CART19 to Treat B-Cell Leukemia or Lymphoma That Are Resistant or Refractory to Chemotherapy

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01029366
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Actual Duration (Months): 73.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a Pilot/Phase I, single arm, single center, open label study to determine the safety, efficacy and cellular kinetics of CART19 (CTL019) in chemotherapy resistant or refractory

CD19+ leukemia and lymphoma subjects. The study consists of three Phases:

1. a Screening Phase, followed by 2) an Intervention/Treatment Phase consisting of apheresis, lymphodepleting chemotherapy (determined by the Investigator and based on subject's disease burden and histology, as well as on the prior chemotherapy history received), infusions of CTL019, tumor collection by bone marrow aspiration or lymph node biopsy (optional, depending on availability), and 3) a Follow-up Phase.

The suitability of subjects' T cells for CTL019 manufacturing was determined at study entry.

Subjects with adequate T cells were leukapheresed to obtain large numbers of peripheral blood mononuclear cells for CTL019 manufacturing. The T cells were purified from the peripheral blood mononuclear cells, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration. The number of subjects who had inadequate T cell collections, expansion or manufacturing compared to the number of subjects who had T cells successfully manufactured is a primary measure of feasibility of this study.

Unless contraindicated and medically not advisable based on previous chemotherapy, subjects were given conditioning chemotherapy prior to CTL019 infusion. The chemotherapy was completed 1 to 4 days before the planned infusion of the first dose of CTL019.

Up to 20 evaluable subjects with CD19+ leukemia or lymphoma were planned to be dosed with CTL019. A single dose of CTL019 (consisting of approximately 5x10^{9 total cells, with a minimal acceptable dose for infusion of 1.5x10}7 CTL019 cells) was to be given to subjects as fractions (10%, 30% and 60% of the total dose) on Day 0, 1 and 2. A second 100% dose of CTL019 was initially permitted to be given on Day 11 to 14 to subjects, providing they had adequate tolerance to the first dose and sufficient CTL019 was manufactured.

Condition or Disease	Intervention/Treatment	Phase
Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma	Biological: CART-19	Phase 1

Detailed Description

Primary objectives:

1. To evaluate the safety and feasibility of a single target dose of 5 times 10e9 total cells, acceptable range of 1.5 times 10e7 to 5 times 10e9 total cells comprised of autologous CART-19 cells that express the TCR zeta and 4-1 BB costimulatory domain.

Secondary objectives:

1. Proof of mechanism: determine if 2nd generation CAR expressing 4-1BB costimulation domains have improved persistence in patients.

2. Proof of concept: determine the effects of CART-19 on CD19 expression in vivo.

3. Proof of bioactivity: Evaluate changes in systemic soluble immune factors in patients

4. Proof of bioactivity: Evaluate impact of CART19 treatment on tumor burden

5. Explore whether CART-19 cells retain anti-tumor activity in vivo.

6. Determine if host immunity develops against CART-19.

7. Characterize the relative subsets of CART-19 T cells (Tcm, Tem, and Treg).

8. Describe survival and response rates

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Redirected Autologous T-cells Engineered to Contain Anti-CD19 Attached to TCR and 4-1BB Signaling Domains in Patient With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma
• Actual Study Start Date: Mar 17, 2010
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CART-19 CLL CART-19 (autologous T cells transduced with CD19 TCR-ζ/4-1BB vector) administered as an IV infusion days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity.Minimum/maximum total dose: 1.5x10^7 / 5x10^9 administered to patients with chronic Lymphocytic Leukemia (CLL) and Acute Lymphoblastic Leukemia (ALL).	Biological: CART-19; Autologous T cells purified from the peripheral blood mononuclear cells of subjects, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration.
Experimental: CART-19 ALL CART-19 (autologous T cells transduced with CD19 TCR-ζ/4-1BB vector) administered as an IV infusion days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity.Minimum/maximum total dose: 1.5x10^7 / 5x10^9 administered to patients with chronic Lymphocytic Leukemia (CLL) and Acute Lymphoblastic Leukemia (ALL).	Biological: CART-19; Autologous T cells purified from the peripheral blood mononuclear cells of subjects, transduced with TCR-ζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [5 years]

Secondary Outcome Measures

1. Overall Response Summary [5 years]

   Efficacy assessments for ALL were performed based on bone marrow and blood morphologic criteria and physical examination findings. The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2013 v.1). Efficacy assessments for CLL were based on lymphadenopathy, hepatomegaly, splenomegaly, bone marrow and blood morphologic and laboratory assessments. The response criteria are consistent with NCCN Guidelines Version 2.2012 CLL/SLL, which is based on the 2008 International Workshop Group on CLL (IWCLL) revisions of the original guidelines for evaluating disease response released in 1996 by the National Cancer Institute Working Group (NCI/WG).

