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The Effect of N-Acetyl Cysteine on Cortical Erosion in Early Stage Schizophrenia (Breier-Stanley)

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ClinicalTrials.gov Identifier: NCT01339858
Recruitment Status : Completed
First Posted : April 21, 2011
Results First Posted : May 8, 2019
Last Update Posted : May 8, 2019
Sponsor:
Collaborator:
Stanley Medical Research Institute
Information provided by (Responsible Party):
Alan Breier, Indiana University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Care Provider);   Primary Purpose: Treatment
Conditions Schizophrenia
Psychotic Disorder NOS
Schizoaffective Disorder
Schizophreniform
Interventions Drug: N-Acetyl Cysteine
Other: sugar pill
Enrollment 60
Recruitment Details  
Pre-assignment Details  
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description 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.

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.

Period Title: Overall Study
Started 30 30
Completed 14 18
Not Completed 16 12
Arm/Group Title N-Acetyl Cysteine Sugar Pill Total
Hide Arm/Group Description 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.

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 of all reporting groups
Overall Number of Baseline Participants 30 30 60
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
<=18 years
2
   6.7%
1
   3.3%
3
   5.0%
Between 18 and 65 years
28
  93.3%
29
  96.7%
57
  95.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants 30 participants 60 participants
22.2  (4.2) 25.0  (5.2) 23.1  (4.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
Female
7
  23.3%
6
  20.0%
13
  21.7%
Male
23
  76.7%
24
  80.0%
47
  78.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 30 participants 30 participants 60 participants
30 30 60
1.Primary Outcome
Title Cortical Thickness
Hide Description 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
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: mm
Left Total Cortical Thickness at 52 Weeks 2.53  (0.03) 2.54  (0.03)
Right Total Cortical Thickness at 52 weeks 2.51  (0.03) 2.52  (0.03)
Left Caudal Middle Frontal Thickness at 52 Weeks 2.59  (0.04) 2.57  (0.04)
Right Caudal Middle Frontal Thickness at 52 Weeks 2.49  (0.04) 2.49  (0.05)
Left Middle Temporal Thickness at 52 Weeks 2.84  (0.04) 2.87  (0.05)
Right Middle Temporal Thickness at 52 Weeks 2.91  (0.04) 2.95  (0.05)
Left Superior Parietal Thickness at 52 Weeks 2.16  (0.03) 2.21  (0.04)
Right Superior Parietal Thickness at 52 Weeks 2.17  (0.03) 2.18  (0.04)
2.Primary Outcome
Title Cortical Volume
Hide Description We anticipate that 12 months treatment with NAC as an add-on treatment will show a difference in cortical volume than treatment with placebo
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: mm^3
Total Cortical Gray Matter Volume at 52 Weeks 233.0  (5.2) 235.8  (6.0)
Total Cortical White Matter Volume at 52 Weeks 423.8  (11.5) 418.5  (13.1)
3.Secondary Outcome
Title Working Memory
Hide Description 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.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Mean (Standard Deviation)
Unit of Measure: Bold signal change
Baseline pre exposure to NAC 0.299  (.20) 0.356  (.24)
6 months exposure to NAC 0.351  (.24) 0.398  (.28)
12 months exposure to NAC 0.315  (.185) 0.406  (.23)
4.Secondary Outcome
Title Number of Participants With Glutamine/Glutamate Level Changes
Hide Description Identify number of participants with 12 months of NAC treatment who had glutamine/glutamate level changes as measured by cortical magnetic resonance spectroscopy measures.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects were excluded from the MR spectroscopy measures due to visible motion between image acquisitions. Data were not collected for the Placebo group.
Arm/Group Title NAC Treated Early Psychosis Patients Placebo Group
Hide Arm/Group Description:
Longitudinal concentrations of glutamine/glutamate (Glx) levels across three scans for NAC treated patients
[Not Specified]
Overall Number of Participants Analyzed 18 0
Measure Type: Count of Participants
Unit of Measure: Participants
18
 100.0%
0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection NAC Treated Early Psychosis Patients
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
5.Secondary Outcome
Title Attention Measures
Hide Description 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.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: Hz
EEG Alpha power 3.81  (0.40) 4.18  (0.73)
EEG Delta power 2.96  (0.25) 3.46  (0.35)
EEG Gamma power 0.37  (0.03) 0.47  (0.05)
EEG Theta power 1.33  (0.30) 1.33  (0.35)
Auditory Steady State Response 40 Hz 0.05  (0.01) 0.06  (0.01)
6.Secondary Outcome
Title Symptoms of a Psychotic Disorder
Hide Description 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.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
PANSS Total Score at 52 Weeks 46.79  (2.24) 56.44  (2.32)
PANSS Cognitive/Disorganized Factor at 52 Weeks 11.09  (0.68) 13.68  (0.70)
PANSS Negative Symptom Factor at 52 Weeks 10.35  (1.02) 13.22  (1.06)
PANSS Positive Symptom Factor at 52 Weeks 14.77  (1.05) 16.38  (1.09)
7.Secondary Outcome
Title Cognitive Functioning
Hide Description 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.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
BACS Composite Score Baseline 26.91  (3.22) 27.70  (3.35)
BACS Composite Score at 52 Weeks 30.03  (3.22) 29.37  (3.36)
8.Secondary Outcome
Title Functional Status
Hide Description 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.
Time Frame Baseline and 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
PSP Adjusted Score at Baseline 62.51  (2.26) 64.46  (2.35)
PSP Adjusted Score at 52 Weeks 64.51  (2.33) 65.44  (2.42)
9.Secondary Outcome
Title Mismatch Negativity Voltage Differences
Hide Description 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.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: microvolts
-2.51  (0.28) -3.44  (0.38)
10.Secondary Outcome
Title Symptoms of a Psychotic Disorder
Hide Description 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).
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description:
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.

