tTF-NGR Phase I Study

• Sponsor: University Hospital Muenster (Other)
• Overall Status: Completed
• CT.gov ID: NCT02902237
• Collaborator: Deutsche Krebshilfe e.V., Bonn (Germany) (Other)
• Enrollment: 24
• Location: 1
• Arm: 1
• Actual Duration (Months): 32.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

In this phase I clinical trial cancer patients suffering from solid tumors or lymphomas, recurring after and/or refractory against standard treatment are treated intravenously (iv) with increasing doses of tTF-NGR(tTF= truncated tissue factor; NGR=Asn-Gly-Arg). The objectives of this trial are to evaluate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with cancer, who had obtained all standard treatment known for their disease entity prior to entry on study. Further objectives are to determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application by MRI as a biological surrogate parameter for biological activity of the investigational medicinal product (IMP), tTF-NGR, and to obtain pharmacokinetic data.

Condition or Disease	Intervention/Treatment	Phase
Malignant Solid Tumors; Lymphomas	Biological: tTF-NGR	Phase 1

Detailed Description

PHASE I STUDY OF tTF-NGR IN PATIENTS WITH RECURRENT OR REFRACTORY MALIGNANT TUMORS OR LYMPHOMAS BEYOND ALL STANDARD TREATMENTS

Short Title: tTF-NGR Phase I Study Sponsor's Study Code: UKM12_0018

EudraCT-No.: 2016-003042-85 Sponsor: Universitätsklinikum Muenster Investigator: Prof. Dr. Christoph Schliemann

Indication: All solid tumors and lymphomas beyond standard therapy Study Design: Phase I Study Investigational Medicinal Product: tTF-NGR

Therapy: Phase I, open label, single arm, non-randomized prospective, monocenter study. tTF-NGR will be given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks and following cycles with dose escalation of 0.5 mg/m2 upon judgement of tolerability and therapeutic activity. Starting dose will be 1 mg/m2/day. Patients within the dose-escalation part will be treated in sequence and not in parallel. Individual patients can undergo a maximum of 8 dose-escalations. Dose-escalation is stopped before the maximum number of 8 escalation steps if tumor response, tumor progression or a Dose-Limiting Toxicity (DLT) is observed. In the case of stable disease (SD) and with good tolerability these patients can obtain further cycles without dose-escalation until tumor progression or Dose-Limiting Toxicity (DLT) and the next patient can start with dose-escalation cycles on the highest tolerable dose for the previous patient.

Objectives:

Primary Objective:

To evaluate the maximum tolerated dose (MTD) and the Dose-Limiting Toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with relapsed or refractory cancer, who had obtained all standard treatment known for their disease entity prior to entry on study.

Secondary Objectives:

1. To determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application as a biological surrogate parameter for biological activity of the IMP in the patients treated within the verification cohorts.

2. To obtain pharmacokinetic data of tTF-NGR.

Endpoints:

Primary Safety Endpoint: Maximum Tolerated Dose (MTD). MTD is the dose below the dose leading to reproducible episodes of Dose Limiting Toxicity (DLT) in at least 2/6 patients. DLT will be characterized by clinical, blood and serum monitoring at specified time points before and during study period.

Secondary Efficacy Endpoints:

1. Occurrence and frequency of inhibition of tumor blood flow as measured by contrast-enhanced Magnetic Resonance Imaging (MRI) in the patients treated in the verification cohorts.

2. Occurrence and frequency of tumor response defined as Complete Response (CR), Partial Response (PR), or Stabile Disease (SD) as defined by RECIST criteria.

Inclusion Criteria:

• age > 18 years

• histologically proven or cytologically confirmed solid malignant tumor or malignant lymphoma

• recurrent or refractory disease after standard therapy and with no known curative or survival-prolonging treatment options according to the judgement of the investigators

• life expectancy of at least 6 weeks according to the judgement of the investigators

• Karnofsky performance status >50

• measurable disease with at least one marker-lesion measurable in 2 dimensions by Vascular Volume-Fraction-MRI

• adequate bone marrow function with absolute neutrophil count > 1000/microliter and platelet count > 50/nl.

