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A Study to Assess Safety and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-1)

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ClinicalTrials.gov Identifier: NCT03697252
Recruitment Status : Completed
First Posted : October 5, 2018
Results First Posted : September 28, 2020
Last Update Posted : October 26, 2020
Sponsor:
Information provided by (Responsible Party):
Karuna Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Schizophrenia
Interventions Drug: Xanomeline and Trospium Chloride Capsules
Drug: Placebo Capsules
Enrollment 182
Recruitment Details The study was conducted in 12 study centers in North America.
Pre-assignment Details A total of 250 participants were screened, 182 were randomized, and 145 participants completed the study.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period. Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Period Title: Overall Study
Started 90 92
Completed 72 73
Not Completed 18 19
Reason Not Completed
Adverse Event             3             2
Withdrawal by Subject             14             14
Lost to Follow-up             0             1
Physician Decision             1             1
Other             0             1
Arm/Group Title KarXT Placebo Total
Hide Arm/Group Description

Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7).

On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks. Total of all reporting groups
Overall Number of Baseline Participants 90 92 182
Hide Baseline Analysis Population Description
The Intent-to-Treat (ITT) population included all participants who were randomized to the study. Participants were analyzed according to randomized treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 90 participants 92 participants 182 participants
43.4  (10.12) 41.6  (10.08) 42.5  (10.11)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 92 participants 182 participants
Female
18
  20.0%
24
  26.1%
42
  23.1%
Male
72
  80.0%
68
  73.9%
140
  76.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 90 participants 92 participants 182 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
2
   2.2%
2
   2.2%
4
   2.2%
Native Hawaiian or Other Pacific Islander
1
   1.1%
1
   1.1%
2
   1.1%
Black or African American
67
  74.4%
70
  76.1%
137
  75.3%
White
20
  22.2%
17
  18.5%
37
  20.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
2
   2.2%
2
   1.1%
1.Primary Outcome
Title Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 5
Hide Description The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants were rated from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 83 87
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-17.40  (1.749) -5.85  (1.668)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KarXT, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -11.56
Confidence Interval (2-Sided) 95%
-16.07 to -7.05
Estimation Comments [Not Specified]
Other Statistical Analysis Statistics are from a mixed model for repeated measures (MMRM). The model includes the treatment group (KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed factors, and baseline PANSS total score, site, age, and gender as covariates. An unstructured covariance matrix is used to model the correlation among repeated measurements and the denominator degrees of freedom are computed using the Kenward-Roger method.
2.Secondary Outcome
Title Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Positive Score at Week 5
Hide Description The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The positive symptoms in schizophrenia are the excess or distortion of normal functions such as hallucinations, delusions, grandiosity, and hostility. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The Modified Intent-to-Treat (MITT) population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 83 87
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-5.62  (0.601) -2.38  (0.573)
3.Secondary Outcome
Title Number of Participants With Each Clinical Global Impression - Severity (CGI-S) Score at Baseline and 5 Weeks
Hide Description The CGI-S modified asked the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 83 87
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline: Score = 1 Number Analyzed 83 participants 87 participants
0
   0.0%
0
   0.0%
Week 5: Score = 1 Number Analyzed 72 participants 73 participants
1
   1.4%
0
   0.0%
Baseline: Score = 2 Number Analyzed 83 participants 87 participants
0
   0.0%
0
   0.0%
Week 5: Score = 2 Number Analyzed 72 participants 73 participants
3
   4.2%
1
   1.4%
Baseline: Score = 3 Number Analyzed 83 participants 87 participants
0
   0.0%
0
   0.0%
Week 5: Score = 3 Number Analyzed 72 participants 73 participants
23
  31.9%
7
   9.6%
Baseline: Score = 4 Number Analyzed 83 participants 87 participants
13
  15.7%
17
  19.5%
Week 5: Score = 4 Number Analyzed 72 participants 73 participants
21
  29.2%
21
  28.8%
Baseline: Score = 5 Number Analyzed 83 participants 87 participants
60
  72.3%
60
  69.0%
Week 5: Score = 5 Number Analyzed 72 participants 73 participants
21
  29.2%
38
  52.1%
Baseline: Score = 6 Number Analyzed 83 participants 87 participants
10
  12.0%
9
  10.3%
Week 5: Score = 6 Number Analyzed 72 participants 73 participants
2
   2.8%
4
   5.5%
Baseline: Score = 7 Number Analyzed 83 participants 87 participants
0
   0.0%
1
   1.1%
Week 5: Score = 7 Number Analyzed 72 participants 73 participants
1
   1.4%
2
   2.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection KarXT, Placebo
Comments Comparison of KarXT and Placebo at Week 5
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Score at Week 5
Hide Description The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. The negative symptoms in schizophrenia are the diminution or loss of normal functions. Participants were rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 83 87
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-3.18  (0.481) -0.90  (0.454)
5.Secondary Outcome
Title Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Factor Score
Hide Description The Marder Negative Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (N1. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance), with a minimum score of 7 and a maximum score of 49.
Time Frame Baseline and Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 83 87
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-3.85  (0.520) -1.32  (0.492)
6.Secondary Outcome
Title Percentage of Participants Who Were Clinical Global Impression - Severity of Illness (CGI-S) Responders
Hide Description The CGI-S modified asks the clinician 1 question: "Considering your total clinical experience, how mentally ill is the participant at this time?" The clinician's answer was rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. A CGI-S responder is defined as a participant with a CGI-S scale equal to 1 or 2.
Time Frame Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population included all participants who were randomized, received at least one dose of study medication, and had a baseline and at least one post-baseline PANSS assessment. Here, the number of participants analyzed indicates participants who were evaluable for this measure at given time points for each group.
Arm/Group Title KarXT Placebo
Hide Arm/Group Description:
Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.
Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
Overall Number of Participants Analyzed 72 73
Measure Type: Number
Unit of Measure: percentage of participants
5.6 1.4
Time Frame From the start of study drug administration up to Week 5
Adverse Event Reporting Description The Safety population included all participants who received at least one dose of study medication.
 