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 Number of Participants Analyzed 30 30
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
2.78  (0.18) 3.00  (0.19)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title N-Acetyl Cysteine Sugar Pill
Hide Arm/Group Description 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.

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.

All-Cause Mortality
N-Acetyl Cysteine Sugar Pill
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
N-Acetyl Cysteine Sugar Pill
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/30 (10.00%)      2/30 (6.67%)    
Psychiatric disorders     
Psychosis Exacerbation  2/30 (6.67%)  2 2/30 (6.67%)  2
Respiratory, thoracic and mediastinal disorders     
Asthma Exacerbation  1/30 (3.33%)  1 0/30 (0.00%)  0
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
N-Acetyl Cysteine Sugar Pill
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   28/30 (93.33%)      27/30 (90.00%)    
Cardiac disorders     
Dyspepsia  2/30 (6.67%)  2 0/30 (0.00%)  0
Gastrointestinal disorders     
Nausea and Vomiting  3/30 (10.00%)  3 5/30 (16.67%)  5
Diarrhea  2/30 (6.67%)  3 0/30 (0.00%)  0
General disorders     
Sedation  2/30 (6.67%)  2 3/30 (10.00%)  3
Insomnia  3/30 (10.00%)  3 2/30 (6.67%)  2
Nasal Congestion  1/30 (3.33%)  1 2/30 (6.67%)  2
Infections and infestations     
Upper Respiratory Infection  2/30 (6.67%)  2 3/30 (10.00%)  3
Metabolism and nutrition disorders     
Weight Gain  3/30 (10.00%)  3 6/30 (20.00%)  6
Hyperlipidemia  0/30 (0.00%)  0 2/30 (6.67%)  2
Musculoskeletal and connective tissue disorders     
Toothache  2/30 (6.67%)  3 0/30 (0.00%)  0
Nervous system disorders     
Headache  3/30 (10.00%)  3 2/30 (6.67%)  2
Dyskinesia  0/30 (0.00%)  0 2/30 (6.67%)  2
Dizziness  2/30 (6.67%)  2 3/30 (10.00%)  4
Psychiatric disorders     
Suicidal Ideation  0/30 (0.00%)  0 2/30 (6.67%)  2
Illness Exacerbation  3/30 (10.00%)  3 0/30 (0.00%)  0
Depressed Mood  4/30 (13.33%)  4 4/30 (13.33%)  5
Skin and subcutaneous tissue disorders     
Rash  2/30 (6.67%)  2 0/30 (0.00%)  0
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Alan Breier
Organization: Indiana University Psychotic Disorders Program
Phone: 317-880-8495
EMail: abreier@iupui.edu
Layout table for additonal information
Responsible Party: Alan Breier, Indiana University
ClinicalTrials.gov Identifier: NCT01339858    
Other Study ID Numbers: 1008-12
First Submitted: April 19, 2011
First Posted: April 21, 2011
Results First Submitted: October 11, 2018
Results First Posted: May 8, 2019
Last Update Posted: May 8, 2019