Eligibility Criteria

Criteria

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

Inclusion

• Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to < 2 year survival) with currently available therapies will be enrolled

• CD19+ leukemia or lymphoma

• ALL in CR2 or CR3 and not eligible for allogeneic SCT because of age, comorbid disease, or lack of available family member or unrelated donor

• Follicular lymphoma, previously identified as CD19+:

• At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy

• Stage III-IV disease

• Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval < 1 year)

• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc)

• CLL:

• At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Patients with high risk disease manifested by deletion chromosome 17p will be eligible if they fail to achieve a CR to initial therapy or progress within 2 years of 1 prior

• Less than 2 years between last chemotherapy and progression (i.e. most recent progression free interval < 2 years)

• Not eligible or appropriate for conventional allogeneic SCT

• Patients who achieve only a partial response to FCR as initial therapy will be eligible.

• Mantle cell lymphoma:

• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT

• Disease responding or stable after most recent therapy (chemotherapy, MoAb, etc...)

• Relapsed after prior autologous SCT

• B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT

• Diffuse large cell lymphoma, previously identified as CD19+:

• Residual disease after primary therapy and not eligible for autologous SCT

• Relapsed after prior autologous SCT

• Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate of conventional allogeneic or autologous SCT

• Expected survival > 12 weeks

• Creatinine < 2.5 mg/dl

• ALT/AST < 3x normal

• Bilirubin < 2.0 mg/dl

• Any relapse after prior autologous SCT will make patient eligible regardless of other prior therapy

• Adequate venous access for apheresis, and no other contraindications for leukapheresis

• Voluntary informed consent is given

Exclusion

• Pregnant or lactating women

• The safety of this therapy on unborn children is not known

• Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion

• Uncontrolled active infection

• Active hepatitis B or hepatitis C infection

• Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary

• Previously treatment with any gene therapy products

• Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to CD3/CD28 costimulation

• Any uncontrolled active medical disorder that would preclude participation as outlined

• HIV infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Abramson Cancer Center of The University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Noelle Frey, MD, Abramson Cancer Center of the University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01029366
• Other Study ID Numbers: UPCC04409, 809517; NCI-2009-01357; NCT00891215
• First Posted: Dec 10, 2009
• Last Update Posted: Jun 26, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Lymphoma; Leukemia; Lymphoma, Follicular; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Prolymphocytic; Recurrence

Study Results

Participant Flow

Recruitment Details	Study Start/End Dates 17-Mar-2010 to 06-Jul-2015

Arm/Group Title	Chronic Lymphocytic Leukemia (CLL) Subjects	Acute Lymphocytic Leukemia (ALL) Subjects
Arm/Group Description	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy. Subjects were given minimum/maximum total dose: 1.5x10⁷/ 5x10⁹.	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy. Subjects were given minimum/maximum total dose: 1.5x10⁷/ 5x10⁹
Period Title: Overall Study
STARTED	18	8
COMPLETED	14	6
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	CLL Subjects	ALL Subjects	Total
Arm/Group Description	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy	Total of all reporting groups
Overall Participants	14	6	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 50%	5 83.3%	12 60%
>=65 years	7 50%	1 16.7%	8 40%
Sex: Female, Male (Count of Participants)
Female	2 14.3%	1 16.7%	3 15%
Male	12 85.7%	5 83.3%	17 85%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 33.3%	2 10%
Not Hispanic or Latino	14 100%	4 66.7%	18 90%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 16.7%	1 5%
White	14 100%	5 83.3%	19 95%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy
Measure Participants	20
Number [participants]	20 142.9%

