficiency have been a focus 
of the Gibson laboratory for more than 25 years. He will not be obtaining 
informed patient consent. He will perform CSF analyses. 
 
Gina Norato is a statistician with extensive experience in clinical trials.  She will 
perform data analysis.  She will not obtain consent.  
 
 
12. ANTICIPATED BENEFIT 
 
The clinical trial has the prospect of direct benefit to the patients with SSADH 
deficiency since the patients may show improvement on neuropsychological 
testing in the areas of attention, reaction time, visual information, and working 
memory during treatment with SGS-742. 
 
The clinical trial is likely to result in generalized knowledge about the effect of 
GABAB antagonists on cerebral function, thereby possibly leading to new 
diagnostic and/or treatment options for individuals with other disorders as well as 
SSADH deficiency, especially neurometabolic disorders featuring epilepsy.  
 
 
13. CLASSIFICATION OF RISK (FOR THE STUDY AS A WHOLE) 
 
For adults the study is more than minimal risk due to the paired pulse TMS. 
 

 
 
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For Adults without consent capacity the study is research involving a minor 
increment over minimal risk due to the paired pulse TMS presenting the prospect 
of direct benefit to the individual  
 
For Children the study is 45CFR46.405 Research involving greater than minimal 
risk but not more than a minor increment over minimal risk, due to the paired 
pulse TMS but presenting the prospect of direct benefit to the individual child 
 
Overall risk and benefit consideration 
The risks are reasonable in relation to anticipated benefit 
 
 
14. CONSENT DOCUMENTS AND PROCESS 
 
Study investigators designated as able to obtain consent in section 11.6 above, 
will obtain informed consent. Each subject will receive an oral and written 
explanation of the purposes, procedures, and risks of this study in a language 
appropriate for the individual’s level of understanding.  A copy of the signed 
consent form will be placed in the medical record, and a copy will be given to 
each study participant.  A member of the protocol team will be available to 
answer questions about the study to be performed. Assent will be obtained from 
minor subjects age 8 and older, when possible, and adults found not capable of 
giving informed consent.  
 
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 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. 

 
 
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The consent form contains all required elements 
 
The consent documents submitted with this protocol include adult patient or 
parent consent, as well as adult and minor assent forms. 
 
2-Parent Consent Procedures: 
If the parents are married, written consent may be obtained from one parent only.  
If the parents are not married, written consent will be obtained from: 1) the 
custodial parent if only one parent has legal custody, or 2) from both parents if 
they share legal custody for medical decision-making. For unmarried parents, 
signature of one parent will suffice if the other parent is deceased, unknown, 
incompetent, or not reasonably available. When signature of both parents is 
required, written consent will be obtained in-person from at least one parent. 
When the second parent is unable to attend the consent process conference in 
person, the following telephone process to obtain written consent will be used.   
 
Telephone Consent Procedures: The unavailable parent will be provided with a 
copy of the consent form, usually by fax, email, or hard copy mail.  Once the 
consent form is received, an Investigator authorized to obtain consent will 
arrange for a telephone call with the parent in the presence of a witness to review 
study and the consent form and to answer any questions. If the parent cannot 
arrange for a witness in his/her location, the consenting investigator will have a 
witness present for the teleconference at NIH.  Once the parent agrees to his/her 
child’s participation, the parent and witness (if present with the parent) will sign 
and date their copy of the consent form. The Investigator will enter a note 
documenting the consent process in the Medical Record. The 2nd parent will 
return their signed copy to the Investigator. Once the copy with the parent 
signature is received, the Investigator and witness (if present at NIH) will sign 
and date the 2nd parent consent form, place the original copy with all signatures 
in the Medical Record, retain a copy for research records, and mail a copy to the 
parent.   
Capacity Assessment: 
ADULT SUBJECTS 
 
 
Adult subjects in this protocol will be evaluated by HSPU/ACAT to 
determine, based on a protocol specific capacity assessment, if the subject has 
capacity to give informed consent. In all cases involving a guardian or an outside 
DPA (Durable Power of Attorney), the investigator will have the NIH legal 
department review the guardianship or DPA papers for authorization of research 
prior to consenting process. 
 
1) If HSPU/ACAT determines that the subject has capacity, informed consent 
will be obtained by a designated investigator with consent monitoring by 
HSPU.  
 

 
 
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2) If HSPU/ACAT determines that the subject lacks capacity to give informed 
consent, and has a legal guardian, the HSPU will conduct an assessment 
of surrogate understanding. Once understanding by the subject’s legal 
guardian has been established, an investigator will obtain informed 
consent from the subject’s legal guardian and HSPU will monitor the 
consent/assent process.   
 
