Safety, Tolerability, and Pharmacokinetics of SAB-301 in Healthy Adults

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02788188
• Collaborator: Naval Medical Research Center (U.S. Fed), SAb Biotherapeutics, Inc. (Industry)
• Enrollment: 38
• Location: 1
• Arms: 7
• Duration (Months): 23.1
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Background:

Middle East Respiratory Syndrome (MERS) is a newly discovered contagious and sometimes fatal respiratory virus. People often get MERS through close contact with an infected person. Scientists are worried that MERS may spread and cause more infections. There are no vaccines or treatments for MERS right now. Researchers think a new therapy called SAB-301 may be able to help. Antibodies are proteins the body makes to attack viruses. SAB-301 is made of antibodies made in cows to fight MERS. The antibodies are collected from plasma, the liquid part of cow blood.

Objective:

To evaluate the safety and tolerability of SAB-301 in healthy adults.

Eligibility:

Healthy people ages 18 60 who:

Do not have chronic medical problems

Do not take any medications (exceptions are acetaminophen, ibuprofen, vitamins, seasonal allergy meds and oral contraception)

Do not have allergies to beef products

Agree to use two forms of contraception while on study (both men and women)

Design:

Participants will be screened with:

Medical history

Physical examination

Blood and urine tests

Participants will have a return visit.

They will have a physical exam and blood tests.

They will be randomly assigned to receive either SAB-301 or a placebo which is given by infusion

through an arm vein over 1 3 hours.

They will be monitored at the clinic for 6 hours after the infusion. They will have additional blood draws.

Participants will have 2-hour visits 1, 3, 7, 21, 42, and 90 days after the infusion. At each visit they will be evaluated and have blood and urine tests.

Condition or Disease	Intervention/Treatment	Phase
Middle East Respiratory Syndrome Coronavirus	Biological: SAB-301; Other: Normal (9%) Saline	Phase 1

Detailed Description

The administration of convalescent plasma or hyperimmune immunoglobulin is often used for treatment of emerging infectious diseases. However, production of large quantities of anti-pathogen human plasma and/or immunoglobulin with high affinity and avidity antibodies currently requires donations by convalescent humans, a process that can limit availability for a number of reasons. One novel alternative source is transchromosomic (Tc) cattle that produce fully human polyclonal IgG (hIgG) de novo and mount a robust antibody immune response after vaccination.

This study will evaluate the safety, tolerability, and immunogenicity of SAB-301, a fully human polyclonal anti-MERS IgG collected from transchromosomic cattle. Beginning with a low single-dose, subjects are randomized to receive either SAB-301 or a normal saline control, and evaluated on Study Days 1, 3, 7, 21, 42, and 90. The safety and tolerability is evaluated using symptoms, clinical laboratory tests, pharmacokinetics, and immunogenicity assays. Utilizing a series of stopping rules and a medical monitor, the dose will be escalated as safety and tolerability are established.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Randomized Double-Blind, Placebo-Controlled, Single Ascending Dose Safety, Tolerability, and Pharmacokinetics Study of SAB-301 in Healthy Adults
• Study Start Date: May 28, 2016
• Actual Primary Completion Date: Apr 10, 2018
• Actual Study Completion Date: Apr 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Cohort 1: 1mg/kg SAB-301 in normal (9%) saline; concentration 1mg/mL (0.1%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Placebo Comparator: Placebo Normal (0.9%) saline in approximately the same volume as each cohort in the experimental drug arm.	Other: Normal (9%) Saline; Normal (0.9%) saline in approximately the same volume as each cohort in the experimental drug arm.
Experimental: Cohort 2 Cohort 2: 2.5 mg/kg SAB-301 in normal (9%) saline; concentration 1mg/mL (0.1%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 3 Cohort 3: 5mg/kg SAB-301 in normal (9%) saline; concentration 4mg/mL (0.4%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 4 Cohort 4: 10mg/kg SAB-301 in normal (9%) saline; concentration 4mg/mL (0.4%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 5 Cohort 5: 20mg/kg SAB-301 in normal (9%) saline; concentration 20mg/mL (2%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 6 Cohort 6: 50mg/kg SAB-301 in normal (9%) saline; concentration 20mg/mL (2%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Having Adverse Events [90 days]

