Trial Outcomes & Findings for The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia (NCT NCT01339858)

NCT ID: NCT01339858

Last Updated: 2019-05-08

Results Overview

We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less cortical erosion as measured by cortical thickness than treatment with placebo

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 60 participants
• Primary outcome timeframe: 12 months
• Results posted on: 2019-05-08

Participant Flow

Participant milestones

Measure	N-Acetyl Cysteine NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Overall Study STARTED	30	30
Overall Study COMPLETED	14	18
Overall Study NOT COMPLETED	16	12

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia

Baseline characteristics by cohort

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.	Total n=60 Participants Total of all reporting groups
Age, Categorical <=18 years	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	28 Participants n=5 Participants	29 Participants n=7 Participants	57 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	22.2 years STANDARD_DEVIATION 4.2 • n=5 Participants	25.0 years STANDARD_DEVIATION 5.2 • n=7 Participants	23.1 years STANDARD_DEVIATION 4.8 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	24 Participants n=7 Participants	47 Participants n=5 Participants
Region of Enrollment United States	30 participants n=5 Participants	30 participants n=7 Participants	60 participants n=5 Participants

PRIMARY outcome

Timeframe: 12 months

We anticipate that 12 months treatment with NAC as an add-on treatment will show significantly less cortical erosion as measured by cortical thickness than treatment with placebo

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Cortical Thickness Left Total Cortical Thickness at 52 Weeks	2.53 mm Standard Error 0.03	2.54 mm Standard Error 0.03
Cortical Thickness Right Total Cortical Thickness at 52 weeks	2.51 mm Standard Error 0.03	2.52 mm Standard Error 0.03
Cortical Thickness Left Caudal Middle Frontal Thickness at 52 Weeks	2.59 mm Standard Error 0.04	2.57 mm Standard Error 0.04
Cortical Thickness Right Caudal Middle Frontal Thickness at 52 Weeks	2.49 mm Standard Error 0.04	2.49 mm Standard Error 0.05
Cortical Thickness Left Middle Temporal Thickness at 52 Weeks	2.84 mm Standard Error 0.04	2.87 mm Standard Error 0.05
Cortical Thickness Right Middle Temporal Thickness at 52 Weeks	2.91 mm Standard Error 0.04	2.95 mm Standard Error 0.05
Cortical Thickness Left Superior Parietal Thickness at 52 Weeks	2.16 mm Standard Error 0.03	2.21 mm Standard Error 0.04
Cortical Thickness Right Superior Parietal Thickness at 52 Weeks	2.17 mm Standard Error 0.03	2.18 mm Standard Error 0.04

PRIMARY outcome

Timeframe: 12 months

We anticipate that 12 months treatment with NAC as an add-on treatment will show a difference in cortical volume than treatment with placebo

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Cortical Volume Total Cortical Gray Matter Volume at 52 Weeks	233.0 mm^3 Standard Error 5.2	235.8 mm^3 Standard Error 6.0
Cortical Volume Total Cortical White Matter Volume at 52 Weeks	423.8 mm^3 Standard Error 11.5	418.5 mm^3 Standard Error 13.1

SECONDARY outcome

Timeframe: Baseline and 12 months

determine if 12 months of NAC add-on treatment is superior to placebo as determined by brain activity during n-back working memory task during fMRI.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Working Memory Baseline pre exposure to NAC	0.299 Bold signal change Standard Deviation .20	0.356 Bold signal change Standard Deviation .24
Working Memory 6 months exposure to NAC	0.351 Bold signal change Standard Deviation .24	0.398 Bold signal change Standard Deviation .28
Working Memory 12 months exposure to NAC	0.315 Bold signal change Standard Deviation .185	0.406 Bold signal change Standard Deviation .23

SECONDARY outcome

Timeframe: 12 months

Population: Several subjects were excluded from the MR spectroscopy measures due to visible motion between image acquisitions. Data were not collected for the Placebo group.

Identify number of participants with 12 months of NAC treatment who had glutamine/glutamate level changes as measured by cortical magnetic resonance spectroscopy measures.

