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

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Study Description

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. 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.

Condition or disease	Intervention/treatment	Phase
Metabolic Disease; Seizures	Drug: SGS-742; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	19 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
Study Start Date :	December 20, 2013
Actual Primary Completion Date :	January 31, 2019
Actual Study Completion Date :	April 3, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: phase II; study drug or placebo (blinded)	Drug: SGS-742; Drug: Placebo
Experimental: phase I for 6 months; Study drug or placebo (blinded) for 6 months	Drug: SGS-742; Drug: Placebo
Experimental: phase I; study drug or placebo (blinded)	Drug: SGS-742; Drug: Placebo
Experimental: phase II crossover; crossover study drug or placebo blinded	Drug: SGS-742; Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Performance on neurological testing and responses to parent questionnaire [ Time Frame: on-going ]

Secondary Outcome Measures :

1. TMS parameters of cortical excitation and inhibition [ Time Frame: on-going ]
2. Clinical examination and neuropsychological tests [ Time Frame: on-going ]

Eligibility Criteria

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Ages Eligible for Study:	4 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA
• Aged 4 years or older
• 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 , 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.

EXCLUSION CRITERIA

• 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

Contacts and Locations

Locations

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Washington
Washington State University
Pullman, Washington, United States

Sponsors and Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

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Principal Investigator:	Sara K Inati, M.D.	National Institute of Neurological Disorders and Stroke (NINDS)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

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.

Arnold S, Berthele A, Drzezga A, Tölle 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.

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.

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Responsible Party:	National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier:	NCT02019667 History of Changes
Other Study ID Numbers:	140033; 14-N-0033
First Posted:	December 24, 2013
Last Update Posted:	April 9, 2019
Last Verified:	October 22, 2018

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):

GABA; Seizures; Neurotransmitters

Additional relevant MeSH terms:

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Seizures; Metabolic Diseases; Amino Acid Metabolism, Inborn Errors; Developmental Disabilities; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Neurodevelopmental Disorders	Mental Disorders; (3-aminopropyl)(n-butyl)phosphinic acid; Neuroprotective Agents; Protective Agents; Physiological Effects of Drugs; GABA Antagonists; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action