A Study to Investigate the Safety, Tolerability, and Pharmacokinetics (PK) of Oseltamivir and Its Carboxylate Metabolite, RO0640802 in Healthy Participants

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02717754
• Collaborator: (none)
• Enrollment: 99
• Locations: 2
• Arms: 3
• Duration (Months): 5
• Patients Per Site: 49.5
• Patients Per Site Per Month: 10

Study Details

Study Description

Brief Summary

This multi-center, randomized, double-blind, multiple-dose, placebo-controlled, parallel-group study will assess the safety and PK of oseltamivir (Tamiflu) and its carboxylate metabolite, RO0640802 in healthy participants. Participants will be randomized to receive 100 milligrams (mg) oseltamivir, 200 mg oseltamivir, or placebo, all administered intravenously twice daily (BID). The anticipated time on study treatment is 5 days.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteer	Drug: Oseltamivir; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Official Title: A Multiple-Center, Randomized, Double-blind, Multiple-Dose, Placebo-Controlled, Parallel-Group Study to Investigate the Safety, Tolerability, and Pharmacokinetics of RO0640796 (Oseltamivir) and Its Carboxylate Metabolite, RO0640802, Following Intravenous Administrations in Healthy Subjects
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oseltamivir 100 mg Participants will receive 100 mg oseltamivir intravenous BID for 5 days.	Drug: Oseltamivir; Oseltamivir will be administered at 100 or 200 mg intravenous BID for 5 days.; Other Names: Tamiflu, RO0640796
Experimental: Oseltamivir 200 mg Participants will receive 200 mg oseltamivir intravenous BID for 5 days.	Drug: Oseltamivir; Oseltamivir will be administered at 100 or 200 mg intravenous BID for 5 days.; Other Names: Tamiflu, RO0640796
Placebo Comparator: Placebo Participants will receive oseltamivir matched placebo intravenous BID for 5 days.	Drug: Placebo; Oseltamivir matched placebo will be administered intravenous for 5 days.

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5]

   AUC is a measure of the plasma concentration of the drug over time. AUC is presented in nanogram times (*) hour per milliliter (ng*hour/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

2. Maximum Plasma Concentration (Cmax) of Oseltamivir and RO0640802 at Steady State [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5]

   Cmax is the maximum observed plasma concentration, presented in nanogram per milliliter (ng/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

Secondary Outcome Measures

1. Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1]

   AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

2. Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5]

   AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

3. Cmax of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1]

   Cmax is the maximum observed plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

4. Time to Reach Maximum Plasma Concentration (Tmax) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5]

   Tmax is time of observed maximum plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

5. Half-Life (t1/2) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5]

   t1/2 is the time measured for the plasma concentration to decrease by one half. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

6. Volume of Distribution (Vd) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5]

   Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

7. Clearance (CL) of Oseltamivir and RO0640802 [Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5]

   CL is a quantitative measure of the rate at which a drug substance is removed from the body. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

8. Minimum Plasma Concentration (Cmin) of RO0640802 [12-hour post dose on Day 1, 5 and predose on Day 2, 3, 4, 5]

   Collection of the 12-hour post-dose sample took place prior to administration of the second daily dose of drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Participants with Body Mass Index (BMI) 18-34 kilograms per meter square (kg/m^2), inclusive

• Male participants who are willing to use barrier contraception for the duration of the study and for 3 months following the end of treatment

• Female participants who are of non-child bearing potential

• Female participants who are of child bearing potential utilizing two effective methods of contraception for the duration of the study and for 3 months following the end of treatment

Exclusion Criteria:

• Evidence of clinically significant disease or disorder (for example, renal, cardiac, bronchopulmonary)

• Any other condition or disease which would place the participant at undue risk, or interfere with the assessment, or with the ability of the participant to complete the study

• Clinically significant orthostatic hypotension present at screening or history of clinically significant hypotensive episodes or symptoms of fainting, dizziness, or lightheadedness.

