NCT02019667

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

Completed Phase 2 Results posted Last updated 24 February 2020

What this trial tests

Phase 2 trial testing SGS-742 in Metabolic Disease in 19 participants. Completed in 3 April 2019.

Timeline

31 March 2014

Primary endpoint
31 January 2019

3 April 2019

Quick facts

Lead sponsor	National Institute of Neurological Disorders and Stroke (NINDS)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	triple
Primary purpose	treatment
Enrollment	19
Start date	31 March 2014
Primary completion	31 January 2019
Estimated completion	3 April 2019
Sites	2 locations across United States

Drugs / interventions tested

• SGS-742 — full drug profile →
• Placebo

Conditions studied

• Metabolic Disease — all drugs for Metabolic Disease →
• Seizures — all drugs for Seizures →

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Who can join

4 and older, any sex, with Metabolic Disease or Seizures. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline on the Adaptive Behavior Assessment System (ABAS) Test at the End of the Study Drug and Placebo Treatment Periods Primary · baseline and six months

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

Group	Value	95% CI
Placebo	5.2	± 7.1
Study Drug	4.5	± 7.5

Change From Baseline of TMS Measurement of Motor Threshold at the End of the Study Drug and Placebo Treatment Periods Secondary · Baseline and Six months

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

Group	Value	95% CI
Placebo	-2	± 7.1
Study Drug	-0.5	± 6.8

Change From Baseline of TMS Measurement of Intracortical Facilitation at the End of the Study Drug and Placebo Treatment Periods Secondary · Baseline and Six months

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, an

Group	Value	95% CI
Placebo	49.9	± 61.9
Study Drug	40.5	± 50.2

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

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 a

Group	Value	95% CI
Placebo	35.5	± 123.4
Study Drug	-11.0	± 54.8

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

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 conditio

Group	Value	95% CI
Placebo	-9.3	± 112.0
Study Drug	0.3	± 98.6

Results of Physical Examination at the End of the Study Drug and Placebo Treatment Periods Secondary · Six months

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

0

Group	Value	95% CI
Placebo	0
Study Drug	0

1

Group	Value	95% CI
Placebo	14
Study Drug	15

2

Group	Value	95% CI
Placebo	4
Study Drug	3

3

Group	Value	95% CI
Placebo	0
Study Drug	0

4

Group	Value	95% CI
Placebo	0
Study Drug	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were collected over a 16-21 month time period which included a 6 month +/- 2 week Phase 1 period, a 9 week +/- 2 week Washout period, a 6 month +/- 2 week Phase 2 period, followed by a 9 week +/- Washout period.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 0/18 (0%)

Deaths: 0/18

Washout Period Following Placebo

Serious: 0/16 (0%)

Deaths: 0/16

Study Drug

Serious: 0/19 (0%)

Deaths: 0/19

Washout Period Following Study Drug

Serious: 0/18 (0%)

Deaths: 0/18

Other adverse events (51 terms — click to expand)

Reaction	System	Placebo	Washout Period Following P…	Study Drug	Washout Period Following S…
Fatigue	General disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Fever	General disorders	—	—	—	—
Irritability	Psychiatric disorders	—	—	—	—
Lethargy	Nervous system disorders	—	—	—	—
Allergic Rhinitis	Ear and labyrinth disorders	—	—	—	—
Anorexia	Metabolism and nutrition disorders	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Hyperactivity	Nervous system disorders	—	—	—	—
Sleepiness	Nervous system disorders	—	—	—	—
Upper Respiratory Infection	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—	—
Abnormal Urinary Analysis results	Renal and urinary disorders	—	—	—	—
Acne	Skin and subcutaneous tissue disorders	—	—	—	—
Agitation	Psychiatric disorders	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—
Anorexia	Gastrointestinal disorders	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Blister	Skin and subcutaneous tissue disorders	—	—	—	—
Blister in the oral cavity	Gastrointestinal disorders	—	—	—	—
Bloating	Gastrointestinal disorders	—	—	—	—
Bruising	Injury, poisoning and procedural complications	—	—	—	—
Concentration Impairment	Nervous system disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Dry Mouth	Gastrointestinal disorders	—	—	—	—
Ear Pain	Ear and labyrinth disorders	—	—	—	—
Flushing	Vascular disorders	—	—	—	—
Head lice	Infections and infestations	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Increased appetite	Gastrointestinal disorders	—	—	—	—
Insomnia	Nervous system disorders	—	—	—	—
Labile	Psychiatric disorders	—	—	—	—
Labile	Infections and infestations	—	—	—	—
Muscle weakness upper limb	Musculoskeletal and connective tissue disorders	—	—	—	—
Nasal congestion	Ear and labyrinth disorders	—	—	—	—

Data from ClinicalTrials.gov NCT02019667 adverse events section.

Sponsor's own 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.

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism.
   Malaspina P, Roullet JB, Pearl PL, Ainslie GR, et al · · 2016 · cited 63× · PMID 27311541 · DOI 10.1016/j.neuint.2016.06.009
2. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies.
   Parviz M, Vogel K, Gibson KM, Pearl PL. · · 2014 · cited 55× · PMID 25485164 · DOI 10.3233/pep-14097
3. Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification.
   Pearl PL, Parviz M, Vogel K, Schreiber J, et al · · 2015 · cited 39× · PMID 25558043 · DOI 10.1111/dmcn.12668
4. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.
   Vogel KR, Ainslie GR, Walters DC, McConnell A, et al · · 2018 · cited 29× · PMID 29460030 · DOI 10.1007/s10545-018-0153-8
5. A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency.
   Schreiber JM, Wiggs E, Cuento R, Norato G, et al · · 2021 · cited 11× · PMID 34015244 · DOI 10.1177/08830738211012804
6. Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue.
   Walters DC, Lawrence R, Kirby T, Ahrendsen JT, et al · · 2021 · cited 10× · PMID 33557678 · DOI 10.1177/0883073820987742
7. Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: Therapeutic implications for SSADH deficiency, a GABA metabolic disorder.
   Vogel KR, Ainslie GR, McConnell A, Roullet JB, et al · · 2018 · cited 9× · PMID 29031482 · DOI 10.1016/j.tiv.2017.10.015
8. Longitudinal metabolomics in dried bloodspots yields profiles informing newborn screening for succinic semialdehyde dehydrogenase deficiency.
   Brown M, Turgeon C, Rinaldo P, Pop A, et al · · 2020 · cited 7× · PMID 32395407 · DOI 10.1002/jmd2.12075