   Number of participants who experienced an adverse event

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

• INCLUSION CRITERIA:

1. Age greater than or equal to 18 years and less than or equal to 60 years

2. Body mass index (BMI) of 19-32 kg/m(2)

3. Estimated glomerular filtration rate greater than or equal to 70 mL/min at screening, calculated using the CKD-EPI formula

4. Subjects must agree to:

• Not take any prescription or OTC medications with the exception of acetaminophen, ibuprofen, vitamins, seasonal allergy medications, and/or contraceptive medications for a period 7 days prior to study drug administration (i.e., Day 0)

1. One of the following in order to avoid pregnancy:

• Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of the subject s signing of the informed consent form through 60 days after the last dose of study drug. At least one of the methods of contraception should be a barrier method.

• Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of the subject s signing of the informed consent form through 60 days after the last dose of study drug.

EXCLUSION CRITERIA:

1. Any history of allergy, anaphylaxis, or severe reaction to beef products (including milk and gelatin)

2. Any history of allergy, anaphylaxis, or severe reaction to IGIV or human blood products

3. Any chronic medical problem that requires daily oral medications (except Tylenol, ibuprofen, oral contraceptives, vitamins, and seasonal allergy medications).

4. History of cardiovascular disease, cardiomyopathy, heart failure, or unexplained syncope

5. Subjects that have had confirmed MERS

6. Women who are breast-feeding

7. Positive urine or serum pregnancy test

8. Abnormal chemistry panel

-defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table

--evaluating only sodium (Na), potassium (K), serum bicarbonate (total CO2), blood urea nitrogen (BUN), creatinine, glucose, asp (ALT), aspartate aminotransferase (AST), total bilirubin, lactate dehydrogenase (LDH), and estimated glomerular filtration rate (GFR) by the CKD-EPI equation.

1. Abnormal complete blood count (CBC)

-defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table--evaluating only the WBC (to include absolute neutrophil, lymphocyte, and eosinophil counts), hemoglobin, hematocrit, and platelets.

1. Abnormal urinalysis

-defined as any clinically significant baseline Grade 1 or greater toxicity--evaluating only protein, and RBCs

1. Positive rheumatoid factor

2. IgA deficiency (defined as IgA < 7 mg/dL)

3. Participation in another research study with receipt of any investigational drug within 5 half-lives or 30 days, whichever is longer, prior to study drug administration (i.e., Day 0) and until completion of the study

4. Participation in any other research study for 30 days after study drug administration

5. Receipt of blood products within 2 months prior to study drug administration (i.e. Day

1. Receipt of any vaccination within 30 days prior to study drug administration (i.e. Day

1. Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject s ability to complete and/or participate in this clinical study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Naval Medical Research Center
• SAb Biotherapeutics, Inc.

Investigators

• Principal Investigator: Richard T Davey, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 1, 2016

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Matsushita H, Liu Y, Postnikova EN, Ork BL, Glenn G, Flyer D, Defang G, Raviprakash K, Kochel T, Wang J, Nie W, Smith G, Hensley LE, Olinger GG, Kuhn JH, Holbrook MR, Johnson RF, Perlman S, Sullivan E, Frieman MB. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med. 2016 Feb 17;8(326):326ra21. doi: 10.1126/scitranslmed.aaf1061.
• Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol. 2003 Jun;73(2):97-100.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02788188
• Other Study ID Numbers: 160119; 16-I-0119
• First Posted: Jun 2, 2016
• Last Update Posted: Jun 12, 2018
• Last Verified: Jul 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): First in Human; Middle East Respiratory Syndrome (MERS); Tc Bovine-Derived; Transchromosomic Cattle
• Additional relevant MeSH terms: Coronavirus Infections