2. Secondary Outcome

Title	Overall Response Summary
Description	Efficacy assessments for ALL were performed based on bone marrow and blood morphologic criteria and physical examination findings. The definitions for response are primarily based on the standardized response criteria defined by National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2013 v.1). Efficacy assessments for CLL were based on lymphadenopathy, hepatomegaly, splenomegaly, bone marrow and blood morphologic and laboratory assessments. The response criteria are consistent with NCCN Guidelines Version 2.2012 CLL/SLL, which is based on the 2008 International Workshop Group on CLL (IWCLL) revisions of the original guidelines for evaluating disease response released in 1996 by the National Cancer Institute Working Group (NCI/WG).
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CLL Subjects	ALL Subjects
Arm/Group Description	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy	Patients receive CART-19 cells transduced with a lentiviral vector to express anti-CD19 scFv TCRζ:41BB administered on days 0, 1, 2 and 11 in the absence of disease progression or unacceptable toxicity laboratory biomarker analysis polymerase chain reaction reverse transcriptase-polymerase chain reaction anti-CD19-CAR retroviral vector-transduced autologous T cells: Given IV genetically engineered lymphocyte therapy
Measure Participants	14	6
Complete Remission	21.4 152.9%	83.4 1390%
Partial Remission	21.4 152.9%	0 0%
No Remission	57.1 407.9%	16.7 278.3%
Overall Response Rate	42.9 306.4%	83.3 1388.3%

