Trial Outcomes & Findings for Pembrolizumab in Treating Patients With Advanced Merkel Cell Cancer (NCT NCT02267603)

NCT ID: NCT02267603

Last Updated: 2023-07-05

Results Overview

ORR will be estimated as the number of responders as a percent of the number of eligible participants who received at least one dose of treatment. If a substantial amount of data is missing, analyses will be performed using parametric generalized linear models fit by maximum likelihood. A generalized linear model for the ORR will use a binomial error distribution. The model will include as covariates all available baseline predictors of the missing outcomes. Responses to continued pembrolizumab will be chronicled and reported.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 50 participants
• Primary outcome timeframe: Up to 3 years
• Results posted on: 2023-07-05

Participant Flow

The study was expanded from 24 patients to 50 patients at the request of the pharmaceutical collaborator.

Participant milestones

Measure	Treatment (Pembrolizumab) Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Overall Study STARTED	50
Overall Study COMPLETED	6
Overall Study NOT COMPLETED	44

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pembrolizumab in Treating Patients With Advanced Merkel Cell Cancer

Baseline characteristics by cohort

Measure	Treatment (Pembrolizumab) n=50 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	40 Participants n=93 Participants
Age, Categorical >=65 years	10 Participants n=93 Participants
Sex: Female, Male Female	16 Participants n=93 Participants
Sex: Female, Male Male	34 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants
Race (NIH/OMB) White	45 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=93 Participants
Region of Enrollment United States	50 participants n=93 Participants

PRIMARY outcome

Timeframe: Up to 3 years

ORR will be estimated as the number of responders as a percent of the number of eligible participants who received at least one dose of treatment. If a substantial amount of data is missing, analyses will be performed using parametric generalized linear models fit by maximum likelihood. A generalized linear model for the ORR will use a binomial error distribution. The model will include as covariates all available baseline predictors of the missing outcomes. Responses to continued pembrolizumab will be chronicled and reported.

Outcome measures

Measure	Treatment (Pembrolizumab) n=50 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Objective Response Rate (ORR) Defined as the Proportion of Patients Who Have Achieved Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Number participants with partial response (PR)	16 Participants
Objective Response Rate (ORR) Defined as the Proportion of Patients Who Have Achieved Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Number participants with complete response (CR)	12 Participants
Objective Response Rate (ORR) Defined as the Proportion of Patients Who Have Achieved Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Combined total participants with either PR or CR	28 Participants

SECONDARY outcome

Timeframe: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 16 months

Survival curves for PFS will be estimated using the Kaplan-Meier method. Assessed percentage of participants with progression free survival up to 16 months.

Outcome measures

Measure

Treatment (Pembrolizumab) n=50 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV

Progression-free Survival (PFS) Using RECIST 1.1

49.9 % of participants

SECONDARY outcome

Timeframe: Time interval between the date of first response (CR/PR) and the date of progression, assessed up to 3 years

Population: Thirty participants with durable response were assessed by RECIST 1.1.

Survival curves for DOR will be estimated using the Kaplan-Meier method.

Outcome measures

Measure

Treatment (Pembrolizumab) n=30 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV

Duration of Response (DOR)

NA months Interval 4.0 to 77.4 Median was not reached due to insufficient number of events, i.e., (too few participants had reached progression at data cutoff.)

SECONDARY outcome

Timeframe: Time interval between the start of treatment to death due to any cause, assessed up to 60 months.

Survival curves for OS will be estimated using the Kaplan-Meier method.

Outcome measures

Measure

Treatment (Pembrolizumab) n=50 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV

Overall Survival (OS)

47.2 months Interval 26.0 to 68.4

SECONDARY outcome

Timeframe: Up to 90 days post-treatment

Safety will be assessed by quantifying the toxicities and grades experienced by subjects including serious AEs (SAEs) and events of clinical interest. Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, laboratory tests, vital signs, and electrocardiogram measurements. Assessed number of participants who experienced grade 3 to 5 adverse events.

Outcome measures

Measure	Treatment (Pembrolizumab) n=50 Participants Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Incidence of Adverse Events (AEs) Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Grade 3-5 Adverse Events	29 Participants
Incidence of Adverse Events (AEs) Graded Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Grade 3-5 Drug Related Adverse Events	15 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

This will include immunohistochemical and gene expression analysis focusing on delineating the immune components and immunologic milieu within the tumor before therapy.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: After 2 years of treatment

Responses will be assessed at baseline, after initiating therapy, and correlated with clinical responses over time. Among patients with corresponding MHC-peptide tetramers, pre- and post-treatment samples of circulating MCPyV-specific CD8 T cells will be isolated and subjected to deep immunophenotyping by messenger ribonucleic acid (mRNA) expression analysis.