Study Results

Participant Flow

Arm/Group Title	Cohort 1: 1.0mg/kg	Cohort 2: 2.5mg/kg	Cohort 3: 5mg/kg	Cohort 4: 10mg/kg	Cohort 5: 20mg/kg	Cohort 6: 50mg/kg	Placebo
Arm/Group Description	SAB-301 1 mg/kg IV single infusion	SAB-301 2.5 mg/kg IV single infusion	SAB-301 5 mg/kg IV single infusion	SAB-301 10 mg/kg IV single infusion	SAB-301 20 mg/kg IV single infusion	SAB-301 50 mg/kg IV single infusion	Normal Saline IV single infusion
Period Title: Overall Study
STARTED	2	2	4	4	8	8	10
COMPLETED	2	2	4	4	8	8	10
NOT COMPLETED	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1: 1.0mg/kg	Cohort 2: 2.5mg/kg	Cohort 3: 5mg/kg	Cohort 4: 10mg/kg	Cohort 5: 20mg/kg	Cohort 6: 50mg/kg	Placebo	Total
Arm/Group Description	SAB-301 1 mg/kg IV single infusion	SAB-301 2.5 mg/kg IV single infusion	SAB-301 5 mg/kg IV single infusion	SAB-301 10 mg/kg IV single infusion	SAB-301 20 mg/kg IV single infusion	SAB-301 50 mg/kg IV single infusion	Normal Saline IV single infusion	Total of all reporting groups
Overall Participants	2	2	4	4	8	8	10	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 100%	2 100%	4 100%	4 100%	8 100%	8 100%	10 100%	38 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	2 100%	3 75%	3 75%	4 50%	3 37.5%	3 30%	18 47.4%
Male	2 100%	0 0%	1 25%	1 25%	4 50%	5 62.5%	7 70%	20 52.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 25%	1 12.5%	1 12.5%	0 0%	3 7.9%
Not Hispanic or Latino	2 100%	2 100%	4 100%	3 75%	7 87.5%	7 87.5%	10 100%	35 92.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	1 12.5%	2 20%	3 7.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	2 50%	0 0%	2 25%	0 0%	2 20%	6 15.8%
White	2 100%	2 100%	2 50%	4 100%	5 62.5%	7 87.5%	4 40%	26 68.4%
More than one race	0 0%	0 0%	0 0%	0 0%	1 12.5%	0 0%	0 0%	1 2.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 20%	2 5.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Having Adverse Events
Description	Number of participants who experienced an adverse event
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

Number of participants who completed both treatment and placebo

Arm/Group Title	Cohort 1: 1.0mg/kg	Cohort 2: 2.5mg/kg	Cohort 3: 5mg/kg	Cohort 4: 10mg/kg	Cohort 5: 20mg/kg	Cohort 6: 50mg/kg	Placebo
Arm/Group Description	SAB-301 1 mg/kg IV single infusion	SAB-301 2.5 mg/kg IV single infusion	SAB-301 5 mg/kg IV single infusion	SAB-301 10 mg/kg IV single infusion	SAB-301 20 mg/kg IV single infusion	SAB-301 50 mg/kg IV single infusion	Normal Saline IV single infusion
Measure Participants	2	2	4	4	8	8	10
Count of Participants [Participants]	1 50%	2 100%	2 50%	4 100%	7 87.5%	8 100%	10 100%