3) If HSPU determines that the subject lacks consent capacity and there is 
no legal guardian, the PI has 3 options: 
 
A. If HSPU determines that the subject lacks capacity to provide 
informed consent, and if the subject has a Durable Power of 
Attorney (DPA) for health care, this DPA may be invoked by the 
medically responsible investigator or an investigator with 
credentials to obtain informed consent under this protocol. 
HSPU will conduct an assessment of surrogate understanding. 
Once understanding by the DPA has been established, the 
designated investigator will obtain informed consent from this 
DPA with HSPU monitoring the consent/assent process. 
 
B. If HSPU determines that the subject lacks capacity to give 
informed consent and has no guardian or DPA, HSPU will 
determine if the subject understands the meaning and intent to 
assign an NIH DPA.  The NIH DPA will be invoked by the 
medically responsible investigator or by an investigator with 
credentials to obtain informed consent under this protocol. 
HSPU will perform an Assessment of Surrogate Understanding. 
An investigator will then obtain informed consent from the NIH 
DPA, and assent from the subject, with HSPU monitoring the 
process.  
 
C. If HSPU determines that the subject lacks capacity to give 
consent, the subject does not have a guardian or DPA and is 
unable to appoint an NIH DPA, then a Next of Kin surrogate 
may be appointed as outlined in MAS 87-4.  ACAT will perform 
an Assessment of Surrogate Understanding. An investigator will 
obtain consent from the surrogate and assent from the subject 
with HSPU monitoring the process. 
 
 
15. DATA AND SAFETY MONITORING 
15.1 Study Monitor 
 
This protocol will utilize a Safety Monitoring Committee (SMC) to review AEs and 
safety reports.  The Safety Monitoring Committee will be composed of: 

 
 
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Dr. Codrin Lungu is the Program Director of the Division of Clinical Research, 
NINDS. He is a board-Certified neurologist with extensive clinical trial 
experience. Dr. Lauren Bowen is a board-certified neurologist and a member of 
Dr. Avindra Nath’s research section at NIH. She has extensive neurology 
experience.  
 
The monitoring plan will include SMC review once six subjects have completed 
the treatment phase (Period 1 and Period 2) of the study. Thereafter, the SMC 
will review safety data, including seizure frequency, toxicity reports, 
neuropsychological and mood testing, laboratory tests, EEG, ECG and clinical 
examination once per year 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.  
 
15.2 Criteria for stopping the study 
 
New enrollment will be halted 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 there is evidence of Grade 3 toxicity on 
the NCI CTC.   
 
 
16. QUALITY ASSURANCE 
 
The purpose of  QA monitoring is to assess compliance with applicable 
regulatory requirements and good clinical practice guidelines, as well as to 
provide recommendations for improving the management of clinical research 
data over the life-cycle of the protocol. The protocol will be monitored according 
to the NINDS Monitoring SOP. 
 
 
A Contract Research Organization (CRO) will provide on-site monitoring of this 
protocol.  The study team and the monitor will determine the frequency of 
monitoring visits which will be described in the QA Monitoring Plan.  The 
frequency of visits will include, at a minimum, annual interim monitoring visits 
until the protocol has undergone a close-out visit, unless otherwise indicated by 
the Sponsor.  The sponsor via the CRO, will be responsible for providing 
adequate oversight of the investigation to ensure adequate protection of the 
rights, welfare, and safety of human subjects and the quality and integrity of the 
resulting data. 
 
 

 
 
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17. 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 iRIS. 
 
It is anticipated that participants in this study will occasionally miss or fail to 
complete an assessment or procedure, such as a completion of a rating scale or 
a blood draw, or fail to complete a procedure or visit within protocol-specified 
time frames.  Omissions such as these will be considered expected events and 
not protocol deviations provided they are infrequent and do not include data 
needed to assess safety or the primary study outcome.  Cumulative proportions 
of these missed events in the study population will be presented to the IRB 
annually. In addition, the rate of omissions will be monitored by the Investigators. 
If an individual misses more than 15% of the required assessments/procedures 
or if more than 15% of the participants miss completion of the same assessment 
or procedure, it will be considered a deviation and a deviation report will be sent 
to the IRB within two weeks.  
 
If the total number of expected items (study visits, study 
assessments/procedures) is less than 16, then two or more missed items are 
reportable. If the total number of expected items is greater than 16, then, if more 
than 15% are missed, it is reportable. 
 
