Trial Outcomes & Findings for Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A (NCT NCT02572817)

NCT ID: NCT02572817

Last Updated: 2019-06-25

Results Overview

The clinical status at Day 7 was based on a 6-point ordinal scale: 1. Death 2. In ICU 3. Non-ICU hospitalization, requiring supplemental oxygen (O2) 4. Non-ICU hospitalization, not requiring supplemental oxygen 5. Not hospitalized, but unable to resume normal activities 6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 138 participants
• Primary outcome timeframe: Day 7
• Results posted on: 2019-06-25

Participant Flow

Participant milestones

Measure	High-titer Anti-influenza Plasma mITT High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Overall Study STARTED	91	47
Overall Study COMPLETED	82	41
Overall Study NOT COMPLETED	9	6

Reasons for withdrawal

Measure	High-titer Anti-influenza Plasma mITT High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Overall Study Death	6	3
Overall Study Lost to Follow-up	3	3

Baseline Characteristics

The NEW score was only measured for the adult participants. Only non-missing scores were summarized.

Baseline characteristics by cohort

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma	Total n=138 Participants Total of all reporting groups
Age, Continuous	58 years n=91 Participants	63 years n=47 Participants	61 years n=138 Participants
Age, Customized < 18 years	8 Participants n=91 Participants	5 Participants n=47 Participants	13 Participants n=138 Participants
Age, Customized ≥ 18 years	83 Participants n=91 Participants	42 Participants n=47 Participants	125 Participants n=138 Participants
Sex: Female, Male Female	41 Participants n=91 Participants	26 Participants n=47 Participants	67 Participants n=138 Participants
Sex: Female, Male Male	50 Participants n=91 Participants	21 Participants n=47 Participants	71 Participants n=138 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	2 Participants n=91 Participants	0 Participants n=47 Participants	2 Participants n=138 Participants
Race/Ethnicity, Customized Asian	2 Participants n=91 Participants	2 Participants n=47 Participants	4 Participants n=138 Participants
Race/Ethnicity, Customized Black or African American	16 Participants n=91 Participants	8 Participants n=47 Participants	24 Participants n=138 Participants
Race/Ethnicity, Customized White	69 Participants n=91 Participants	36 Participants n=47 Participants	105 Participants n=138 Participants
Race/Ethnicity, Customized Other	2 Participants n=91 Participants	1 Participants n=47 Participants	3 Participants n=138 Participants
Region of Enrollment United States	91 participants n=91 Participants	47 participants n=47 Participants	138 participants n=138 Participants
Baseline National Early Warning (NEW) score	5 units on a scale n=82 Participants • The NEW score was only measured for the adult participants. Only non-missing scores were summarized.	5 units on a scale n=42 Participants • The NEW score was only measured for the adult participants. Only non-missing scores were summarized.	5 units on a scale n=124 Participants • The NEW score was only measured for the adult participants. Only non-missing scores were summarized.
Baseline Pediatric Early Warning (PEW) score	9 units on a scale n=8 Participants • The PEW score was only measured for the pediatric participants.	8 units on a scale n=5 Participants • The PEW score was only measured for the pediatric participants.	8 units on a scale n=13 Participants • The PEW score was only measured for the pediatric participants.
Baseline Sequential Organ Failure Assessment (SOFA) Score	3 units on a scale n=80 Participants • The SOFA score was only measured for the adult participants. Only non-missing scores were summarized.	3 units on a scale n=41 Participants • The SOFA score was only measured for the adult participants. Only non-missing scores were summarized.	3 units on a scale n=121 Participants • The SOFA score was only measured for the adult participants. Only non-missing scores were summarized.
Baseline Pediatric Logistic Organ Dysfunction (PELOD) Score	0 units on a scale n=8 Participants • The PELOD score was only measured for the pediatric participants. Only non-missing scores were summarized.	3 units on a scale n=4 Participants • The PELOD score was only measured for the pediatric participants. Only non-missing scores were summarized.	0.5 units on a scale n=12 Participants • The PELOD score was only measured for the pediatric participants. Only non-missing scores were summarized.

PRIMARY outcome

Timeframe: Day 7

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment (with available data).

