Trial Outcomes & Findings for A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome (NCT NCT01880437)

Last Updated: 2015-12-15

Results Overview

CR was defined as achieved if the neutrophils count was greater than (\>) 1000 cells per microliter (µL), platelets count \>100000/µL, bone marrow blasts percentage (%) less than (\<) 5, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of extra medullary disease (EMD). CRi was defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils \>1000 cells/µL or Not applicable \[NA\] or platelets count \>100000/µL or NA), bone marrow blasts \<5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA) was defined as bone marrow blasts \<5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR was defined as neutrophils count \>1000 cells/µL, platelets count \>100000/µL, and \>50% decrease from baseline to a range of 5-25% of bone marrow blasts or blasts \<5% with Auer rods.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

38 participants

Primary outcome timeframe

Week 8

Results posted on

2015-12-15

Participant Flow

A total of 47 participants were screened; of which,7 participants failed screening and 2 participants were erroneously entered but did not receive study drug.A total of 38 participants were enrolled and treated. It was planned to enroll 2 cohorts; Cohort 1 (vismodegib) and Cohort 2 (vismodegib + cytarabine).

Based on lower-than-expected efficacy observed in interim data review, study was terminated prior to initiation of Cohort 2. Results are reported as per subgroups of Cohort 1: "Poor Risk Cytogenetics", "FLT-3 Mutation Positive", "Neither Poor Risk Cytogenetics Nor FLT-3", unless otherwise specified.

Participant milestones

Participant milestones
Measure	Poor Risk Cytogenetics Participants with relapsed/refractory acute myeloid leukemia (AML) or relapsed/refractory high-risk myelodysplastic syndrome (MDS) falling under 'poor risk cytogenetics' subgroup received oral 150 milligrams (mg) dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT-3 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Overall Study STARTED	15	4	19
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	15	4	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Poor Risk Cytogenetics Participants with relapsed/refractory acute myeloid leukemia (AML) or relapsed/refractory high-risk myelodysplastic syndrome (MDS) falling under 'poor risk cytogenetics' subgroup received oral 150 milligrams (mg) dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT-3 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Overall Study Death	12	4	17
Overall Study Study terminated by Sponsor	3	0	2

Baseline Characteristics

A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Poor Risk Cytogenetics n=15 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive n=4 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT-3 n=19 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Total n=38 Participants Total of all reporting groups
Age, Continuous	61.5 years STANDARD_DEVIATION 20.7 • n=5 Participants	54.5 years STANDARD_DEVIATION 5.9 • n=7 Participants	66.2 years STANDARD_DEVIATION 14.7 • n=5 Participants	63.1 years STANDARD_DEVIATION 16.9 • n=4 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	2 Participants n=7 Participants	9 Participants n=5 Participants	17 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	2 Participants n=7 Participants	10 Participants n=5 Participants	21 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 8

Population: As the primary efficacy time-point (Week 8) was not reached for all participants due to study termination based on interim data analysis, the analysis of this outcome measure could not be performed, as per planned analysis.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)

Population: Efficacy analysis population included all enrolled participants. Here "number of participants analyzed" included participants who were evaluable for tumor response at anytime during the study.

CR was defined as achieved if the neutrophils count \>1000 cells/µL, platelets count \>100000/µL, bone marrow blasts \<5%, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of EMD. CRi was defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils \> 1000 cells/µL or NA or platelets count \>100000/µL or NA, bone marrow blasts \<5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA) was defined as bone marrow blasts \<5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR was defined as neutrophils count \>1000 cells/µL, platelets count \>100000/µL, and \>50% decrease from baseline to a range of 5-25% of bone marrow blasts or blasts \<5% with Auer rods. The 95% confidence intervals (CI) were constructed using Blyth-Still-Cassella method.

Outcome measures

Outcome measures
Measure	Poor Risk Cytogenetics n=13 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive n=4 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT3 n=16 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment CR	0 percentage of participants Interval 0.0 to 22.51	0 percentage of participants Interval 0.0 to 52.71	0 percentage of participants Interval 0.0 to 19.75
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment CRi	0 percentage of participants Interval 0.0 to 22.51	0 percentage of participants Interval 0.0 to 52.71	6.3 percentage of participants Interval 0.32 to 29.88
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment MLFS	0 percentage of participants Interval 0.0 to 22.51	0 percentage of participants Interval 0.0 to 52.71	0 percentage of participants Interval 0.0 to 19.75
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment PR	0 percentage of participants Interval 0.0 to 22.51	0 percentage of participants Interval 0.0 to 52.71	6.3 percentage of participants Interval 0.32 to 29.88

SECONDARY outcome

Timeframe: Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)

Population: Efficacy population including participants who were considered as responders.