Outcome measures

Measure	N-Acetyl Cysteine n=18 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Number of Participants With Glutamine/Glutamate Level Changes	18 Participants	0 Participants

SECONDARY outcome

Timeframe: 12 months

determine if 12 months of NAC add-on treatment is superior to placebo for attention measures (e.g., mismatch negativity, P300) as measured by electrophysiology methods. Electrophysiology measures will be recorded from a 64 channel, silver/silver-chloride scalp electrode montage.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Attention Measures EEG Alpha power	3.81 Hz Standard Error 0.40	4.18 Hz Standard Error 0.73
Attention Measures EEG Delta power	2.96 Hz Standard Error 0.25	3.46 Hz Standard Error 0.35
Attention Measures EEG Gamma power	0.37 Hz Standard Error 0.03	0.47 Hz Standard Error 0.05
Attention Measures EEG Theta power	1.33 Hz Standard Error 0.30	1.33 Hz Standard Error 0.35
Attention Measures Auditory Steady State Response 40 Hz	0.05 Hz Standard Error 0.01	0.06 Hz Standard Error 0.01

SECONDARY outcome

Timeframe: 12 months

Determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Positive and Negative Syndrome Scale (PANSS). The PANSS is a semi-structured interview, containing 30 items that assess positive, negative, and general psychopathology symptoms. Positive symptoms=7 items, negative symptoms=7 items, and general psych.=16 items. Scores for each item range from 1-absent to 7-extreme. To calculate total score, all items on the scale are summed to yield a score from 30-210,a lower score reflecting fewer symptoms. To calculate factor scores various items from positive, negative, and general psych. are summed together to yield Cognitive/Disorganized, Negative, and Positive factor scores. Cog/Disorg factor scores sum 7 items, ranging from 7-49. Neg factor scores sum 7 items, ranging from 7-49. Pos factor scores sum 8 items, ranging from 8-56. For all factor scores a lower score reflects less symptom severity.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Symptoms of a Psychotic Disorder PANSS Negative Symptom Factor at 52 Weeks	10.35 scores on a scale Standard Error 1.02	13.22 scores on a scale Standard Error 1.06
Symptoms of a Psychotic Disorder PANSS Positive Symptom Factor at 52 Weeks	14.77 scores on a scale Standard Error 1.05	16.38 scores on a scale Standard Error 1.09
Symptoms of a Psychotic Disorder PANSS Total Score at 52 Weeks	46.79 scores on a scale Standard Error 2.24	56.44 scores on a scale Standard Error 2.32
Symptoms of a Psychotic Disorder PANSS Cognitive/Disorganized Factor at 52 Weeks	11.09 scores on a scale Standard Error 0.68	13.68 scores on a scale Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline and 12 months

determine if 12 months of NAC add-on treatment is superior to placebo for cognitive functioning as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). The BACS is a battery specifically designed to measure treatment-related changes in cognition by utilizing 6 tasks, and has alternate forms, thus minimizing practice effects. Each task generates a raw score (with a higher score indicating better performance): verbal memory 0-75; digit sequencing 0-28; token motor task 0-100; semantic&letter fluency 0-148; symbol coding 0-110; and tower of London 0-22. The raw scores are used to generate a composite score that is calculated by summing t-scores derived by comparisons with a normative sample of 404 healthy controls. The six brief assessments' t-scores, are summed, and averaged to provide a composite t-score. The composite score min and max are between -43 and 100. A higher score indicating better cognitive performance.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Cognitive Functioning BACS Composite Score Baseline	26.91 scores on a scale Standard Error 3.22	27.70 scores on a scale Standard Error 3.35
Cognitive Functioning BACS Composite Score at 52 Weeks	30.03 scores on a scale Standard Error 3.22	29.37 scores on a scale Standard Error 3.36

SECONDARY outcome

Timeframe: Baseline and 12 months

determine if 12 months of NAC add-on treatment is superior to placebo for functional measures as measured by the Personal and Social Performance Scale (PSP). The PSP scale is a 100-point, single item, clinician rated scale to assess 4 domains of functioning, including personal and social relationships, socially useful activities, self care and disturbing and aggressive behaviors. A score from 0-100 is generated, with a higher score representing better performance.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Functional Status PSP Adjusted Score at Baseline	62.51 scores on a scale Standard Error 2.26	64.46 scores on a scale Standard Error 2.35
Functional Status PSP Adjusted Score at 52 Weeks	64.51 scores on a scale Standard Error 2.33	65.44 scores on a scale Standard Error 2.42

SECONDARY outcome

Timeframe: 12 months

Determine if 12 months of NAC add-on treatment is superior to placebo for attention measures as measured by the voltage of the Mismatch Negativity (MMN) of the event-related potential. The voltage of the peak MMN response was measured at the Fz electrode site.