The clinical status at Day 7 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=46 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 7 Non-ICU hospitalization without supplemental O2	8 Participants	5 Participants
Clinical Status at Day 7 Death	2 Participants	2 Participants
Clinical Status at Day 7 in ICU	15 Participants	10 Participants
Clinical Status at Day 7 Non-ICU hospitalization with supplemental O2	16 Participants	7 Participants
Clinical Status at Day 7 Not hospitalized, unable for normal activity	30 Participants	11 Participants
Clinical Status at Day 7 Not hospitalized, able for normal activity	20 Participants	11 Participants

SECONDARY outcome

Timeframe: Day 1

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

The clinical status at Day 1 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=46 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 1 Death	0 Participants	0 Participants
Clinical Status at Day 1 in ICU	38 Participants	18 Participants
Clinical Status at Day 1 Non-ICU hospitalization with supplemental O2	30 Participants	14 Participants
Clinical Status at Day 1 Non-ICU hospitalization without supplemental O2	21 Participants	14 Participants
Clinical Status at Day 1 Not hospitalized, unable for normal activity	2 Participants	0 Participants
Clinical Status at Day 1 Not hospitalized, able for normal activity	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 2

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

The clinical status at Day 2 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=46 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 2 Non-ICU hospitalization without supplemental O2	19 Participants	13 Participants
Clinical Status at Day 2 Death	1 Participants	0 Participants
Clinical Status at Day 2 in ICU	35 Participants	17 Participants
Clinical Status at Day 2 Non-ICU hospitalization with supplemental O2	24 Participants	12 Participants
Clinical Status at Day 2 Not hospitalized, unable for normal activity	6 Participants	3 Participants
Clinical Status at Day 2 Not hospitalized, able for normal activity	6 Participants	1 Participants

SECONDARY outcome

Timeframe: Day 3

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

The clinical status at Day 3 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=90 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=43 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 3 Non-ICU hospitalization without supplemental O2	17 Participants	12 Participants
Clinical Status at Day 3 Death	1 Participants	0 Participants
Clinical Status at Day 3 in ICU	29 Participants	15 Participants
Clinical Status at Day 3 Non-ICU hospitalization with supplemental O2	20 Participants	10 Participants
Clinical Status at Day 3 Not hospitalized, unable for normal activity	11 Participants	4 Participants
Clinical Status at Day 3 Not hospitalized, able for normal activity	12 Participants	2 Participants

SECONDARY outcome

Timeframe: Day 14

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

The clinical status at Day 14 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=86 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=45 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 14 in ICU	10 Participants	6 Participants
Clinical Status at Day 14 Not hospitalized, unable for normal activity	26 Participants	12 Participants
Clinical Status at Day 14 Death	4 Participants	4 Participants
Clinical Status at Day 14 Non-ICU hospitalization with supplemental O2	3 Participants	2 Participants
Clinical Status at Day 14 Non-ICU hospitalization without supplemental O2	6 Participants	1 Participants
Clinical Status at Day 14 Not hospitalized, able for normal activity	37 Participants	20 Participants

SECONDARY outcome

Timeframe: Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

The clinical status at Day 28 was based on a 6-point ordinal scale:

1. Death

2. In ICU

3. Non-ICU hospitalization, requiring supplemental oxygen (O2)

4. Non-ICU hospitalization, not requiring supplemental oxygen

5. Not hospitalized, but unable to resume normal activities

6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=88 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=45 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Clinical Status at Day 28 Death	6 Participants	4 Participants
Clinical Status at Day 28 in ICU	5 Participants	3 Participants
Clinical Status at Day 28 Non-ICU hospitalization with supplemental O2	0 Participants	2 Participants
Clinical Status at Day 28 Non-ICU hospitalization without supplemental O2	2 Participants	1 Participants
Clinical Status at Day 28 Not hospitalized, unable for normal activity	24 Participants	11 Participants
Clinical Status at Day 28 Not hospitalized, able for normal activity	51 Participants	24 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Duration (in days) of initial hospitalization, restricted to duration between randomization and last visit

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Initial Hospitalization	5 days Interval 3.0 to 12.0	6 days Interval 4.0 to 12.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Number of deaths during study follow-up

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
28-day Mortality	6 Participants	4 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Number of deaths in the hospital during initial hospitalization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
In-hospital Mortality During Initial Hospitalization	4 Participants	3 Participants

SECONDARY outcome

Timeframe: Day 7, Day 14, Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Two categories were considered for the composite of mortality and hospitalization:

Dead or hospitalized Alive and not hospitalized

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 7 · Alive and not hospitalized	50 Participants	22 Participants
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 14 · Dead or hospitalized	23 Participants	13 Participants
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 7 · Dead or hospitalized	41 Participants	24 Participants
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 14 · Alive and not hospitalized	63 Participants	32 Participants
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 28 · Dead or hospitalized	13 Participants	10 Participants
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 Composite mortality and hospitalization, Day 28 · Alive and not hospitalized	75 Participants	35 Participants

SECONDARY outcome

Timeframe: Day 0, Day 3, Day 7

Population: Modified intent-to-treat adult population: subgroup of randomized adult participants who received any study treatment

The National Early Warning (NEW) score was only measured for the adult participants.

