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

Metabolic Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02019667
• Other study ID #: 140033
• Secondary ID: 14-N-0033
• Status: Completed
• Phase: Phase 2
• Start date: March 31, 2014
• Est. completion date: April 3, 2019

Study information

• Verified date: October 2018
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: April 3, 2019
• Est. primary completion date: January 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

• 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

Related Conditions & MeSH terms

• Metabolic Disease
• Metabolic Diseases
• Seizures

Intervention

Drug:
• SGS-742

• Placebo

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods	Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at a sufficient intensity to trigger action potentials in nearby neurons. The motor threshold is defined as the minimum percentage of the stimulator output that evoked a motor evoked potential of more than 50µV in at least 5 out of 10 trials. Motor threshold was measured at the end of the study drug period and the end of the Placebo period. The differences between Placebo and Baseline, and SGS and Baseline were obtained. A decrease from baseline value indicates increased cortical excitability and an increase from baseline value indicates reduced cortical excitability. These values were averaged across individuals to report a mean and standard deviation of this baseline-to-treatment period change. The mean for each treatment can be compared to have a baseline-adjusted treatment effect.	Baseline and Six months
Secondary	Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods	Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at a sufficient intensity to trigger action potentials in nearby neurons. Intracortical facilitation (ICF) and inhibition (ICI) were studied using a paired stimulus paradigm. The motor threshold (MT) was first established. The conditioning stimulus (70% MT) followed by the test stimulus (120% MT) was delivered at an interstimulus interval (ISI) of 10 ms for ICF. Each run consisted of 10 trials, and the amplitude ratio of the mean conditioned Motor Evoked Potential (MEP) to control MEP was determined. A larger amplitude ratio indicates greater cortical excitability. The differences between Placebo and Baseline, and SGS and Baseline were obtained. These values were averaged across individuals to report a mean.	Baseline and Six months
Secondary	Change From Baseline of TMS Measurement of Short Interval Intracortical Inhibition (Short ICI) at the End of the Study Drug and Placebo Treatment Periods	Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at a sufficient intensity to trigger action potentials in nearby neurons. Intracortical facilitation and inhibition were studied using a paired stimulus paradigm. The motor threshold (MT) was first established. The conditioning stimulus (70% MT) followed by the test stimulus (120% MT) was delivered at an interstimulus interval (ISI) of 2 ms for short ICI. Each run consisted of 10 trials, and the amplitude ratio of the mean conditioned Motor Evoked Potential (MEP) to control MEP was determined. A larger amplitude ratio indicates greater cortical excitability. The differences between Placebo and Baseline, and SGS and Baseline were obtained. These values were averaged across individuals to report a mean.	Baseline and Six months
Secondary	Change From Baseline of TMS Measurement of Long Interval Intracortical Inhibition (Long ICI) at the End of the Study Drug and Placebo Treatment Periods	Transcranial Magnetic Stimulation (TMS) is a non-invasive technique which applies magnetic pulses to the brain via a coil inducing an electrical current in the brain. Stimulation is typically applied at a sufficient intensity to trigger action potentials in nearby neurons.Intracortical facilitation and inhibition were studied using a paired stimulus paradigm. The motor threshold (MT) was first established. The conditioning stimulus (70% MT) followed by the test stimulus (120% MT) was delivered at 100 ms for long ICI. Each run consisted of 10 trials, and the amplitude ratio of the mean conditioned Motor Evoked Potential (MEP) to control MEP was determined. A larger amplitude ratio indicates greater cortical excitability. The differences between Placebo and Baseline, and SGS and Baseline were obtained. These values were averaged across individuals to report a mean.	Baseline and Six months
Secondary	Results of Physical Examination at the End of the Study Drug and Placebo Treatment Periods	A physical examination was administered by a physician to subjects at the end of each six month treatment period, i.e., following completion of a six month period on SGS-742 or Placebo. Results of the examination ranged from 0-4 with scores defined as follows: 0=No observation; 1=Stable baseline findings; 2=New asymptomatic finding; 3=Patient reports some worsening of a baseline daily function associated with new finding; 4=Patient unable to carry out a baseline daily function associated with new finding	Six months

External Links

•   NIH Clinical Center Detailed Web Page