• Participants with abnormal electrocardiogram (ECG), bradycardia or mean QTc at screening

• Positive result for Hepatitis B, Hepatitis C, human immunodeficiency virus (HIV) 1 or 2 at screening

• Renal impairment

• Transplant recipients

• A known clinically relevant history of allergy or hypersensitivity

• Any clinically relevant abnormal laboratory test results

• A clinically relevant history of abuse of alcohol or other drugs of abuse

• Any major illness within 30 days prior to the screening examination

• Smoking of more than 10 cigarettes a day or an equivalent amount of tobacco in the form of cigars or pipe

• Participation in a clinical study with an investigational drug within 3 months prior to Day 1

• Donation/loss of more than 500 milliliters (mL) of blood within 3 months prior to Day 1

• Positive pregnancy test at screening or Day -1 and lactating women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States	72204
2		Austin	Texas	United States	78744

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02717754
• Other Study ID Numbers: NP25140
• First Posted: Mar 24, 2016
• Last Update Posted: Jun 27, 2016
• Last Verified: May 1, 2016

• Additional relevant MeSH terms: Oseltamivir

Study Results

Participant Flow

Recruitment Details	In total 99 participants were included in study, but as first 50 participants were administered infusion incorrectly thus only 49 participants were considered evaluable for pharmacokinetics. The 50 participants were reported for safety under arm groups placebo (incorrect infusion duration), oseltamivir 100 or 200 mg (incorrect infusion duration).

Arm/Group Title	Placebo	Oseltamivir 100 mg	Oseltamivir 200 mg	Placebo (Incorrect Infusion Duration)	Oseltamivir 100 mg (Incorrect Infusion Duration)	Oseltamivir 200 mg (Incorrect Infusion Duration)
Arm/Group Description	Participants received oseltamivir matched placebo twice daily (BID) for 5 days.	Participants received 100 milligrams (mg) oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.	Participants were randomized to receive oseltamivir matched placebo intravenous BID for 5 days but received incorrect infusion duration.	Participants were randomized to receive oseltamivir 100 mg intravenous BID for 5 days but received incorrect infusion duration.	Participants were randomized to receive oseltamivir 200 mg intravenous BID for 5 days but received incorrect infusion duration.
Period Title: Overall Study
STARTED	10	19	20	10	20	20
COMPLETED	10	19	20	0	0	0
NOT COMPLETED	0	0	0	10	20	20

Baseline Characteristics

Arm/Group Title	Placebo	Oseltamivir 100 mg	Oseltamivir 200 mg	Placebo (Incorrect Infusion Duration)	Oseltamivir 100 mg (Incorrect Infusion Duration)	Oseltamivir 200 mg (Incorrect Infusion Duration)	Total
Arm/Group Description	Participants received oseltamivir matched placebo BID for 5 days.	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.	Participants were randomized to receive oseltamivir matched placebo intravenous BID for 5 days but received incorrect infusion duration.	Participants were randomized to receive oseltamivir 100 mg intravenous BID for 5 days but received incorrect infusion duration.	Participants were randomized to receive oseltamivir 200 mg intravenous BID for 5 days but received incorrect infusion duration.	Total of all reporting groups
Overall Participants	10	19	20	10	20	20	99
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.1 (6.19)	28.3 (6.97)	30.2 (7.73)	29.7 (7.90)	31.1 (7.80)	28.6 (8.09)	29.4040 (7.44904)
Sex: Female, Male (Count of Participants)
Female	5 50%	10 52.6%	4 20%	1 10%	3 15%	4 20%	27 27.3%
Male	5 50%	9 47.4%	16 80%	9 90%	17 85%	16 80%	72 72.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time 0 to 12 Hour (AUC0-12h) of Oseltamivir and RO0640802 at Steady State
Description	AUC is a measure of the plasma concentration of the drug over time. AUC is presented in nanogram times (*) hour per milliliter (ng*hour/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis population included all participants who were dosed correctly. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Oseltamivir	581 (178)	1143 (178)
RO0640802	4147 (742)	7966 (1427)

2. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Oseltamivir and RO0640802 at Steady State
Description	Cmax is the maximum observed plasma concentration, presented in nanogram per milliliter (ng/mL). RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Oseltamivir	266 (73.1)	496 (69.7)
RO0640802	488 (84.1)	960 (178)

3. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Oseltamivir and RO0640802
Description	AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Oseltamivir	612 (134)	1139 (220)
RO0640802	3606 (761)	7336 (1952)

4. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Oseltamivir and RO0640802
Description	AUC is a measure of the plasma concentration of the drug over time. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1: Oseltamivir	609 (134)	1136 (220)
Day 1: RO0640802	2273 (405)	4566 (714)
Day 5: Oseltamivir	580 (178)	1142 (178)
Day 5: RO0640802	4127 (738)	7932 (1417)

5. Secondary Outcome

Title	Cmax of Oseltamivir and RO0640802
Description	Cmax is the maximum observed plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Oseltamivir	284 (54.3)	503 (93.1)
RO0640802	301 (69.8)	577 (88.9)

6. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of Oseltamivir and RO0640802
Description	Tmax is time of observed maximum plasma concentration. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1: Oseltamivir	1.85 (0.377)	1.65 (0.491)
Day 1: RO0640802	3.90 (0.91)	3.95 (1.28)
Day 5: Oseltamivir	1.64 (0.492)	1.81 (0.416)
Day 5: RO0640802	3.69 (0.917)	3.41 (0.851)

7. Secondary Outcome

Title	Half-Life (t1/2) of Oseltamivir and RO0640802
Description	t1/2 is the time measured for the plasma concentration to decrease by one half. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1: Oseltamivir	1.22 (0.32)	1.53 (0.293)
Day 1: RO0640802	6.89 (2.08)	7.17 (2.19)
Day 5: Oseltamivir	1.40 (0.327)	1.88 (0.457)
Day 5: RO0640802	7.97 (1.82)	8.17 (2.23)

8. Secondary Outcome

Title	Volume of Distribution (Vd) of Oseltamivir and RO0640802
Description	Vd is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1: Oseltamivir	171 (36.4)	183 (39)
Day 1: RO0640802	250 (55)	251 (45.7)
Day 5: Oseltamivir	189 (103)	192 (31.0)
Day 5: RO0640802	266 (58.9)	280 (65.9)

9. Secondary Outcome

Title	Clearance (CL) of Oseltamivir and RO0640802
Description	CL is a quantitative measure of the rate at which a drug substance is removed from the body. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	Predose (0 hour), 1, 2, 3, 3.5, 4, 5, 6, 8, 10, 12 hours post dose on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1: Oseltamivir	289 (55)	393 (67)
Day 1: RO0640802	26.0 (5.4)	25.4 (6.1)
Day 5: Oseltamivir	192 (74.6)	179 (30.3)
Day 5: RO0640802	21.7 (3.80)	22.6 (3.9)

10. Secondary Outcome

Title	Minimum Plasma Concentration (Cmin) of RO0640802
Description	Collection of the 12-hour post-dose sample took place prior to administration of the second daily dose of drug. RO0640802 is the pharmacologically active carboxylate metabolite of oseltamivir.
Time Frame	12-hour post dose on Day 1, 5 and predose on Day 2, 3, 4, 5

Outcome Measure Data

Analysis Population Description

PK analysis population. Only participants who received oseltamivir were analyzed.

Arm/Group Title	Oseltamivir 100 mg	Oseltamivir 200 mg
Arm/Group Description	Participants received 100 mg oseltamivir intravenous BID for 5 days.	Participants received 200 mg oseltamivir intravenous BID for 5 days.
Measure Participants	19	20
Day 1 (12-hour post dose)	131 (29.3)	264 (59.1)
Day 2 (Pre dose)	209 (43.6)	388 (95.4)
Day 3 (Pre dose)	235 (56.3)	450 (101)
Day 4 (Pre dose)	277 (104)	443 (143)
Day 5 (Pre dose)	262 (68.4)	502 (130.4)
Day 5 (12-hour post dose)	238 (61.8)	458 (110)