The range of the NEW score is from 0 to 20, with lower values representing a better outcome.

Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=83 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=42 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Change From Baseline to Day 3 and Day 7 in National Early Warning (NEW) Score Change in NEW from baseline to Day 3	-2 units on a scale Interval -4.0 to 0.0	-1 units on a scale Interval -3.0 to 0.0
Change From Baseline to Day 3 and Day 7 in National Early Warning (NEW) Score Change in NEW from baseline to Day 7	-2 units on a scale Interval -4.0 to 0.0	-2 units on a scale Interval -4.0 to -0.5

SECONDARY outcome

Timeframe: Day 0, Day 3, Day 7

Population: Modified intent-to-treat pediatric population: subgroup of randomized pediatric participants who received any study treatment

The Pediatric Early Warning (PEW) score was only measured for the pediatric participants.

The range is from 0 to 26, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=8 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=5 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Change From Baseline to Day 3 and Day 7 in Pediatric Early Warning (PEW) Score Change in PEW from baseline to Day 3	0 units on a scale Interval -3.0 to 2.0	-1 units on a scale Interval -6.0 to -1.0
Change From Baseline to Day 3 and Day 7 in Pediatric Early Warning (PEW) Score Change in PEW from baseline to Day 7	-4.5 units on a scale Interval -7.0 to -0.5	-5 units on a scale Interval -8.0 to -3.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry.

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who required new or increased oxygen at randomization.

Duration (in days) of total supplemental oxygen use among those participants who required new or increased oxygen at randomization.

The duration is restricted to duration between randomization and last visit.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=65 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=34 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Supplemental Oxygen	6 days Interval 3.0 to 21.0	7 days Interval 3.0 to 29.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who did not require oxygen at randomization.

Incidence of new oxygen use during the study among those participants who did not require oxygen at randomization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=20 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=11 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Incidence of New Oxygen Use During the Study Yes	7 Participants	3 Participants
Incidence of New Oxygen Use During the Study No	13 Participants	8 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were in the ICU at randomization.

Duration (in days) of ICU stay among those participants who were in ICU at randomization.

The duration is restricted to duration between randomization and last visit.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=40 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=20 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Intensive Care Unit (ICU) Stay	5 days Interval 3.5 to 12.5	8 days Interval 4.0 to 25.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were not in the ICU at randomization.

Incidence of new ICU admission during the study among those participants who were not in ICU at randomization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=51 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=27 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Incidence of New ICU Admission Use During the Study Yes	3 Participants	0 Participants
Incidence of New ICU Admission Use During the Study No	48 Participants	27 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were on mechanical ventilation at randomization.

Duration (in days) of mechanical ventilation use among those participants who were on mechanical ventilation at randomization.

The duration is restricted to duration between randomization and last visit.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=25 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=14 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Mechanical Ventilation Use	9 days Interval 4.0 to 16.0	15.5 days Interval 7.0 to 29.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were not on mechanical ventilation at randomization.

Incidence of new mechanical ventilation use during the study among those participants who were not on mechanical ventilation at randomization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=66 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=33 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Incidence of New Mechanical Ventilation Use Stay Use During the Study Yes	3 Participants	2 Participants
Incidence of New Mechanical Ventilation Use Stay Use During the Study No	63 Participants	31 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants with ARDS at randomization.

Duration (in days) of ARDS use among those participants with ARDS at randomization.

The duration is restricted to duration between randomization and last visit.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=15 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=3 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Acute Respiratory Distress Syndrome (ARDS)	9 days Interval 4.0 to 15.0	8 days Interval 4.0 to 29.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants without ARDS at randomization.

Incidence of new ARDS during the study among those participants without ARDS at randomization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=75 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=44 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Incidence of New ARDS During the Study Yes	3 Participants	5 Participants
Incidence of New ARDS During the Study No	72 Participants	39 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were on ECMO at randomization.

Duration (in days) of ECMO use among those participants on ECMO at randomization.