• normal global coagulation parameters (Quick, PTT, TZ, fibrinogen), no prophylactic anticoagulation

• adequate liver function (total bilirubin < 3x the upper normal limit (ULN), SGPT/SGOT < 3x ULN)

• adequate renal function (serum creatinine < 3x ULN)

• no history of coronary heart disease, stroke, transitory ischemic attacks, pulmonary embolism, or deep vein thrombosis

• time elapsed from previous therapy (including other IMPs) > 3 weeks with recovery from side effects

• exclusion of central nervous system (CNS) disease and CNS vascular abnormalities by MRI

• ability to understand and provide written informed consent

• written informed consent given

• for female patients with child-bearing potential exclusion of pregnancy by adequate testing within 48 hours prior to entry on study

• females of childbearing potential as well as fertile males must agree to use a highly effective form of contraception (Pearl Index < 1) during the study and for 120 days following the last dose of the IMP

Exclusion Criteria:

• clinically significant unrelated illness which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results

• known hypersensitivity reactions to prior application of E. coli-derived material

• women with breast-feeding activity

• concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities)

• clinical application of any other drug with known antitumor activity

• prophylactic anticoagulation within the last 3 days

NOTE: Since this is a phase I study for end-stage cancer patients, patients who would be excluded from the protocol strictly for laboratory abnormalities only can be included at the Investigator's discretion. This will be documented as an exception to the criteria and will be signed and filed in the CRF and the Trial Master File.

Statistical Methods: Descriptive statistics are performed to characterize MTD (= dose level below DLT occurring in 2/6 patients) Financial Support: Deutsche Krebshilfe, grant 111004 Schedule Planned start date of the study (FPFV): 01.11.2016 Planned end date of recruitment (LPFV): 01.11.2017 Planned end date of the study (LPLV): 01.05.2018

Studied period (years): (date of first enrolment) 2017 03 29; (date of last completed) 2019 12 19

Study centre: Department of Medicine A (Hematology, Hemostaseology, Oncology) University Hospital Muenster, Germany Albert-Schweitzer-Campus 1 D-48149 Muenster, Germany

Methodology:

We have treated 17 patients with advanced cancer beyond standard therapies with tTF-NGR applied as a 1-hour infusion via central venous access for 5 consecutive days and rest periods of 2 weeks before the next cycle. The study allowed for intraindividual dose escalations from cycle to cycle and established MTD and DLT by verification cohorts of 6 patients. This was an investigator-initiated, monocenter, single-arm, open-label study.

Number of patients (planned and analysed):

The number of patients required to complete this study was determined by the occurrence of DLT. Eventually, 24 patients had to be screened and 17 of them treated and analyzed in order to evaluate the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single-arm, mono-center, open-label phase I trial with intraindividual dose escalationSingle-arm, mono-center, open-label phase I trial with intraindividual dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of tTF-NGR in Patients With Recurrent or Refractory Malignant Tumors and Lymphomas Beyond All Standard Treatments
• Actual Study Start Date: Mar 1, 2017
• Actual Primary Completion Date: Nov 5, 2019
• Actual Study Completion Date: Nov 5, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: tTF-NGR tTF-NGR will be given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks and following cycles with dose escalation of 0.5 mg/m2 upon judgement of tolerability and therapeutic activity. Starting dose will be 1 mg/m2/day. Dose-escalation is stopped before the maximum number of 8 escalation steps if tumor response, tumor progression or a Dose-Limiting Toxicity (DLT) is observed.

Biological: tTF-NGR; tTF-NGR will be given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks and following cycles with dose escalation of 0.5 mg/m2 upon judgement of tolerability and therapeutic activity. Starting dose will be 1 mg/m2/day. Dose-escalation is stopped before the maximum number of 8 escalation steps if tumor response, tumor progression or a Dose-Limiting Toxicity (DLT) is observed.; Other Names: truncated tissue factor (tTF)-NGR

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) and Dose-limiting Toxicity (DLT) [Measures: daily during treatment, weekly during rest periods of 2 weeks, monthly after End of Therapy, up to 3 months.]

   DLT will be characterized by clinical, blood and serum monitoring at specified time points before and during study period. AE, SAE, and SUSAR reporting was according to CTCAE 4.0 and GCP guidelines.

