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

NCT02019667 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14003314-N-0033
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 2

Brief Summary

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. 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.

Conditions

Metabolic Disease; Seizures

Keywords

GABA; Seizures; Neurotransmitters

Outcome Measures

Primary Outcomes (1)

• Change From Baseline on the Adaptive Behavior Assessment System (ABAS) Test at the End of the Study Drug and Placebo Treatment Periods

  The ABAS questionnaire was completed by the participant's parent or caregiver at the end of each six month treatment period.The ABAS provides a comprehensive picture of adaptive skills across the lifespan. The questionnaire addresses Conceptual, Social and Practical skills including communication, self-direction, use of leisure time, health, safety and self-care. The General Adaptive Composite score ranges from \<40 to \>160 with a lower score representing lower adaptive behavior. The difference between Placebo and Baseline and Study Drug and Baseline were obtained. These values were averaged across individuals to report a mean and a standard deviation of the baseline-to-treatment period change. The means for each treatment can be compared to have a baseline-adjusted treatment effect interpretation. A positive change represents an improvement in adaptive skills compared with baseline and a negative change represents a decline in adaptive skills compared with baseline.

  baseline and six months

Secondary Outcomes (5)

• Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods

  Baseline and Six months

• Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods

  Baseline and Six months

• Change From Baseline of TMS Measurement of Short Interval Intracortical Inhibition (Short ICI) at the End of the Study Drug and Placebo Treatment Periods

  Baseline and Six months

• Change From Baseline of TMS Measurement of Long Interval Intracortical Inhibition (Long ICI) at the End of the Study Drug and Placebo Treatment Periods

  Baseline and Six months

• Results of Physical Examination at the End of the Study Drug and Placebo Treatment Periods

  Six months

Study Arms (2)

Placebo

EXPERIMENTAL

Participants with SSADH Deficiency when on placebo for six months

Drug: Placebo

Study Drug

EXPERIMENTAL

Participants with SSADH Deficiency receiving SGS-742 when on study drug for six months

Drug: SGS-742

Interventions

SGS-742 DRUG

Study Drug

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 4 years or older
• 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 , attention deficit, anxiety, obsessivecompulsive disorder, and autistic traits
• 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.

You may not qualify if:

• Current alcohol use (\>14 drinks/wk in men and \>7 drinks/wk in women or or recreational drug use
• Contraindications to MRI: metal in the body including pacemakers, medication pumps, aneurysm clips, metallic prostheses (including metal pins and rods, heart valves or cochlear implants), shrapnel fragments, permanent eye liner or small metal fragments in the eye that welders and other metal workers may have
• Claustrophobia
• Cannot lie comfortably flat on the back for up to 2h in the MRI scanner
• 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.
• Patients requiring treatment with drugs known to affect the GABAergic system, including vigabatrin and benzodiazepines.
• Pregnant and lactating women

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (2)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Washington State University

Pullman, Washington, United States

Location

Related Publications (4)

• Al-Essa MA, Bakheet SM, Patay ZJ, Powe JE, Ozand PT. Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography (FDG PET), MRI of the brain and biochemical observations in a patient with 4-hydroxybutyric aciduria; a progressive neurometabolic disease. Brain Dev. 2000 Mar;22(2):127-31. doi: 10.1016/s0387-7604(99)00121-7.

  PMID: 10722966 BACKGROUND

• Arnold S, Berthele A, Drzezga A, Tolle TR, Weis S, Werhahn KJ, Henkel A, Yousry TA, Winkler PA, Bartenstein P, Noachtar S. Reduction of benzodiazepine receptor binding is related to the seizure onset zone in extratemporal focal cortical dysplasia. Epilepsia. 2000 Jul;41(7):818-24. doi: 10.1111/j.1528-1157.2000.tb00248.x.

  PMID: 10897152 BACKGROUND

• Arnulf I, Konofal E, Gibson KM, Rabier D, Beauvais P, Derenne JP, Philippe A. Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep. Sleep. 2005 Apr;28(4):418-24. doi: 10.1093/sleep/28.4.418.

  PMID: 16171286 BACKGROUND

• Schreiber JM, Wiggs E, Cuento R, Norato G, Dustin IH, Rolinski R, Austermuehle A, Zhou X, Inati SK, Gibson KM, Pearl PL, Theodore WH. A Randomized Controlled Trial of SGS-742, a gamma-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency. J Child Neurol. 2021 Nov;36(13-14):1189-1199. doi: 10.1177/08830738211012804. Epub 2021 May 20.

  PMID: 34015244 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Metabolic Diseases; Seizures

Interventions

(3-aminopropyl)(n-butyl)phosphinic acid

Condition Hierarchy (Ancestors)

Nutritional and Metabolic Diseases; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. William Theodore
• Organization: National Institutes of Health

theodorw@ninds.nih.gov

301-496-1505

Study Officials

• Sara K Inati, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2013
• First Posted: December 24, 2013
• Study Start: March 31, 2014
• Primary Completion: January 31, 2019
• Study Completion: April 3, 2019
• Last Updated: February 24, 2020
• Results First Posted: February 24, 2020

Record last verified: 2018-10

Locations

US (2)