The duration is restricted to duration between randomization and last visit.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=5 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=1 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Duration of Extracorporeal Membrane Oxygenation (ECMO)	16 days Interval 14.0 to 18.0	20 days Interval 20.0 to 20.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment, further subset to those participants who were not on ECMO at randomization.

Incidence of new ECMO use during the study among those participants not on ECMO at randomization

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=86 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=46 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Incidence of New ECMO Use During the Study Yes	1 Participants	0 Participants
Incidence of New ECMO Use During the Study No	85 Participants	46 Participants

SECONDARY outcome

Timeframe: Day 0, Day 3, Day 7

Population: Modified intent-to-treat adult population: subgroup of randomized adult participants who received any study treatment.

The Sequential Organ Failure Assessment (SOFA) score was only measured for the adult participants.

The range is from 0 to 24, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=75 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=40 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Change From Baseline to Day 3 and Day 7 in Sequential Organ Failure Assessment (SOFA) Score Change in SOFA from baseline to Day 3	0 units on a scale Interval -1.0 to 0.0	0 units on a scale Interval -1.0 to 0.0
Change From Baseline to Day 3 and Day 7 in Sequential Organ Failure Assessment (SOFA) Score Change in SOFA from baseline to Day 7	-1 units on a scale Interval -2.0 to 0.0	0 units on a scale Interval -2.0 to 1.0

SECONDARY outcome

Timeframe: Day 0, Day 3, Day 7

Population: Modified intent-to-treat pediatric population: subgroup of randomized pediatric participants who received any study treatment

The Pediatric Logistic Organ Dysfunction (PELOD) score was only measured for the pediatric participants.

The range is from 0 to 71, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=8 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=4 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Change From Baseline to Day 3 and Day 7 in Pediatric Logistic Organ Dysfunction (PELOD) Score Change in PELOD from baseline to Day 3	0 units on a scale Interval 0.0 to 9.5	10 units on a scale Interval 5.0 to 14.0
Change From Baseline to Day 3 and Day 7 in Pediatric Logistic Organ Dysfunction (PELOD) Score Change in PELOD from baseline to Day 7	0 units on a scale Interval 0.0 to 4.5	0 units on a scale Interval -1.5 to 0.0

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Disposition at discharge after initial hospitalization was categorized as follows:

Death, Ongoing at 28 days, Chronic nursing facility, Rehabilitation, Home with home health care, Home without assistance.

The number of deaths at discharge after initial hospitalization do not necessarily match the overall number of deaths.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Disposition After Initial Hospitalization Rehabilitation	4 Participants	3 Participants
Disposition After Initial Hospitalization Home with home health care	13 Participants	8 Participants
Disposition After Initial Hospitalization Death	4 Participants	4 Participants
Disposition After Initial Hospitalization Ongoing at 28 days	3 Participants	3 Participants
Disposition After Initial Hospitalization Chronic nursing facility/	7 Participants	4 Participants
Disposition After Initial Hospitalization Home without assistance	60 Participants	25 Participants

SECONDARY outcome

Timeframe: Day 3

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment. This group was further subset wo those with available OP sample results at Day 3.

Detectable influenza virus at Day 3 in oropharyngeal samples

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=85 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=40 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Detectable Influenza Virus at Day 3 Detectable	65 Participants	35 Participants
Detectable Influenza Virus at Day 3 Undetectable	20 Participants	5 Participants

SECONDARY outcome

Timeframe: Day 1, Day 3, Day 7

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Hemagglutination inhibition assay (HAI) titers as measured by serial dilutions at Days 1, 3, 7 for A/H1N1. HAI for A/H1N1 was tested in all influenza seasons while the study was ongoing.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1 Day 1	46.9 ratios Interval 38.5 to 57.1	19.7 ratios Interval 13.9 to 27.8
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1 Day 3	50.6 ratios Interval 40.9 to 62.6	23.7 ratios Interval 16.7 to 33.6
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1 Day 7	63.1 ratios Interval 49.5 to 80.6	37.1 ratios Interval 23.2 to 59.4

SECONDARY outcome

Timeframe: Day 1, Day 3, Day 7

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment

Hemagglutination inhibition assay (HAI) titers as measured by serial dilutions at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2. HAI for A/HongKong/4801/2014 H3N2 was tested in all influenza seasons while the study was ongoing.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2 Day 1	53.7 ratios Interval 43.2 to 66.7	22.4 ratios Interval 16.6 to 30.3
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2 Day 3	55.2 ratios Interval 44.0 to 69.4	36.8 ratios Interval 24.6 to 36.8
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2 Day 7	75.7 ratios Interval 57.5 to 99.8	53 ratios Interval 30.9 to 90.7

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment.

