Trial Outcomes & Findings for Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1) (NCT NCT04846868)

Last Updated: 2025-11-05

Results Overview

MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The larger the MCCB overall composite T-score, the better patient cognition. A mean T-score of 50 and a standard deviation of 10 reflects the general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on on-treatment periods. On-treatment is defined as the period of first drug administration/first resumed dose after interruption until last drug administration + REP (residual effect period). The change from baseline was analyzed with a MMRM (mixed-effects model for repeated measures) with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was the repeated measure.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

620 participants

Primary outcome timeframe

MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Results posted on

2025-11-05

Participant Flow

Randomized, placebo-controlled, double-blind, multicenter, multinational, 26-week, parallel group trial. Patients could roll-over to safety follow-up extension trial (study 1346-0014). A dedicated ocular sub-study was implemented in several countries participating in the trial to investigate the ocular safety of iclepertin in patients with schizophrenia.

All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	Iclepertin 10 mg Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.	Placebo-matching Iclepertin 10 mg Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.
Overall Study STARTED	312	308
Overall Study Treated	312	307
Overall Study Ocular safety sub-study	26	22
Overall Study COMPLETED	266	273
Overall Study NOT COMPLETED	46	35

Reasons for withdrawal

Reasons for withdrawal
Measure	Iclepertin 10 mg Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.	Placebo-matching Iclepertin 10 mg Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.
Overall Study Adverse Event	12	11
Overall Study Protocol deviation	6	2
Overall Study Perceived lack of efficacy	3	2
Overall Study Change of residence	2	3
Overall Study Burden of study procedures	1	1
Overall Study No reason available	2	5
Overall Study Other reason listed	20	10
Overall Study Not treated	0	1

Baseline Characteristics

Clinical Trial of Iclepertin Effect on Cognition and Functional Capacity in Schizophrenia (CONNEX-1)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Iclepertin 10 mg n=312 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.	Placebo-matching Iclepertin 10 mg n=307 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Total n=619 Participants Total of all reporting groups
Age, Continuous	34.5 Years STANDARD_DEVIATION 9.0 • n=15 Participants	33.8 Years STANDARD_DEVIATION 8.8 • n=161 Participants	34.2 Years STANDARD_DEVIATION 8.9 • n=100 Participants
Sex: Female, Male Female	107 Participants n=15 Participants	104 Participants n=161 Participants	211 Participants n=100 Participants
Sex: Female, Male Male	205 Participants n=15 Participants	203 Participants n=161 Participants	408 Participants n=100 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	123 Participants n=15 Participants	123 Participants n=161 Participants	246 Participants n=100 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	189 Participants n=15 Participants	184 Participants n=161 Participants	373 Participants n=100 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=15 Participants	0 Participants n=161 Participants	0 Participants n=100 Participants
Race (NIH/OMB) American Indian or Alaska Native	53 Participants n=15 Participants	63 Participants n=161 Participants	116 Participants n=100 Participants
Race (NIH/OMB) Asian	88 Participants n=15 Participants	97 Participants n=161 Participants	185 Participants n=100 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=15 Participants	0 Participants n=161 Participants	1 Participants n=100 Participants
Race (NIH/OMB) Black or African American	21 Participants n=15 Participants	19 Participants n=161 Participants	40 Participants n=100 Participants
Race (NIH/OMB) White	139 Participants n=15 Participants	122 Participants n=161 Participants	261 Participants n=100 Participants
Race (NIH/OMB) More than one race	10 Participants n=15 Participants	6 Participants n=161 Participants	16 Participants n=100 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=15 Participants	0 Participants n=161 Participants	0 Participants n=100 Participants
MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score	28.6 Units on a scale STANDARD_DEVIATION 13.7 • n=15 Participants	28.8 Units on a scale STANDARD_DEVIATION 14.0 • n=161 Participants	28.7 Units on a scale STANDARD_DEVIATION 13.9 • n=100 Participants

PRIMARY outcome

Timeframe: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=294 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=288 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Change From Baseline in Overall Composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) After 26 Weeks of Treatment	2.22 Units on a scale Standard Error 0.3065	2.283 Units on a scale Standard Error 0.3094