Adverse Events

Time Frame	Up to 10 days after last dose of study drug (32 days)
Adverse Event Reporting Description	In total 99 participants were included in study, but as first 50 participants were administered infusion incorrectly thus only 49 participants were considered evaluable for pharmacokinetics. The 50 participants were reported for safety under arm groups placebo (incorrect infusion duration), oseltamivir 100 or 200 mg (incorrect infusion duration).
Arm/Group Title	Placebo		Oseltamivir 100 mg		Oseltamivir 200 mg		Placebo (Incorrect Infusion Duration)		Oseltamivir 100 mg (Incorrect Infusion Duration)		Oseltamivir 200 mg (Incorrect Infusion Duration)
Arm/Group Description	Participants received oseltamivir matched placebo for 5 days.		Participants received 100 mg oseltamivir intravenous BID for 5 days.		Participants received 200 mg oseltamivir intravenous BID for 5 days.		Participants were randomized to receive oseltamivir matched placebo intravenous BID for 5 days but received incorrect infusion duration.		Participants were randomized to receive oseltamivir 100 mg intravenous BID for 5 days but received incorrect infusion duration.		Participants were randomized to receive oseltamivir 200 mg intravenous BID for 5 days but received incorrect infusion duration.
All Cause Mortality
	Placebo		Oseltamivir 100 mg		Oseltamivir 200 mg		Placebo (Incorrect Infusion Duration)		Oseltamivir 100 mg (Incorrect Infusion Duration)		Oseltamivir 200 mg (Incorrect Infusion Duration)
	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	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Oseltamivir 100 mg		Oseltamivir 200 mg		Placebo (Incorrect Infusion Duration)		Oseltamivir 100 mg (Incorrect Infusion Duration)		Oseltamivir 200 mg (Incorrect Infusion Duration)
	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	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Oseltamivir 100 mg		Oseltamivir 200 mg		Placebo (Incorrect Infusion Duration)		Oseltamivir 100 mg (Incorrect Infusion Duration)		Oseltamivir 200 mg (Incorrect Infusion Duration)
	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	7/10 (70%)		17/19 (89.5%)		20/20 (100%)		2/10 (20%)		8/20 (40%)		13/20 (65%)
Ear and labyrinth disorders
Tinnitus	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Eye disorders
Visual impairment	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Gastrointestinal disorders
Abdominal pain	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Constipation	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Diarrhoea	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		1/20 (5%)		0/20 (0%)
Nausea	1/10 (10%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		2/20 (10%)		1/20 (5%)
General disorders
Infusion site pain	3/10 (30%)		15/19 (78.9%)		15/20 (75%)		0/10 (0%)		0/20 (0%)		1/20 (5%)
Infusion site erythema	1/10 (10%)		6/19 (31.6%)		10/20 (50%)		0/10 (0%)		1/20 (5%)		4/20 (20%)
Infusion site swelling	3/10 (30%)		3/19 (15.8%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Infusion site induration	0/10 (0%)		4/19 (21.1%)		2/20 (10%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Vessel puncture site pain	0/10 (0%)		2/19 (10.5%)		2/20 (10%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Catheter site pain	1/10 (10%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Infusion site anaesthesia	1/10 (10%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Catheter site swelling	1/10 (10%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Feeling hot	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Infusion site coldness	1/10 (10%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Infusion site extravasation	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Infusion site warmth	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Vessel puncture site reaction	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Injection site pain	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		2/20 (10%)		9/20 (45%)
Injection site swelling	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		1/20 (5%)		6/20 (30%)
Injection site erythema	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		2/20 (10%)		2/20 (10%)
Injection site oedema	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		1/20 (5%)		0/20 (0%)
Oedema peripheral	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		1/20 (5%)		0/20 (0%)
Infections and infestations
Nasopharyngitis	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
Contusion	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		1/20 (5%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Musculoskeletal discomfort	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Musculoskeletal pain	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Nervous system disorders
Dizziness	1/10 (10%)		2/19 (10.5%)		1/20 (5%)		1/10 (10%)		0/20 (0%)		0/20 (0%)
Headache	0/10 (0%)		1/19 (5.3%)		2/20 (10%)		0/10 (0%)		1/20 (5%)		0/20 (0%)
Paraesthesia	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Sneezing	1/10 (10%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Oropharyngeal pain	0/10 (0%)		0/19 (0%)		0/20 (0%)		1/10 (10%)		0/20 (0%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/10 (10%)		0/19 (0%)		2/20 (10%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Dry skin	0/10 (0%)		0/19 (0%)		1/20 (5%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Ecchymosis	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Seborrhoeic dermatitis	0/10 (0%)		1/19 (5.3%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)
Hyperhidrosis	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		1/20 (5%)		0/20 (0%)
Rash	0/10 (0%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		1/20 (5%)
Vascular disorders
Vein disorders	1/10 (10%)		0/19 (0%)		0/20 (0%)		0/10 (0%)		0/20 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.