Outcome measures

Outcome data not reported

Adverse Events

Treatment (Pembrolizumab)

Serious events: 22 serious events

Other events: 50 other events

Deaths: 16 deaths

Serious adverse events

Measure	Treatment (Pembrolizumab) n=50 participants at risk Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Blood and lymphatic system disorders Anemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Atrial fibrillation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Myocarditis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Pericardial effusion	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Sinus bradycardia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Ventricular arrhythmia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Abdominal pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Colitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Dysphagia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Gastrooesophageal reflux disease	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Small intestinal haemorrhage	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Small intestinal obstruction	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Chills	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Disease progression	16.0% 8/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Fatigue	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Malaise	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Pyrexia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Lung infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Mastitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Sepsis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Sialoadenitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Streptococcal bacteraemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Tuberculosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Urinary tract infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Alanine aminotransferase increased	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Aspartate aminotransferase increased	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood alkaline phosphatase increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood bilirubin increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Acidosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Decreased appetite	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Dehydration	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypercalcaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperglycaemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypernatraemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperuricaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Muscular weakness	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paraneoplastic syndrome	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Delirium	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Acute kidney injury	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Epistaxis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Pneumonitis	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Lichenoid keratosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Pain of skin	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Rash maculo-papular	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Embolism	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Haematoma	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Hypotension	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.