Secondary Outcome Measures

1. 1: Assessment of Anti-tumor Activity: MRI K-trans in [ 10^-3/Min] and/or CEUS in [Arbitrary Units]; 2: Pharmacokinetic Profile: AUC in [ng*h/mL] [1: Tumor blood flow: baseline, 5 h post-dose, at 5 d at each cycle of therapy and 6 months. 2: Pharmacokinetic measures: 0 h, 0.5 h, 1 h, 1.5 h, 3 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h post-dose]

   1: Anti-tumor activity: Tumor blood flow was measured with MRI and/or CEUS; 2: Pharmacokinetic data of tTF-NGR: tTF-NGR blood levels were analyzed by TF-ELISA.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• age ≥ 18 years

• histologically proven or cytologically confirmed solid malignant tumor or malignant lymphoma

• recurrent or refractory disease after standard therapy and with no known curative or survival-prolonging treatment options according to the judgement of the investigators

• life expectancy of at least 6 weeks according to the judgement of the investigators

• Karnofsky performance status ≥ 50

• measurable disease with at least one marker-lesion measurable in 2 dimensions by Vascular Volume-Fraction-MRI and/or CEUS.

• adequate bone marrow function with absolute neutrophil count > 1000/microliter and platelet count > 50/nl

• normal global coagulation parameters (Quick, partial thromboplastin time (PTT), thrombin time (TZ), fibrinogen), no prophylactic anticoagulation

• ability to understand and provide written informed consent

• adequate liver function (total bilirubin < 3x the upper normal limit (ULN), serum glutamic pyruvic transaminase/serum glutamic-oxaloacetic transaminase (SGPT/SGOT) < 3x ULN)

• adequate renal function (serum creatinine < 3x ULN)

• no history of coronary heart disease, stroke, transitory ischemic attacks, pulmonary embolism, or deep vein thrombosis

• time elapsed from previous therapy (including other IMPs) ≥ 3 weeks with recovery from side effects

• exclusion of central nervous system (CNS) disease and CNS vascular abnormalities by MRI

• ability to understand and provide written informed consent

• written informed consent given

• for female patients with child-bearing potential exclusion of pregnancy by adequate testing within 48 hours prior to entry on study

• females of childbearing potential as well as fertile males must agree to use a highly effective form of contraception (Pearl Index < 1) during the study and for 120 days following the last dose of the IMP

Exclusion criteria:

• clinically significant unrelated illness which in the judgement of the investigators could compromise the patient's ability to tolerate the IMP or be likely to interfere with the study procedures or results

• known hypersensitivity reactions to prior application of E. coli-derived material

• women with breast-feeding activity

• concomitant use of any other investigational agent (agent for which there is currently no approved indication from regulatory authorities)

• clinical application of any other drug with known anti tumor activity

• prophylactic anticoagulation within the last 3 days

NOTE: Since this is a phase I study for end-stage cancer patients, patients who would be excluded from the protocol strictly for laboratory abnormalities only can be included at the Investigator's discretion. This will be documented as an exception to the criteria and will be signed and filed in the CRF and the Trial Master File.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Muenster	Muenster	NRW	Germany	48149

Sponsors and Collaborators

• University Hospital Muenster
• Deutsche Krebshilfe e.V., Bonn (Germany)

Investigators

• Principal Investigator: Christoph Schliemann, Prof., University Hospital of Muenster

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 28, 2016

More Information

Additional Information:

• publication in cancers

Publications

None provided.

• Responsible Party: University Hospital Muenster
• ClinicalTrials.gov Identifier: NCT02902237
• Other Study ID Numbers: UKM12_0018; 2016-003042-85
• First Posted: Sep 15, 2016
• Last Update Posted: Dec 8, 2020
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University Hospital Muenster: tTF-NGR; vascular targeting; CD13; aminopeptidase N; first-in-class phase I study
• Additional relevant MeSH terms: Lymphoma; Thromboplastin

Study Results

Participant Flow

Recruitment Details	All patients were recruited in the University Hospital Muenster on an out-patient basis.
Pre-assignment Detail	24 patients were screened, 6 were screening failures(1: fast disease progression, 1: retraction of consent; 3: fast disease progression, 1: new brain metastasis diagnosed in screening). One patient died from sepsis before treatment with tTF-NGR, 17 patients obtained at least 1 application of tTF-NGR and were evaluable for safety, toxicity ans efficacy.

