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

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.

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