Clinical trial NCT02019667: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
Official title: Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metabolic Disease
Seizures
Keywords: GABA
Seizures
Neurotransmitters
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2013-12-24
Enrollment: 19
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Change From Baseline on the Adaptive Behavior Assessment System (ABAS) Test at the End of the Study Drug and Placebo Treatment Periods
timeFrame: baseline and six months
Secondary outcomes:
measure: Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods
timeFrame: Baseline and Six months
measure: Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods
timeFrame: Baseline and Six months
measure: Change From Baseline of TMS Measurement of Short Interval Intracortical Inhibition (Short ICI) at the End of the Study Drug and Placebo Treatment Periods
timeFrame: Baseline and Six months
measure: Change From Baseline of TMS Measurement of Long Interval Intracortical Inhibition (Long ICI) at the End of the Study Drug and Placebo Treatment Periods
timeFrame: Baseline and Six months
measure: Results of Physical Examination at the End of the Study Drug and Placebo Treatment Periods
timeFrame: Six months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Pullman
country: United States
facility: Washington State University
state: Washington
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: Sara K Inati, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.