SECONDARY outcome

Timeframe: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The SCoRS is an interview based- assessment tool to evaluate the cognitive function of individuals with schizophrenia that incorporates the input of the patient, the caregiver and the interviewer. It is composed of 20 items on a 7-point Likert scale, ranging from 20 to 140 points, where a higher score indicates a greater cognitive impairment. The estimated treatment effect included the effect of any concomitant therapies and partner change in SCoR assessment for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with mixed-effects model for repeated measures (MMRM) with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=292 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=292 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Key Secondary Endpoint: Change From Baseline in the Schizophrenia Cognition Rating Scale (SCoRS) Interviewer Total Score After 26 Weeks of Treatment	-5.480 Units on a scale Standard Error 0.4140	-5.246 Units on a scale Standard Error 0.4150

SECONDARY outcome

Timeframe: MMRM included measurements at baseline, Week 12, and Week 26. Change from baseline values at Week 26 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The VRFCAT is a computerized assessment measuring the functional capacity of an individual to perform everyday tasks. It generates a composite score based on the amount of time taken to complete the tasks. The lower the VRFCAT T-score, the better patient's functional capacity. A mean T-score of 50 and a standard deviation of 10 reflects the T-score in a general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with MMRM with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=296 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=292 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Key Secondary Endpoint: Change From Baseline to Week 26 in the Adjusted Total Time T-score in the Virtual Reality Functional Capacity Assessment Tool (VRFCAT)	3.652 Units on a scale Standard Error 0.8018	3.108 Units on a scale Standard Error 0.8089

SECONDARY outcome

Timeframe: MMRM included measurements at Visit 1a (Week -2/Week -1), Week 15, and Week 24. Change from Visit 1a values at Week 24 is reported.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) score evaluates how cognitive difficulties impact the daily life of individuals with schizophrenia. It is composed of 28 items on a 5-category Likert scale (1=not at all/not at all hard, 5=very much/very hard), and the total score was derived by calculating the average score of the first 26 items, where higher scores mean a worse patient experience. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline was analyzed with MMRM with the fixed effects: treatment at each visit, stratification factor using the screening MCCB overall composite T-score, and baseline MCCB overall composite T-score at each visit. Visit was treated as the repeated measure.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=292 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=291 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Change From Screening Visit 1a in Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) Total Score at Week 24	-0.305 Units on a scale Standard Error 0.0316	-0.258 Units on a scale Standard Error 0.0317

SECONDARY outcome

Timeframe: At baseline and at Week 26.

Population: Randomized set: all patients randomized into the trial, regardless of whether a patient was treated with trial medication. Patients on an off-treatment period due to temporary treatment discontinuation or early permanent treatment discontinuation were excluded from the analysis of this endpoint according to the strategy to handle intercurrent events defined in the statistical analysis plan. One patient was randomized in error and discontinued from the trial before the start of trial medication.

The Tower of London (ToL) evaluates executive functioning, reasoning, problem-solving, and goal-directed behavior. It measures the number of correct responses in solving an exercise that consists on moving colored balls to match a target configuration. The higher the ToL T-score, the better patient's cognitive function. A mean T-score of 50 and a standard deviation of 10 reflects the T-score in a general population. The estimated treatment effect included the effect of any concomitant therapies for all randomized patients on-treatment. On-treatment is defined as the period of 1st drug administration/1st resumed dose after interruption until last drug administration + REP. The change from baseline comparing the groups was analyzed using analysis of covariance (ANCOVA) model including treatment, stratification factor of screening MCCB overall composite T-score, and baseline number of correct responses on Tower of London T-score.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=279 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=273 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Change From Baseline in the T-score of the Number of Correct Responses on Tower of London at Week 26	0.475 Units on a scale Standard Error 0.6477	1.103 Units on a scale Standard Error 0.6547

SECONDARY outcome

Timeframe: At baseline and at Week 24.

Population: Ocular sub-study set: all treated patients who consented to participate in the ocular sub-study. Only patients with measurements were included in the analysis.