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Mismatch Negativity Voltage Differences	-2.51 microvolts Standard Error 0.28	-3.44 microvolts Standard Error 0.38

SECONDARY outcome

Timeframe: 12 months

determine if 12 months of NAC add-on treatment is superior to placebo for symptom management of a psychotic disorder as assessed by the Clinical Global Impressions Severity Scale (CGI-S). The CGI-S is used for repeated evaluations of global psychopathology and is a 7 point Likert scale rating severity on a scale of 1 (normal, not ill) to 7 (very severely ill).

Outcome measures

Measure	N-Acetyl Cysteine n=30 Participants NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 Participants matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Symptoms of a Psychotic Disorder	2.78 scores on a scale Standard Error 0.18	3.00 scores on a scale Standard Error 0.19

Adverse Events

N-Acetyl Cysteine

Serious events: 3 serious events

Other events: 28 other events

Deaths: 0 deaths

Sugar Pill

Serious events: 2 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Measure	N-Acetyl Cysteine n=30 participants at risk NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 participants at risk matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Respiratory, thoracic and mediastinal disorders Asthma Exacerbation	3.3% 1/30 • Number of events 1	0.00% 0/30
Psychiatric disorders Psychosis Exacerbation	6.7% 2/30 • Number of events 2	6.7% 2/30 • Number of events 2

Other adverse events

Measure	N-Acetyl Cysteine n=30 participants at risk NAC and matched placebo will be supplied in unmarked capsules. Each NAC capsule will contain 600 mg of NAC. Dosing will begin at 600 mg/d and titrated up over 5 weeks until a maximum dose of 3600 mg/d is reached. Dose adjustments downward to 1920 mg/d will be permitted if tolerability issues are encountered at the maximum dose.	Sugar Pill n=30 participants at risk matched placebo sugar pill: matched placebo will be supplied in unmarked capsules. Dosing regimen will be the same as in the N-Acetyl Cysteine arm.
Nervous system disorders Headache	10.0% 3/30 • Number of events 3	6.7% 2/30 • Number of events 2
Psychiatric disorders Suicidal Ideation	0.00% 0/30	6.7% 2/30 • Number of events 2
General disorders Sedation	6.7% 2/30 • Number of events 2	10.0% 3/30 • Number of events 3
General disorders Insomnia	10.0% 3/30 • Number of events 3	6.7% 2/30 • Number of events 2
Psychiatric disorders Illness Exacerbation	10.0% 3/30 • Number of events 3	0.00% 0/30
Psychiatric disorders Depressed Mood	13.3% 4/30 • Number of events 4	13.3% 4/30 • Number of events 5
Nervous system disorders Dyskinesia	0.00% 0/30	6.7% 2/30 • Number of events 2
Nervous system disorders Dizziness	6.7% 2/30 • Number of events 2	10.0% 3/30 • Number of events 4
Skin and subcutaneous tissue disorders Rash	6.7% 2/30 • Number of events 2	0.00% 0/30
Gastrointestinal disorders Nausea and Vomiting	10.0% 3/30 • Number of events 3	16.7% 5/30 • Number of events 5
Gastrointestinal disorders Diarrhea	6.7% 2/30 • Number of events 3	0.00% 0/30
General disorders Nasal Congestion	3.3% 1/30 • Number of events 1	6.7% 2/30 • Number of events 2
Musculoskeletal and connective tissue disorders Toothache	6.7% 2/30 • Number of events 3	0.00% 0/30
Infections and infestations Upper Respiratory Infection	6.7% 2/30 • Number of events 2	10.0% 3/30 • Number of events 3
Metabolism and nutrition disorders Weight Gain	10.0% 3/30 • Number of events 3	20.0% 6/30 • Number of events 6
Metabolism and nutrition disorders Hyperlipidemia	0.00% 0/30	6.7% 2/30 • Number of events 2
Cardiac disorders Dyspepsia	6.7% 2/30 • Number of events 2	0.00% 0/30

Additional Information

Alan Breier

Indiana University Psychotic Disorders Program

Phone: 317-880-8495

Email: abreier@iupui.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place