 
All adverse events, deviations, and unanticipated problems will be summarized 
and reported at the time of Continuing Review. 
 
Seizures are a clinical feature of SSADH and an expected event for this 
population.  This patient population may experience seizures and resulting 
emergency room visits and/or hospitalization.  We will record these events 
including the resulting emergency room visits and/or hospitalization as part of the 
adverse events reported at the time of continuing review.  Reporting of seizures 

 
 
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and emergency-related treatment at the time of the CR is limited to emergency 
related seizure treatment only and all other SAEs will be reported immediately.   
 
The ISSM will serve as the IND sponsor’s medical monitor and will make final 
determination of relatedness of safety events to the investigational product on 
behalf of the sponsor (NINDS). The PI will immediately (no later than 48hrs) 
report SAEs that are at least temporally associated with the use of the study drug 
to the ISSM 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 
ISSM at the time of 1) IRB continuing review and 2) the annual Safety Monitoring 
Committee’s annual meeting.  The PI will send the AE log to the IRB with the 
next continuing review.  
 
18. ALTERNATIVES TO PARTICIPATION  
 
There is no current proven or approved therapy for SSADH deficiency.  There is 
no other way to obtain SGS-742.   
 
 
19. PRIVACY 
 
All research activities will be conducted in as private a setting as possible. 
 
 
20.  CONFIDENTIALITY 
 
a. For Medical Records 
All medical records are property of the Clinical Center and maintained in secured 
files by the Clinical Center.  The Section staff does not release any information to 
the patient or others involved in the patients care without the patient signing a 
release form.  Only the medical records staff of the Clinical Center has authority 
to release documents. 
 
b. For Research Data 
Samples and data will be stored using codes that we assign. Data will be kept in 
password-protected computers.  Coded samples will be in locked storage at 
WSU. The key to the code will be kept at NIH.  
 
Hard copy data/records with identifiers with be maintained under double lock, in a 
locked cabinet in a room that is locked when unoccupied.  Electronic data with 
identifiers will be maintained in password protected files on secured servers. 
 
Only study investigators, study sponsors, and study monitors will have access to 
the samples and data.   
 
De-identified results from clinical trials will be posted on cctrials.gov 

 
 
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c.  Special precautions  
None 
 
 
21. CONFLICT OF INTEREST 
 
21.1 Distribution of NIH Guidelines 
 
NIH guidelines on conflict of interest have been distributed to all investigators.   
 
21.2 Conflict of interest  
 
There are no conflicts-of-interest to report for NIH investigators.  Non-NIH 
investigators will abide by the conflict-of-interest policies of their own institutions. 
 
21.3 Role of a commercial company  
 
NIH will purchase SGS-742 from IRIX Pharmaceuticals, using funds provided by 
the Pediatric Neurotransmitter Disease Association and a bench-to-Bedside 
grant. IRIX has no further interest in the study and will have no further 
participation.  All rights to use SGS-742 for the study have been transferred to 
NIH by the original IND holder. 
 
 
22. TECHNOLOGY TRANSFER 
 
A material transfer agreement has been established with Dr K Michael Gibson of 
Washington State University for CSF analysis. 
 
 
23. 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. 
 
Travel for an escort will be provided. 
 
 
24. REFERENCES.   
 

 
 
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in mice deficient for succinate semiadlehyde dehydrogenase.  J Neurochem; 81: 
71-79. 
 
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DS and Krystal JH (2001) Reductions in occipital cortex GABA levels in panic 
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dehydrogenase deficiency.  Ann Neurol 54 Suppl 6:S66-72.   
 
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excretion of gamma-hydroxybutyric acid in a patient with neurological 
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deficient mouse brain.  Program No. 431.15.  Abstract Viewer/Itinerary Planner.  
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promoting Pathway to Exert Its Sedative Effects. Anesthesiology 98: 428–36 
 
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Metabolic Bases of Inherited Disease.  Scriver CR et al, editors.  Online: 
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25. ATTACHMENTS/ APPENDICES 
 
1. Eligibility checklist 
2. Study Calendar 
3. NCI common terminology/toxicity table  
4. Case report forms (CRFs) 

 
 
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5. Symptom/side effect questionnaire 
6. Investigator’s Brochure 
7.  WSU recruitment letter (no longer in use) 
 
26. CONSENT FORMS 
 
a. Adult or parent consent 
b. Single patient consent 
c. Child assent 8 – 11 
d. Child assent 12 – 17  
e. Adult Assent