Number of participants with reported grade 3 and 4 adverse events (AEs) throughout the study duration. In cases where participants had multiple reports of grade 3 and 4 AEs, they were only counted once.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Number of Participants With Grade 3 and 4 Adverse Events (AEs).	34 Participants	14 Participants

SECONDARY outcome

Timeframe: From Day 0 to Day 28

Population: Modified intent-to-treat population: subgroup of randomized participants who received any study treatment.

Number of participants with reported serious adverse events (SAEs) throughout the study duration.

Outcome measures

Measure	High-titer Anti-influenza Plasma mITT n=91 Participants High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 Participants Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Number of Participants With Serious Adverse Events (SAEs).	31 Participants	15 Participants

Adverse Events

High-titer Anti-influenza Plasma mITT

Serious events: 31 serious events

Other events: 0 other events

Deaths: 6 deaths

Low-titer Anti-influenza Plasma mITT

Serious events: 15 serious events

Other events: 0 other events

Deaths: 4 deaths

Serious adverse events

Measure	High-titer Anti-influenza Plasma mITT n=91 participants at risk High-titer anti-influenza mITT (modified intent to treat) is the subgroup of high-titer anti-influenza plasma participants who received any study plasma	Low-titer Anti-influenza Plasma mITT n=47 participants at risk Low-titer anti-influenza mITT (modified intent to treat) is the subgroup of low-titer anti-influenza plasma participants who received any study plasma
Vascular disorders Shock haemorrhagic	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Blood and lymphatic system disorders Thrombocytopenia	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Blood and lymphatic system disorders Thrombotic thrombocytopenic purpura	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Atrial fibrillation	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Atrial flutter	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Cardiac arrest	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Cardiac failure	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Cardiomyopathy	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Pericardial effusion	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Pericardial haemorrhage	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Supraventricular tachycardia	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Cardiac disorders Ventricular tachycardia	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Gastrointestinal disorders Abdominal pain	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Gastrointestinal disorders Gastrointestinal haemorrhage	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
General disorders Asthenia	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
General disorders Generalised oedema	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
General disorders Multi-organ failure	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Gastroenteritis norovirus	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Pneumonia	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Sepsis	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Septic shock	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Sinusitis	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Systemic candida	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Infections and infestations Tracheitis	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Injury, poisoning and procedural complications Allergic transfusion reaction	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	4.3% 2/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Injury, poisoning and procedural complications Toxicity to various agents	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Injury, poisoning and procedural complications Transfusion-related circulatory overload	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Injury, poisoning and procedural complications Traumatic liver injury	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Blood creatinine increased	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Blood potassium decreased	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Creatinine renal clearance decreased	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Haemoglobin decreased	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Liver function test abnormal	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations Platelet count decreased	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Investigations White blood cell count decreased	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Metabolism and nutrition disorders Fluid overload	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Metabolism and nutrition disorders Lactic acidosis	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung carcinoma cell type unspecified stage IV	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Mantle cell lymphoma refractory	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Nervous system disorders Cerebral haemorrhage	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Nervous system disorders Encephalopathy	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Nervous system disorders Hypoxic-ischaemic encephalopathy	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Nervous system disorders Ischaemic stroke	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Psychiatric disorders Delirium	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Psychiatric disorders Mental status changes	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Renal and urinary disorders Acute kidney injury	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Renal and urinary disorders Renal failure	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	4.4% 4/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	4.3% 2/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Haemothorax	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.2% 2/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Respiratory distress	3.3% 3/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Vascular disorders Extremity necrosis	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Vascular disorders Haemorrhage	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Vascular disorders Hypotension	0.00% 0/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	2.1% 1/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.
Vascular disorders Peripheral ischaemia	1.1% 1/91 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.	0.00% 0/47 • From study entry (Day 0) to Day 28 The protocol required reporting of all grade 3 and 4 adverse events (AEs), all serious AEs and any AE leading to plasma discontinuation (regardless of grade). Clinically evident diagnoses were recorded as AEs. All worsening laboratory values were evaluated as potential AEs. The grading reference was the "Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events" Version 2.0, November 2014.

Other adverse events

Adverse event data not reported

Additional Information

John Beigel, M.D.

National Institute of Allergy and Infectious Diseases (NIAID)

Phone: 301-451-9881

Email: jbeigel@niaid.nih.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place