Adverse Events

Time Frame	90 Days
Arm/Group Title	Cohort 1: 1.0mg/kg		Cohort 2: 2.5mg/kg		Cohort 3: 5mg/kg		Cohort 4: 10mg/kg		Cohort 5: 20mg/kg		Cohort 6: 50mg/kg		Placebo
Arm/Group Description	SAB-301 1 mg/kg IV single infusion		SAB-301 2.5 mg/kg IV single infusion		SAB-301 5 mg/kg IV single infusion		SAB-301 10 mg/kg IV single infusion		SAB-301 20 mg/kg IV single infusion		SAB-301 50 mg/kg IV single infusion		Normal Saline IV single infusion
All Cause Mortality
	Cohort 1: 1.0mg/kg		Cohort 2: 2.5mg/kg		Cohort 3: 5mg/kg		Cohort 4: 10mg/kg		Cohort 5: 20mg/kg		Cohort 6: 50mg/kg		Placebo
	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	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Serious Adverse Events
	Cohort 1: 1.0mg/kg		Cohort 2: 2.5mg/kg		Cohort 3: 5mg/kg		Cohort 4: 10mg/kg		Cohort 5: 20mg/kg		Cohort 6: 50mg/kg		Placebo
	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	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Psychiatric disorders
Suicide attempt	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: 1.0mg/kg		Cohort 2: 2.5mg/kg		Cohort 3: 5mg/kg		Cohort 4: 10mg/kg		Cohort 5: 20mg/kg		Cohort 6: 50mg/kg		Placebo
	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	1/2 (50%)		2/2 (100%)		2/4 (50%)		4/4 (100%)		7/8 (87.5%)		8/8 (100%)		10/10 (100%)
Gastrointestinal disorders
Abdominal pain	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Diarrhoea	0/2 (0%)		0/2 (0%)		1/4 (25%)		1/4 (25%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Dyspepsia	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Nausea	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Toothache	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
General disorders
Fatigue	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		1/8 (12.5%)		0/8 (0%)		0/10 (0%)
Pyrexia	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Infections and infestations
Chlamydial infection	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Gastroenteritis	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Impetigo	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Nasopharyngitis	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		1/8 (12.5%)		1/8 (12.5%)		2/10 (20%)
Otitis media	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		0/8 (0%)		0/10 (0%)
Pharyngitis	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Pharyngitis streptococcal	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Skin candida	1/2 (50%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Tinea capitis	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Urinary tract infection	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		1/10 (10%)
Injury, poisoning and procedural complications
Contusion	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Investigations
Alanine aminotransferase increased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Aspartate aminotransferase increased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		0/8 (0%)		0/10 (0%)
Blood bicarbonate decreased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		2/8 (25%)		0/10 (0%)
Blood bilirubin increased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Blood creatine phosphokinase increased	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		1/8 (12.5%)		1/8 (12.5%)		1/10 (10%)
Blood glucose decreased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Blood glucose increased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		3/10 (30%)
Blood potassium decreased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Blood sodium decreased	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Weight decreased	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
White blood cells urine positive	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Metabolism and nutrition disorders
Hyponatraemia	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)		1/2 (50%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Back pain	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Musculoskeletal pain	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		0/8 (0%)		0/10 (0%)
Myalgia	0/2 (0%)		0/2 (0%)		0/4 (0%)		1/4 (25%)		2/8 (25%)		0/8 (0%)		1/10 (10%)
Nervous system disorders
Headache	0/2 (0%)		1/2 (50%)		1/4 (25%)		2/4 (50%)		1/8 (12.5%)		1/8 (12.5%)		2/10 (20%)
Lethargy	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Presyncope	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		1/8 (12.5%)		0/10 (0%)
Tremor	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Psychiatric disorders
Depression	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Renal and urinary disorders
Albuminuria	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		2/8 (25%)		2/8 (25%)		2/10 (20%)
Glycosuria	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Haematuria	0/2 (0%)		0/2 (0%)		1/4 (25%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		0/10 (0%)
Proteinuria	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Oropharyngeal pain	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		2/8 (25%)		0/10 (0%)
Rhinorrhoea	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		1/8 (12.5%)		0/8 (0%)		1/10 (10%)
Sinus congestion	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		2/8 (25%)		0/8 (0%)		1/10 (10%)
Sneezing	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		0/8 (0%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Rash	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		0/10 (0%)
Vascular disorders
Hypotension	0/2 (0%)		0/2 (0%)		0/4 (0%)		0/4 (0%)		0/8 (0%)		1/8 (12.5%)		1/10 (10%)

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.