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Adverse events during post-infusion period, regardless of study drug relationship, by primary system organ class and maximum CTC grade
Arm/Group Title	Chronic Lymphocytic Leukemia		Acute Lymphocytic Leukemia
Arm/Group Description	CART-19 (autologous T cells transduced with CD19 TCR-ζ/4-1BB vector) administered as an IV infusion. Minimum/maximum total dose: 1.5x10^7 / 5x10^9.		CART-19 (autologous T cells transduced with CD19 TCR-ζ/4-1BB vector) administered as an IV infusion. Minimum/maximum total dose: 1.5x10^7 / 5x10^9.
All Cause Mortality
	Chronic Lymphocytic Leukemia		Acute Lymphocytic Leukemia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Chronic Lymphocytic Leukemia		Acute Lymphocytic Leukemia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Febrile Neutropenia	3/14 (21.4%)	3	0/6 (0%)	0
anaemia	2/14 (14.3%)	2	0/6 (0%)	0
Haemolytic anaemia	1/14 (7.1%)	1	0/6 (0%)	0
Cardiac disorders
Myocardial Infarction	1/14 (7.1%)	1	0/6 (0%)	0
General disorders
pyrexia	4/14 (28.6%)	4	1/6 (16.7%)	1
Chest Discomfort	1/14 (7.1%)	1	0/6 (0%)	0
Chills	1/14 (7.1%)	1	0/6 (0%)	0
Pain in extremity	1/14 (7.1%)	1	0/6 (0%)	0
Immune system disorders
Cytokine Release Syndrome	6/14 (42.9%)	6	5/6 (83.3%)	5
Infections and infestations
Pneumonia	2/14 (14.3%)	2	0/6 (0%)	0
Cellulitis	1/14 (7.1%)	1	0/6 (0%)	0
Clostridium difficle infection	1/14 (7.1%)	1	0/6 (0%)	0
Influenza like illness	1/14 (7.1%)	1	0/6 (0%)	0
Neutropenic sepsis	1/14 (7.1%)	1	0/6 (0%)	0
Pneumonia fungal	1/14 (7.1%)	1	0/6 (0%)	0
Pseudomas Infection	1/14 (7.1%)	1	0/6 (0%)	0
Investigations
Histocytosis Haematophagic	1/14 (7.1%)	1	0/6 (0%)	0
Metabolism and nutrition disorders
Tumor Lysis Syndrome	2/14 (14.3%)	2	0/6 (0%)	0
Nervous system disorders
Headache	1/14 (7.1%)	1	0/6 (0%)	0
Psychiatric disorders
Confusion State	1/14 (7.1%)	1	0/6 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	1/14 (7.1%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	2/14 (14.3%)	2	0/6 (0%)	0
Dyspnoea	1/14 (7.1%)	1	0/6 (0%)	0
Vascular disorders
Hypertension	1/14 (7.1%)	1	0/6 (0%)	0
Hypotension	1/14 (7.1%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Chronic Lymphocytic Leukemia		Acute Lymphocytic Leukemia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Neutropenia	7/14 (50%)	7	3/6 (50%)	3
Anaemia	6/14 (42.9%)	6	4/6 (66.7%)	4
Thrombocytopenia	6/14 (42.9%)	6	2/6 (33.3%)	2
Lymphopenia	5/14 (35.7%)	5	0/6 (0%)	0
Neutrophil count decreased	5/14 (35.7%)	5	0/6 (0%)	0
Febrile Neutropenia	4/14 (28.6%)	4	2/6 (33.3%)	2
Lymphocyte count decreased	4/14 (28.6%)	4	0/6 (0%)	0
Cardiac disorders
Tachycardia	5/14 (35.7%)	5	2/6 (33.3%)	2
ATrial fibrillation	3/14 (21.4%)	3	0/6 (0%)	0
Gastrointestinal disorders
Nausea	8/14 (57.1%)	8	1/6 (16.7%)	1
Diarrhoea	7/14 (50%)	7	4/6 (66.7%)	4
Gastrooesophageal reflux disease	4/14 (28.6%)	4	2/6 (33.3%)	2
Abdominal distension	3/14 (21.4%)	3	0/6 (0%)	0
Constipation	3/14 (21.4%)	3	1/6 (16.7%)	1
General disorders
Fatigue	13/14 (92.9%)	13	2/6 (33.3%)	2
Pyrexia	11/14 (78.6%)	11	2/6 (33.3%)	2
Chills	8/14 (57.1%)	8	0/6 (0%)	0
Odema Peripheral	7/14 (50%)	7	2/6 (33.3%)	2
Immune system disorders
Cytokine Release Syndrome	8/14 (57.1%)	8	6/6 (100%)	6
Investigations
Blood Albumin decreased	8/14 (57.1%)	8	1/6 (16.7%)	1
White Blood Cell Count Decreased	8/14 (57.1%)	8	2/6 (33.3%)	2
Blood Calcium decreased	6/14 (42.9%)	6	1/6 (16.7%)	1
Blood Sosoim decreased	6/14 (42.9%)	6	1/6 (16.7%)	1
Aspartate aminotransferase increased	5/14 (35.7%)	5	0/6 (0%)	0
Blood Glucose increased	5/14 (35.7%)	5	0/6 (0%)	0
Alanine aminotransferase increased	4/14 (28.6%)	4	1/6 (16.7%)	1
Blood Glucose decreased	4/14 (28.6%)	4	0/6 (0%)	0
Blood Magnesium decreased	4/14 (28.6%)	4	1/6 (16.7%)	1
Hypomagnesaemia	4/14 (28.6%)	4	0/6 (0%)	0
Blood Alkaline phosphatase increased	3/14 (21.4%)	3	0/6 (0%)	0
Blood bilirubin increased	3/14 (21.4%)	3	0/6 (0%)	0
blood creatinine increased	3/14 (21.4%)	3	0/6 (0%)	0
Blood lactate dehydrogenase increased	3/14 (21.4%)	3	0/6 (0%)	0
Blood phosphorous decreased	3/14 (21.4%)	3	3/6 (50%)	3
Blood urinc acid increased	3/14 (21.4%)	3	0/6 (0%)	0
platelet count decreased	3/14 (21.4%)	3	1/6 (16.7%)	1
Metabolism and nutrition disorders
Hypokalemia	7/14 (50%)	7	3/6 (50%)	3
Decreased Appetite	6/14 (42.9%)	6	0/6 (0%)	0
Hypocalcaemia	3/14 (21.4%)	3	1/6 (16.7%)	1
Tumor Lysis Syndrome	3/14 (21.4%)	3	1/6 (16.7%)	1
Hyperglycaemia	2/14 (14.3%)	2	2/6 (33.3%)	2
Nervous system disorders
Headache	5/14 (35.7%)	5	2/6 (33.3%)	2
Dizziness	4/14 (28.6%)	4	0/6 (0%)	0
Psychiatric disorders
Insomnia	6/14 (42.9%)	6	0/6 (0%)	0
Anxiety	5/14 (35.7%)	5	1/6 (16.7%)	1
Confusion state	3/14 (21.4%)	3	2/6 (33.3%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	6/14 (42.9%)	6	0/6 (0%)	0
cough	4/14 (28.6%)	4	2/6 (33.3%)	2
Skin and subcutaneous tissue disorders
Rash	5/14 (35.7%)	5	1/6 (16.7%)	1
Vascular disorders
hypertension	4/14 (28.6%)	4	0/6 (0%)	0
Hypotension	4/14 (28.6%)	4	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

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.