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Protocol Title: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency

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Protocol Title: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency 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. 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 [email protected] Sara Inati M.D. OCD NINDS 10/7-5680 301-435-6269 Adjunct Principal Investigator Phillip L. Pearl, M.D Boston 300 Longwood 202- 884-5439 [email protected] Children’s Avenue Hospital, 9th floor Boston, MA Boston, MA 02115 Lead Associate Investigator William H Theodore CES/NINDS 10/7D-43 301-496-1505 [email protected] MD Associate Investigators Rosemarie NINDS CTU 10-CRC [email protected] Cuento CRNP 7-5644 301-451-9284 John CNMC NEUROLOGY [email protected] Schreiber MD Washington DC 202-884-5439 Eric BNU DIR NINDS 10/7D-41 [email protected] Wassermann MD K Michael Professor and Chair) PBS Building [email protected] Gibson PhD WSU College of room 347 Pharmacy 412 E. Spokane Falls Blvd Spokane, WA 99202 Edythe Wiggs, NINDS/DIR/CNP/OCD 10-CRC [email protected] PhD 7-5685 301-451-9285 Gina Norato, NINDS CTU 10/2A23 [email protected] ScM 301-496-4358 Research Contact Rosemarie NINDS CTU 10-CRC [email protected] Cuento CRNP 7-5644 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) CNS IRB Protocol Template (rev 9.21.11) 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 CNS IRB Protocol Template (rev 9.21.11) page 2 of 54 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. CNS IRB Protocol Template (rev 9.21.11) page 3 of 54 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 .......................................................................................................................................
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