Arm/Group Title KarXT Placebo
Hide Arm/Group Description

Participants received oral Capsule KarXT (xanomeline 125 mg/trospium 30 mg BID) in a treatment period of 5 weeks. Participants were started on a lead in dose of xanomeline 50 mg/trospium 20 mg twice a day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7).

On Day 8, dosing was titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the Participant was continuing to experience adverse events from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All Participants who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, had the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period.

Participants received the matching placebo to KarXT orally twice daily for a treatment period of 5 weeks.
All-Cause Mortality
KarXT Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/89 (0.00%)      0/90 (0.00%)    
Hide Serious Adverse Events
KarXT Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/89 (1.12%)      0/90 (0.00%)    
Psychiatric disorders     
Psychotic disorder * 1  1/89 (1.12%)  1 0/90 (0.00%)  0
1
Term from vocabulary, MedDRA (21.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
KarXT Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   48/89 (53.93%)      39/90 (43.33%)    
Cardiac disorders     
Tachycardia * 1  3/89 (3.37%)  3 2/90 (2.22%)  2
Gastrointestinal disorders     
Constipation * 1  15/89 (16.85%)  16 3/90 (3.33%)  3
Nausea * 1  15/89 (16.85%)  15 4/90 (4.44%)  4
Dry mouth * 1  8/89 (8.99%)  8 1/90 (1.11%)  1
Dyspepsia * 1  8/89 (8.99%)  11 4/90 (4.44%)  4
Vomiting * 1  8/89 (8.99%)  8 4/90 (4.44%)  4
Diarrhoea * 1  2/89 (2.25%)  3 4/90 (4.44%)  4
Investigations     
Weight increased * 1  3/89 (3.37%)  3 4/90 (4.44%)  4
Gamma-Glutamyltransferase increased * 1  2/89 (2.25%)  2 0/90 (0.00%)  0
Metabolism and nutrition disorders     
Decreased appetite * 1  2/89 (2.25%)  2 0/90 (0.00%)  0
Nervous system disorders     
Headache * 1  6/89 (6.74%)  7 5/90 (5.56%)  5
Somnolence * 1  5/89 (5.62%)  5 4/90 (4.44%)  4
Akathisia * 1  3/89 (3.37%)  3 0/90 (0.00%)  0
Dizziness * 1  3/89 (3.37%)  3 3/90 (3.33%)  3
Sedation * 1  2/89 (2.25%)  2 2/90 (2.22%)  2
Psychiatric disorders     
Agitation * 1  2/89 (2.25%)  2 1/90 (1.11%)  1
Insomnia * 1  2/89 (2.25%)  2 2/90 (2.22%)  2
Skin and subcutaneous tissue disorders     
Hyperhidrosis * 1  2/89 (2.25%)  2 1/90 (1.11%)  1
1
Term from vocabulary, MedDRA (21.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Stephen Brannan
Organization: Karuna Therapeutics, Inc.
Phone: 857-449-2234
EMail: sbrannan@karunatx.com
Layout table for additonal information
Responsible Party: Karuna Therapeutics
ClinicalTrials.gov Identifier: NCT03697252    
Other Study ID Numbers: KAR-004
First Submitted: October 3, 2018
First Posted: October 5, 2018
Results First Submitted: September 1, 2020
Results First Posted: September 28, 2020
Last Update Posted: October 26, 2020