Arm/Group Title	tTF-NGR
Arm/Group Description	tTF-NGR will be given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks and following cycles with dose escalation of 0.5 mg/m2 upon judgement of tolerability and therapeutic activity. Starting dose will be 1 mg/m2/day. Dose-escalation is stopped before the maximum number of 8 escalation steps if tumor response, tumor progression or a Dose-Limiting Toxicity (DLT) is observed.
Period Title: Overall Study
STARTED	17
COMPLETED	17
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	tTF-NGR
Arm/Group Description	This was a single-arm, mono-center, open-label trial. tTF-NGR was given as a 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks to all 17 patients treated. 8 patients received 2 cycles, 1 patient received 3 cycles, and 8 patients received 1 cycle.
Overall Participants	17
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 94.1%
>=65 years	1 5.9%
Sex: Female, Male (Count of Participants)
Female	4 23.5%
Male	13 76.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	17 100%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Germany	17 100%
Disease type (Count of Participants)
germ cell tumor	3 17.6%
hepatocellular tumor	2 11.8%
lung tumor	2 11.8%
colorectal tumor	4 23.5%
soft tissue sarcoma	5 29.4%
thyroid tumor	1 5.9%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) and Dose-limiting Toxicity (DLT)
Description	DLT will be characterized by clinical, blood and serum monitoring at specified time points before and during study period. AE, SAE, and SUSAR reporting was according to CTCAE 4.0 and GCP guidelines.
Time Frame	Measures: daily during treatment, weekly during rest periods of 2 weeks, monthly after End of Therapy, up to 3 months.

Outcome Measure Data

Analysis Population Description

All 17 patients treated with tTF-NGR were analysed for safety and toxicity.

Arm/Group Title	tTF-NGR
Arm/Group Description	All 17 patients obtaining at least 1 dose of tTF-NGR were analysed for MTD and DLT.
Measure Participants	17
MTD (3 mg/m^2 tTF-NGR/day x 5, q day 22)	8 47.1%
DLT: isolated and reversible elevation of Troponin T hs (grade 3 CTCAE 4.0)	5 29.4%
other patient, who obtained other doses than MTD without DLT	4 23.5%

2. Secondary Outcome

Title	1: Assessment of Anti-tumor Activity: MRI K-trans in [ 10^-3/Min] and/or CEUS in [Arbitrary Units]; 2: Pharmacokinetic Profile: AUC in [ng*h/mL]
Description	1: Anti-tumor activity: Tumor blood flow was measured with MRI and/or CEUS; 2: Pharmacokinetic data of tTF-NGR: tTF-NGR blood levels were analyzed by TF-ELISA.
Time Frame	1: Tumor blood flow: baseline, 5 h post-dose, at 5 d at each cycle of therapy and 6 months. 2: Pharmacokinetic measures: 0 h, 0.5 h, 1 h, 1.5 h, 3 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h post-dose

Outcome Measure Data

Analysis Population Description

All 17 patients obtaining at least 1 dose of tTF-NGR were analysed for efficacy and were assayed for tTF-NGR pharmacokinetics.

Arm/Group Title	tTF-NGR
Arm/Group Description	All 17 patients obtaining at least 1 dose of tTF-NGR were analysed for safety and efficacy. All 17 patients were assayed for tTF-NGR pharmacokinetics.
Measure Participants	17
yes	17 100%
no	0 0%
yes	17 100%
no	0 0%