Other adverse events

Measure	Treatment (Pembrolizumab) n=50 participants at risk Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression\* or unacceptable toxicity. \* NOTE: Patients with confirmed disease progression may continue to receive treatment if they are otherwise clinically stable until there is an increase in tumor burden of 25% or more following initial confirmation of progression. Under exceptional circumstances, and with protocol P.I. and CITN P.I. approval, patients may receive treatment beyond 2 years. Laboratory Biomarker Analysis: Ancillary studies Pembrolizumab: Given IV
Blood and lymphatic system disorders Anaemia	32.0% 16/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Leukocytosis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Leukopenia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Lymph node pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Lymphadenopathy	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Lymphopenia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Microcytic anaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Monocytosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Blood and lymphatic system disorders Thrombocytopenia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Acute myocardial infarction	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Atrial fibrillation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Bundle branch block left	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Cardiac failure acute	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Palpitations	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Sinus bradycardia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Sinus tachycardia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Tachycardia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Cardiac disorders Ventricular tachycardia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Ear and labyrinth disorders Deafness	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Ear and labyrinth disorders Hypoacusis	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Ear and labyrinth disorders Paraesthesia ear	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Adrenal insufficiency	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Adrenocorticotropic hormone deficiency	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Autoimmune hypothyroidism	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Hyperthyroidism	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Hypothyroidism	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Endocrine disorders Thyroiditis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Asthenopia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Diplopia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Eyelid ptosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Ophthalmoplegia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Vision blurred	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Visual acuity reduced	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Visual impairment	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Eye disorders Vitreous floaters	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Abdominal discomfort	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Abdominal distension	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Abdominal pain	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Abdominal pain upper	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Aphthous ulcer	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Breath odour	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Colitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Constipation	28.0% 14/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Diarrhoea	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Dry mouth	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Dyspepsia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Dysphagia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Faeces discoloured	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Gastrointestinal haemorrhage	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Gastrointestinal pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Gastrooesophageal reflux disease	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Haemorrhoids	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Intra-abdominal haematoma	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Large intestine polyp	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Nausea	20.0% 10/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Oesophageal varices haemorrhage	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Pancreatitis	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Stomatitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Gastrointestinal disorders Vomiting	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Asthenia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Chest discomfort	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Chest pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Chills	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Cyst	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Face oedema	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Fatigue	56.0% 28/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Feeling cold	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Feeling hot	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Gait disturbance	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Malaise	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Nodule	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Oedema	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Oedema peripheral	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Peripheral swelling	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Pyrexia	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Swelling	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
General disorders Temperature intolerance	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Hepatobiliary disorders Autoimmune hepatitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Hepatobiliary disorders Cholecystitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Hepatobiliary disorders Hyperbilirubinaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Immune system disorders Seasonal allergy	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Abdominal hernia infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Abscess limb	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Breast cellulitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Bronchitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Cellulitis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Conjunctivitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Diverticulitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Eye infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Fungal infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Gastrointestinal infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Genital herpes	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Herpes virus infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Herpes zoster	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Lung infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Nasopharyngitis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Oral candidiasis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Oral herpes	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Sinusitis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Skin infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Soft tissue infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Streptococcal infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Upper respiratory tract infection	28.0% 14/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Urinary tract infection	12.0% 6/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Infections and infestations Vaginal infection	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Injury, poisoning and procedural complications Contusion	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Injury, poisoning and procedural complications Excoriation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Injury, poisoning and procedural complications Fall	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Injury, poisoning and procedural complications Infusion related reaction	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Injury, poisoning and procedural complications Tooth fracture	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Alanine aminotransferase increased	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Amylase increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Aspartate aminotransferase increased	16.0% 8/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood alkaline phosphatase decreased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood alkaline phosphatase increased	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood bilirubin increased	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood creatine phosphokinase increased	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood creatinine increased	12.0% 6/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood glucose increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood lactate dehydrogenase increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood magnesium increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood pressure increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood testosterone decreased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood thyroid stimulating hormone increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood urea increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Blood urine present	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Lipase increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Lymphocyte count decreased	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Neutrophil count decreased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Neutrophil count increased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Platelet count decreased	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Sputum normal	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Thyroxine free increased	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations Weight decreased	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Investigations White blood cell count decreased	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Decreased appetite	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Dehydration	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypercalcaemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperchloraemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperglycaemia	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperkalaemia	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypernatraemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyperuricaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypoalbuminaemia	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypocalcaemia	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypochloraemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypokalaemia	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypomagnesaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hyponatraemia	20.0% 10/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypophosphataemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypoproteinaemia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Hypovitaminosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Increased appetite	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Metabolism and nutrition disorders Malnutrition	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Arthralgia	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Back pain	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Bone pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Flank pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Groin pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Joint range of motion decreased	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Muscle fatigue	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Muscle twitching	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Muscular weakness	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Musculoskeletal discomfort	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Myalgia	12.0% 6/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Neck mass	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Osteoarthritis	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Pain in extremity	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Polyarthritis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Paraneoplastic syndrome	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Burning sensation	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Cerebral ischaemia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Dizziness	16.0% 8/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Dysgeusia	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Encephalopathy	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Headache	20.0% 10/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Hyperaesthesia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Hypoaesthesia	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Lethargy	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Memory impairment	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Nystagmus	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Paraesthesia	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Peripheral motor neuropathy	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Peripheral sensory neuropathy	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Sciatica	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Syncope	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Nervous system disorders Tremor	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Anxiety	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Confusional state	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Delirium	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Disorientation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Insomnia	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Irritability	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Mental status changes	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Mood altered	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Psychiatric disorders Sleep disorder	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Acute kidney injury	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Dysuria	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Glycosuria	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Haematuria	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Nephritis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Nephrolithiasis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Pollakiuria	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Proteinuria	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Urinary retention	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Renal and urinary disorders Urinary tract pain	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Reproductive system and breast disorders Breast pain	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Reproductive system and breast disorders Breast swelling	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Reproductive system and breast disorders Oedema genital	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Reproductive system and breast disorders Pruritus genital	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Cough	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Dysphonia	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.0% 8/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Haemoptysis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Hypercapnia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Nasal congestion	16.0% 8/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Nasal polyps	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Pneumonitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Productive cough	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Respiratory, thoracic and mediastinal disorders Sinus congestion	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Actinic keratosis	6.0% 3/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Alopecia	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Dry skin	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Eczema	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Erythema	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Hair growth abnormal	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Hypotrichosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Itching scar	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Lichen planus	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Lichenoid keratosis	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Night sweats	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Papule	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Pruritus	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Pruritus generalised	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Psoriasis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Rash	22.0% 11/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Rash erythematous	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Rash maculo-papular	14.0% 7/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Rash pruritic	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Skin burning sensation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Skin and subcutaneous tissue disorders Skin lesion	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Surgical and medical procedures Cancer surgery	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Surgical and medical procedures Cataract operation	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Deep vein thrombosis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Embolism	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Haematoma	4.0% 2/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Hot flush	10.0% 5/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Hypertension	12.0% 6/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Hypotension	8.0% 4/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Lymphoedema	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.
Vascular disorders Phlebitis	2.0% 1/50 • Serious Adverse Events and other (not including serious) adverse events were assessed for up to 36 months. All cause mortality was assessed for up to 60 months.

Additional Information

Administrative Director

Cancer Immunotherapy Trials Network

Phone: 206-667-6609

Email: citn.core.reg@hvtn.org

Results disclosure agreements

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

Restriction type: LTE60