Trial Outcomes & Findings for Dose Optimization Trial of CD19 Redirected Autologous T Cells (NCT NCT01747486)

Last Updated: 2023-06-22

Results Overview

Complete response (including complete response with incomplete marrow recovery) within 3 months (in evaluable patients). The eveluable set comprise of patients who have received CART19 at intended dose level and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

42 participants

Primary outcome timeframe

3 months

Results posted on

2023-06-22

Participant Flow

First Patient Enrolled - 02-Jan-2013 Last Patient Completed - 13-Dec-2017

Study was conducted in 2 stages. Stage 1: subjects were randomized into one of the two arms (Arm 1: Higher dose \& Arm 2 : Lower dose) Stage 2: the selected dose cohort was expanded to enroll additional subjects. Based on the Stage 1 analysis performed in Nov 2014, Arm 1 was chosen for expansion in Stage 2 and enrolled additional 12 subjects.

Participant milestones

Participant milestones
Measure	Target Dose of 1-5x10e8 Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)	Target Dose of 1-5x10e7 Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Stage 1 STARTED	15	15
Stage 1 COMPLETED	3	2
Stage 1 NOT COMPLETED	12	13
Stage 2 STARTED	12	0
Stage 2 COMPLETED	3	0
Stage 2 NOT COMPLETED	9	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Target Dose of 1-5x10e8 Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)	Target Dose of 1-5x10e7 Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Stage 1 Physician Decision	3	0
Stage 1 Withdrawal by Subject	4	3
Stage 1 Disease progression	4	9
Stage 1 Death	1	1
Stage 2 Physician Decision	2	0
Stage 2 Withdrawal by Subject	1	0
Stage 2 New Cancer Therapy	3	0
Stage 2 Disease Progression	3	0

Baseline Characteristics

Dose Optimization Trial of CD19 Redirected Autologous T Cells

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Target Dose of 1-5x10e8 n=27 Participants Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: For baseline measures, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects.	Target Dose of 1-5x10e7 n=15 Participants Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15.	Total n=42 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants	12 Participants n=7 Participants	31 Participants n=5 Participants
Age, Categorical >=65 years	8 Participants n=5 Participants	3 Participants n=7 Participants	11 Participants n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	11 Participants n=7 Participants	32 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	26 Participants n=5 Participants	15 Participants n=7 Participants	41 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	26 Participants n=5 Participants	15 Participants n=7 Participants	41 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	27 participants n=5 Participants	15 participants n=7 Participants	42 participants n=5 Participants

PRIMARY outcome

Timeframe: 3 months

Population: The Evaluable Set comprised all patients who received high dose (1-5×10\^8) or low dose (1-5×10\^7) CTL019 transduced cells as randomized, and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.

Outcome measures

Outcome measures
Measure	Target Dose of 1-5x10e8 n=18 Participants Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)	Target Dose of 1-5x10e7 n=13 Participants Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Number of Patients Achieving Complete Response Within 3 Months Complete Response (CR)	1 Participants	1 Participants
Number of Patients Achieving Complete Response Within 3 Months CR with incomplete marrow recovery (CRi)	5 Participants	0 Participants
Number of Patients Achieving Complete Response Within 3 Months Partial Response (PR)	4 Participants	2 Participants
Number of Patients Achieving Complete Response Within 3 Months PR with incomplete marrow recovery (PRi)	0 Participants	1 Participants
Number of Patients Achieving Complete Response Within 3 Months No Response (NR)/ Progressive Disease (PD)	8 Participants	9 Participants

Adverse Events

Target Dose of 1-5x10e8

Serious events: 23 serious events

Other events: 24 other events

Deaths: 6 deaths

Target Dose of 1-5x10e7

Serious events: 9 serious events

Other events: 11 other events

Deaths: 6 deaths

Serious adverse events

Other adverse events

Additional Information

Noelle Frey, MD

Abramson Cancer Center of the University of Pennsylvania

Phone: 215-662-6901

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Target Dose of 1-5x10e8 n=27 participants at risk Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: For this group, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects.	Target Dose of 1-5x10e7 n=15 participants at risk Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15.
Immune system disorders Cytokine Release Syndrome	44.4% 12/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	40.0% 6/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Pyrexia	18.5% 5/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	33.3% 5/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Blood and lymphatic system disorders Febrile Neutropenia	14.8% 4/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Pneumonia	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Sinusitis	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Upper respiratory tract infection	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Abdominal Pain	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hypercalcaemia	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Renal and urinary disorders Acute kideny injury	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Nervous system disorders Encephalopathy	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Streptococcal sepsis	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Sepsis	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Hypoxia	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Musculoskeletal and connective tissue disorders Myalgia	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Otitis externa	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Pleural effusion	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Pneumonitis	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	3.7% 1/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Influenza	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	13.3% 2/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Diarrhoea	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Fatigue	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Post procedural infection	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Nervous system disorders Syncope	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.

Measure	Target Dose of 1-5x10e8 n=27 participants at risk Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: For this group, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects.	Target Dose of 1-5x10e7 n=15 participants at risk Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells) CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains) Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15.
Investigations White blood cell count decreased	29.6% 8/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	60.0% 9/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Blood and lymphatic system disorders Anaemia	44.4% 12/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	46.7% 7/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Fatigue	37.0% 10/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	40.0% 6/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations CD4 lymphocytes decreased	37.0% 10/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	73.3% 11/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Pyrexia	14.8% 4/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	53.3% 8/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Immune system disorders Cytokine release syndrome	44.4% 12/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	40.0% 6/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations Lymphocyte count decreased	29.6% 8/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Nausea	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	46.7% 7/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	33.3% 5/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Blood and lymphatic system disorders Febrile neutropenia	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	33.3% 5/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Chills	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hypocalcemia	29.6% 8/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Blood and lymphatic system disorders Neutropenia	18.5% 5/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Constipation	18.5% 5/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	20.0% 3/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Psychiatric disorders Insomnia	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	20.0% 3/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations Neutrophil count decreased	22.2% 6/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	40.0% 6/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Vascular disorders Hypotension	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
General disorders Oedema peripheral	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations Platelet count decreased	18.5% 5/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	26.7% 4/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Respiratory, thoracic and mediastinal disorders Hypoxia	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Diarrhoea	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	46.7% 7/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Post procedural infection	0.00% 0/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	6.7% 1/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hypokalemia	18.5% 5/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hypomagnesaemia	14.8% 4/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hyponatremia	14.8% 4/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations Aspratate aminotransferase increased	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Nervous system disorders Headche	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Metabolism and nutrition disorders Hypophosphataemia	11.1% 3/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Renal and urinary disorders Acute kidney injury	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Investigations Blood bilirubin increased	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Clostridium difficile infection	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Skin and subcutaneous tissue disorders Rash	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Infections and infestations Upper respiratory tract infection	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Gastrointestinal disorders Vomiting	7.4% 2/27 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.	0.00% 0/15 • For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.