Adverse Events

Time Frame	All adverse events including serious adverse events were monitored from the first study-related procedure (tTF-NGR application) ,daily during treatment, weekly during rest periods of 2 weeks, monthly from the end of treatment with tTF-NGR up to 3 months.
Adverse Event Reporting Description	AE, SAE, SUSAR were classified according to CTCAE 4.0 criteria and reports were generated according to GCP guidelines.
Arm/Group Title	tTF-NGR Dose: 1,0 mg/m^2		tTF-NGR Dose: 1,5 mg/m^2		tTF-NGR Dose: 2,0 mg/m^2		tTF-NGR Dose: 2,5 mg/m^2		tTF-NGR Dose: 3,0 mg/m^2		tTF-NGR Dose: 4,0 mg/m^2		tTF-NGR Dose: 5,0 mg/m^2
Arm/Group Description	tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks		tTF-NGR was given as 1-hour infusion via central venous access once daily for 5 days with a subsequent rest period of 2 weeks
All Cause Mortality
	tTF-NGR Dose: 1,0 mg/m^2		tTF-NGR Dose: 1,5 mg/m^2		tTF-NGR Dose: 2,0 mg/m^2		tTF-NGR Dose: 2,5 mg/m^2		tTF-NGR Dose: 3,0 mg/m^2		tTF-NGR Dose: 4,0 mg/m^2		tTF-NGR Dose: 5,0 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/8 (0%)		0/5 (0%)		0/3 (0%)
Serious Adverse Events
	tTF-NGR Dose: 1,0 mg/m^2		tTF-NGR Dose: 1,5 mg/m^2		tTF-NGR Dose: 2,0 mg/m^2		tTF-NGR Dose: 2,5 mg/m^2		tTF-NGR Dose: 3,0 mg/m^2		tTF-NGR Dose: 4,0 mg/m^2		tTF-NGR Dose: 5,0 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/2 (0%)		0/2 (0%)		2/2 (100%)		4/8 (50%)		4/5 (80%)		2/3 (66.7%)
Gastrointestinal disorders
Abdominal pain	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Abdominal pain upper	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Lower gastrointestinal haemorrage	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
General disorders
Pyrexia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Ataxia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Infections and infestations
Device related infection	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Investigations
Troponin T increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	2/5 (40%)	2	2/3 (66.7%)	2
Vascular disorders
Transient ischaemic attack	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Deep vein thrombosis (DVT)	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	tTF-NGR Dose: 1,0 mg/m^2		tTF-NGR Dose: 1,5 mg/m^2		tTF-NGR Dose: 2,0 mg/m^2		tTF-NGR Dose: 2,5 mg/m^2		tTF-NGR Dose: 3,0 mg/m^2		tTF-NGR Dose: 4,0 mg/m^2		tTF-NGR Dose: 5,0 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		2/2 (100%)		2/2 (100%)		2/2 (100%)		6/8 (75%)		5/5 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	2/8 (25%)	2	0/5 (0%)	0	0/3 (0%)	0
International normalized ratio increased	1/1 (100%)	2	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Acitvated partial thromboplastin time prolonged	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Anaemia	0/1 (0%)	0	0/2 (0%)	0	2/2 (100%)	2	0/2 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/3 (0%)	0
Cardiac disorders
Supraventricular tachycardia	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Chest pain	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	1	0/3 (0%)	0
Gastrointestinal disorders
Nausea	0/1 (0%)	0	1/2 (50%)	1	1/2 (50%)	2	2/2 (100%)	2	1/8 (12.5%)	1	1/5 (20%)	1	0/3 (0%)	0
Constipation	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Abdominal pain	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Vomiting	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	2/5 (40%)	2	0/3 (0%)	0
Diarrhoea	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	1/5 (20%)	1	0/3 (0%)	0
General disorders
Fatigue	0/1 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
General physical health deterioration	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Pyrexia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	2/8 (25%)	2	3/5 (60%)	3	1/3 (33.3%)	1
Oedema peripheral	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Hyperhidrosis	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Infections and infestations
Bacterial infection: Device related infection	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Investigations
Aspartate aminotransferase increased	1/1 (100%)	2	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Alanine aminotransferase increased	1/1 (100%)	1	1/2 (50%)	1	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Blood alkaline phosphatase increased	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Blood lactate dehydrogenase increased	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Alpha 1 foetoprotein increased	0/1 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Blood cholinesterase decreased	0/1 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Plasmin inhibitor decreased	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Fibrin D dimer increased	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Antithrombin III decreased	1/1 (100%)	1	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Blood bilirubin increased	0/1 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Blood lactic acid increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
N-terminal prohormone brain natriuretic peptide increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Lipase increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	2	0/3 (0%)	0
Amylase increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Blood creatinine increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	2	0/3 (0%)	0
Troponin T increased	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	1/8 (12.5%)	1	2/5 (40%)	2	0/3 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Decreased appetite	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Hyperuricaemia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Hypercalcaemia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Back pain	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	1/2 (50%)	1	0/8 (0%)	0	1/5 (20%)	1	1/3 (33.3%)	1
Musculoskeletal pain	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Arthralgia	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Bone pain	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Nervous system disorders
Headache	0/1 (0%)	0	1/2 (50%)	1	0/2 (0%)	0	1/2 (50%)	1	1/8 (12.5%)	1	0/5 (0%)	0	1/3 (33.3%)	1
Head discomfort	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Vertigo	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0
Renal and urinary disorders
Urinary tract infection	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Haematuria	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/1 (0%)	0	1/2 (50%)	1	1/2 (50%)	1	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Pleural effusion	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	1/8 (12.5%)	1	0/5 (0%)	0	0/3 (0%)	0
Nasopharyngitis	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/1 (0%)	0	1/2 (50%)	2	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Vascular disorders
Haemoptysis	0/1 (0%)	0	0/2 (0%)	0	1/2 (50%)	1	1/2 (50%)	1	0/8 (0%)	0	0/5 (0%)	0	0/3 (0%)	0
Hypotension	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/8 (0%)	0	1/5 (20%)	1	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.