The Humphrey Visual Field 24-2 SITA Standard is a diagnostic test to measure visual fields, or perimetry. The Humphrey visual field test measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. During this test, lights of varying intensities appear in different parts of the visual field while the patient's eye is focused on a central spot. The perception of these lights is charted and then compared to results of a healthy eye at the same age of the patient to determine if any damage has occurred. The tests ranks from 0 to 100%, where 0 means no vision and 100 means perfect vision.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=21 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=23 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Ocular Safety Sub-study: Humphrey Visual Field 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard Left eye - baseline	95.62 Units on a scale Standard Deviation 5.56	93.83 Units on a scale Standard Deviation 8.82
Ocular Safety Sub-study: Humphrey Visual Field 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard Right eye - baseline	95.87 Units on a scale Standard Deviation 5.60	95.87 Units on a scale Standard Deviation 5.60
Ocular Safety Sub-study: Humphrey Visual Field 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard Left eye - Week 24	96.00 Units on a scale Standard Deviation 6.58	94.48 Units on a scale Standard Deviation 10.69
Ocular Safety Sub-study: Humphrey Visual Field 24-2 Swedish Interactive Thresholding Algorithm (SITA) Standard Right eye - Week 24	95.83 Units on a scale Standard Deviation 5.69	95.83 Units on a scale Standard Deviation 5.69

SECONDARY outcome

Timeframe: At baseline and at Week 24.

Population: Ocular sub-study set: all treated patients who consented to participate in the ocular sub-study. Only patients with measurements were included in the analysis.

The central retinal thickness for both eyes was measured by high-definition optical coherence tomography (spectral domain OCT), which evaluates the retinal and sub-retinal structures of both eyes.

Outcome measures

Outcome measures
Measure	Placebo-matching Iclepertin 10 mg n=21 Participants Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.	Iclepertin 10 mg n=25 Participants Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.
Ocular Safety Sub-study: Central Retinal Thickness as Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) Right eye - Week 24	240.49 micrometer Standard Deviation 26.89	235.46 micrometer Standard Deviation 27.81
Ocular Safety Sub-study: Central Retinal Thickness as Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) Left eye - baseline	230.38 micrometer Standard Deviation 26.64	231.52 micrometer Standard Deviation 26.51
Ocular Safety Sub-study: Central Retinal Thickness as Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) Right eye - baseline	235.00 micrometer Standard Deviation 25.45	233.12 micrometer Standard Deviation 31.03
Ocular Safety Sub-study: Central Retinal Thickness as Measured by Spectral Domain Optical Coherence Tomography (SD-OCT) Left eye - Week 24	236.10 micrometer Standard Deviation 25.96	237.67 micrometer Standard Deviation 27.32

Adverse Events

Iclepertin 10 mg

Serious events: 12 serious events

Other events: 81 other events

Deaths: 1 deaths

Placebo-matching Iclepertin 10 mg

Serious events: 16 serious events

Other events: 91 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Iclepertin 10 mg n=312 participants at risk Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.	Placebo-matching Iclepertin 10 mg n=307 participants at risk Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.
Infections and infestations Influenza	2.6% 8/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	5.2% 16/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Infections and infestations Nasopharyngitis	6.7% 21/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	5.2% 16/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Infections and infestations Upper respiratory tract infection	5.1% 16/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	3.6% 11/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Nervous system disorders Headache	7.1% 22/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	8.8% 27/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Insomnia	3.2% 10/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	5.2% 16/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Schizophrenia	5.4% 17/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	7.2% 22/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Iclepertin 10 mg n=312 participants at risk Patients with schizophrenia took orally once a day one 10 milligram (mg) tablet of iclepertin.	Placebo-matching Iclepertin 10 mg n=307 participants at risk Patients with schizophrenia took orally once a day one tablet of placebo-matching iclepertin.
Cardiac disorders Myocardial infarction	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Eye disorders Central serous chorioretinopathy	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Hepatobiliary disorders Liver disorder	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Infections and infestations Pneumonia aspiration	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Injury, poisoning and procedural complications Ankle fracture	0.32% 1/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.00% 0/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Aggression	0.32% 1/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.00% 0/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Depression	0.32% 1/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.00% 0/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Schizophrenia	1.6% 5/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	2.0% 6/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Suicidal ideation	0.64% 2/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	2.0% 6/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Psychiatric disorders Suicide attempt	0.64% 2/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.33% 1/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.
Vascular disorders Hypertensive crisis	0.32% 1/312 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.	0.00% 0/307 • All-cause mortality: From randomization until individual end of study. Up to 246 days. Adverse event reporting: From first drug administration to last drug administration, plus residual effect period OR from first drug administration until first drug administration on the extension trial 1346-0014. Up to 230 days. Treated Set (TS): all patients who signed informed consent and were treated with at least one dose of the trial medication.