DOR is defined as the time from the first occurrence of a documented overall response to the time of relapse, as determined by the investigator using International Working Group (IWG) criteria (Participants not falling under any of the response criteria \[CR or CRi or MLFS or PR\] described under outcome measure 1 were considered as non-responders) or death from any cause during the study (defined as death within 30 days after the last dose of study drug).

Outcome measures

Outcome measures
Measure	Poor Risk Cytogenetics Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT3 n=2 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Duration of Overall Response (DOR) DOR of participants with CRi (n=0,0,1)	—	—	13 weeks The 95% CI was not estimable as only 1 participant was evaluable.
Duration of Overall Response (DOR) DOR of participants with PR (n=0,0,1)	—	—	6.1 weeks The 95% CI was not estimable as only 1 participant was evaluable.

SECONDARY outcome

Timeframe: Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)

Population: Efficacy analysis population.

OS was defined as the time from start of study drug to death from any cause. OS was estimated using Kaplan-Meier analysis. Participants alive at the last date known to be alive were censored for the analysis.

Outcome measures

Outcome measures
Measure	Poor Risk Cytogenetics n=15 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive n=4 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT3 n=19 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Median Overall Survival (OS) Time	3.38 months Interval 2.37 to 4.83	1.43 months Interval 0.33 to 3.94	3.65 months Interval 1.94 to 5.36

SECONDARY outcome

Timeframe: Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)

Population: Efficacy analysis population.

Outcome measures

Outcome measures
Measure	Poor Risk Cytogenetics n=15 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive n=4 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT3 n=19 Participants Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Percentage of Participants With an Event of Death During the Study	80.0 percentage of participants	100.0 percentage of participants	89.5 percentage of participants

SECONDARY outcome

Timeframe: Predose on Days 8, 29 and 57

Population: As the study was terminated prior to Cohort 2 enrollment, PK analysis could not be performed, as planned.

PK data was planned to be reported only if the results of Cohort 2 are available.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Predose, 0.25, 0.5, 1, 3, 6 hours post-dose on Days 1, 8 and 29

Population: No participants were enrolled as the study was terminated prior to the initiation of Cohort 2.

PK data was planned to be reported only if the results of Cohort 2 are available.

Outcome measures

Outcome data not reported

Adverse Events

Poor Risk Cytogenetics

Serious events: 10 serious events

Other events: 13 other events

Deaths: 0 deaths

FLT-3 Mutation Positive

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Neither Poor Risk Cytogenetics Nor FLT-3

Serious events: 13 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Poor Risk Cytogenetics n=15 participants at risk Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	FLT-3 Mutation Positive n=4 participants at risk Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.	Neither Poor Risk Cytogenetics Nor FLT-3 n=19 participants at risk Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
Blood and lymphatic system disorders Febrile neutropenia	13.3% 2/15 • From screening until study completion or early termination visit (Up to 14 months)	25.0% 1/4 • From screening until study completion or early termination visit (Up to 14 months)	21.1% 4/19 • From screening until study completion or early termination visit (Up to 14 months)
Blood and lymphatic system disorders Thrombocytopenia	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Cardiac disorders Pericardial effusion	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Gastrointestinal disorders Abdominal pain	13.3% 2/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Gastrointestinal disorders Haemorrhoids	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Gastrointestinal disorders Lower gastrointestinal haemorrhage	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Gastrointestinal disorders Nausea	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Gastrointestinal disorders Oesophageal pain	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
General disorders Fatigue	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
General disorders Mucosal inflammation	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
General disorders Multi-organ failure	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
General disorders Pyrexia	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	25.0% 1/4 • From screening until study completion or early termination visit (Up to 14 months)	31.6% 6/19 • From screening until study completion or early termination visit (Up to 14 months)
Immune system disorders Graft versus host disease	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Appendicitis	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Atypical pneumonia	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Bacteraemia	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Cellulitis	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Hepatic infection	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Infection	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Lung infection	20.0% 3/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Pneumonia	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	15.8% 3/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Sepsis	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	25.0% 1/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Urinary tract infection	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Infections and infestations Vaginal abscess	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Injury, poisoning and procedural complications Fall	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Injury, poisoning and procedural complications Wrist fracture	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Nervous system disorders Haemorrhage intracranial	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Nervous system disorders Status epilepticus	0.00% 0/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Renal and urinary disorders Haematuria	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Renal and urinary disorders Renal failure acute	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Renal and urinary disorders Urinary retention	13.3% 2/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Renal and urinary disorders Urinary tract pain	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Respiratory, thoracic and mediastinal disorders Epistaxis	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	5.3% 1/19 • From screening until study completion or early termination visit (Up to 14 months)
Surgical and medical procedures Central venous catheterisation	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)
Vascular disorders Hypotension	6.7% 1/15 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/4 • From screening until study completion or early termination visit (Up to 14 months)	0.00% 0/19 • From screening until study completion or early termination visit (Up to 14 months)